Treatment of fgg related diseases and disorders

Abstract

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

Description

Attorney Docket No.54462-754.601 TREATMENT OF FGG RELATED DISEASES AND DISORDERS CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 471,231, filed June 5, 2023, U.S. Provisional Application No.63 / 582,786, filed September 14, 2023, and U.S. Provisional Application No. 63 / 585,551, filed September 26, 2023, all of which applications are incorporated herein by reference in their entirety. INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 54462-754-601_SL.xml, created June 3, 2024, which is 6,430,720 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety. BACKGROUND

[0003] Psychiatric and neurological diseases are widely abundant, and may affect a wide variety of people. Improved therapeutics are needed for treating these disorders. SUMMARY

[0004] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that targets fibrinogen gamma gene (FGG). Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves a mental disorder measurement of a mental disorder. In some embodiments, the mental disorder comprises a psychiatric disorder. In some embodiments, the psychiatric disorder comprises a depressive disorder (e.g., major depressive disorder, persistent depressive disorder, treatment resistant depression and signs or symptoms of depression), post-traumatic stress disorder, mood disorder, anxiety disorder, eating disorder, substance-use disorder, bipolar disorder, personality disorder, schizophrenia, or schizoaffective disorder. In some embodiments, the mental disorder measurement is chosen from the group consisting of a Montgomery-Asberg Depression Rating Scale (MADRS) score, a Hamilton Depression Rating Scale-17 score, anxiety signs and symptoms, eating disorder signs and symptoms, substance-use disorder signs and symptoms, post-traumatic stress disorder signs and symptoms, bipolar disorder signs and symptoms, schizophrenia signs and symptoms, and psychosis signs and symptoms. In some embodiments, the mental disorder comprises a neurological disorder. In some embodiments, the neurological disorder comprises Alzheimer’s disease, dementia, delirium, cognitive decline, vascular dementia, headache (e.g., migraine), chronic pain (e.g., fibromyalgia), chronic fatigue syndrome (e.g., myalgic encephalomyelitis), chronic traumatic encephalopathy, traumatic brain injury, or motor neuron disease (e.g., amyotrophic lateral sclerosis). In some embodiments, the mental disorder measurement is chosen from the group consisting of cognitive function, central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinalAttorney Docket No.54462-754.601 fluid (CSF) or plasma beta-amyloid 42, beta-amyloid 40, the ratio of beta-amyloid 42 to beta-amyloid 40, tau, phospho-tau, neurofilament light chain (NfL), Lewy bodies, or alpha-synuclein, headache symptoms or signs, migraine symptoms or signs, chronic pain symptoms or signs, fibromyalgia symptoms or signs, chronic fatigue syndrome (e.g., myalgic encephalomyelitis) symptoms or signs, and motor neuron disease (e.g., amyotrophic lateral sclerosis) symptoms or signs. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2’-O-allyl, 2’-C-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'- O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises one or more 2’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2’-O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or α- tocopherol, or a combination thereof. In some embodiments, the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the sugar comprises N- acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose. The sugar moiety may comprise ETL17. In some embodiments, the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 12-30 nucleosides in length. In some embodiments, the antisense strand is 12-30 nucleosides in length. Disclosed herein, in some embodiments, are compositions 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 comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 3621. In some embodiments, any one of the following is true with regard to the sense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines,Attorney Docket No.54462-754.601 and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines. In some embodiments, the sense strand comprises any one of modification patterns 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S. In some embodiments, any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines. In some embodiments, the antisense strand comprises any one of modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS. In some embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1-1742 or 3713-3748, or a sequence thereof having 1 or 2 substitutions, additions, or deletions; and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1743-3484 or 3749-3784, or a sequence thereof having 1 or 2 substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1-1742 or 3713-3748, and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1743-3484 or 3749-3784. In some embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3723, 3724, 3726, or 3747, or a sequence thereof having 1 or 2 substitutions, additions, or deletions; and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3759, 3760, 3762, or 3783, or a sequence thereof having 1 or 2 substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3723, 3724, 3726, or 3747, and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3759, 3760, 3762, or 3783. In some embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 352, 1003, 1011, or 1278, or a sequence thereof having 1 or 2 substitutions, additions, or deletions; and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020, or a sequence thereof having 1 or 2 substitutions, additions, or deletions. In someAttorney Docket No.54462-754.601 embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 352, 1003, 1011, or 1278, and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020. In some embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3591-3594, or a sequence thereof having 1 or 2 substitutions, additions, or deletions; and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3595-3598, or a sequence thereof having 1 or 2 substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3591- 3594, and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3595- 3598. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. Disclosed herein, in some embodiments, are compositions 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. Some embodiments include a pharmaceutically acceptable carrier. Disclosed herein, in some embodiments, are methods of treating a subject having a psychiatric disorder or a neurological disorder, comprising administering an effective amount of the composition to the subject. In some embodiments, the psychiatric disorder comprises a depressive disorder (e.g., major depressive disorder, persistent depressive disorder, treatment resistant depression and signs or symptoms of depression), post-traumatic stress disorder, mood disorder, anxiety disorders, eating disorder, substance-use disorder, bipolar disorder, personality disorder, schizophrenia, or a schizoaffective disorder. In some embodiments, the neurological disorder comprises Alzheimer’s disease, dementia, delirium, cognitive decline, vascular dementia, headache (e.g., migraine), chronic pain (e.g., fibromyalgia), chronic fatigue syndrome (e.g., myalgic encephalomyelitis), chronic traumatic encephalopathy, traumatic brain injury, and motor neuron disease (e.g., amyotrophic lateral sclerosis).

[0005] Disclosed herein are compositions comprising an oligonucleotide that targets FGG. Where inhibition or targeting of FGG is disclosed, it is contemplated that some embodiments may include inhibiting or targeting a FGG protein or FGG RNA. For example, by inhibiting or targeting an RNA (e.g., mRNA) encoded by the FGG gene using an oligonucleotide described herein, the FGG protein may be inhibited or targeted as a result of there being less production of the FGG protein by translation of the FGG RNA; or a FGG protein may be targeted or inhibited by an oligonucleotide that binds or interacts with a FGG RNA and reduces production of the FGG protein from the FGG RNA. Thus, targeting FGG may refer to binding a FGG RNA and reducing FGG RNA or protein levels. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).

[0006] Also provided herein are methods of treating a mental disorder, such as a psychiatric disorder or neurological disorder or disease by providing or administering an oligonucleotide that targets FGG to a subject in need thereof. Administration of the oligonucleotide to a subject may improve psychiatric related traits, such as Montgomery-Asberg Depression Rating Scale (MADRS) (e.g., scale ranges from 0 to 60 with a higher score indicating worsening symptoms of depression), Hamilton Depression Rating Scale-17 (e.g., scale ranges from 0 to 52 with a higher score indicating worsening symptoms of depression), anxietyAttorney Docket No.54462-754.601 symptoms and signs, eating disorder symptoms and signs, substance-use disorder symptoms and signs, post-traumatic stress disorder symptoms and signs, bipolar disorder symptoms and signs, schizophrenia symptoms and signs, or psychosis symptoms and signs. Additionally, administration of the oligonucleotide to a subject may improve neurological related traits, such as Cognitive function, central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) or plasma beta- amyloid 42, beta-amyloid 40, the ratio of beta-amyloid 42 to beta-amyloid 40, tau, phospho-tau, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Lewy bodies, or alpha-synuclein, headache symptoms and signs, migraine symptoms and signs, chronic pain symptoms and signs, fibromyalgia symptoms and signs, chronic fatigue syndrome (ME) symptoms and signs, or motor neuron disease (e.g., ALS) symptoms or signs.

[0007] In one aspect, provided herein is a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves a mental disorder measurement in the subject, relative to a baseline mental disorder measurement. In some embodiments, the mental disorder comprises a psychiatric disorder. In some embodiments, the psychiatric disorder comprises a depressive disorder, post-traumatic stress disorder, mood disorder, anxiety disorder, eating disorder, substance-use disorder, bipolar disorder, personality disorder, schizophrenia, or schizoaffective disorder. In some embodiments, the mental disorder measurement comprises a Montgomery-Asberg Depression Rating Scale score, a Hamilton Depression Rating Scale score, or a measurement of an anxiety disorder, depressive disorder, eating disorder, substance-use disorder, post-traumatic stress disorder, bipolar disorder, schizophrenia, or psychosis sign or symptom. In some embodiments, the mental disorder comprises a neurological disorder. In some embodiments, the neurological disorder comprises Alzheimer’s disease, dementia, delirium, cognitive decline, vascular dementia, headache, chronic pain, chronic fatigue syndrome, chronic traumatic encephalopathy, traumatic brain injury, or motor neuron disease. In some embodiments, the mental disorder measurement comprises a measurement of cognitive function, amyloid plaques, tau accumulation, beta-amyloid 42, beta-amyloid 40, the ratio of beta-amyloid 42 to beta-amyloid 40, tau, phospho-tau, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Lewy bodies, or alpha-synuclein, or a sign or symptom of headache, migraine, chronic pain, fibromyalgia, chronic fatigue syndrome, or motor neuron disease. In one aspect, disclosed herein is a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases fibrinogen. In some embodiments, the composition decreases circulating fibrinogen. In some embodiments, the subject has a clotting or coagulation disorder. In some embodiments, the subject has a thrombophilia. In some embodiments, the subject has a venous thromboembolism. In some embodiments, the composition further comprises an oligonucleotide that comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. In some embodiments, the oligonucleotideAttorney Docket No.54462-754.601 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises a modified nucleoside.

[0008] In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2’-O-allyl, 2’-C- allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises 2'-O-methyl nucleoside, 2'- deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl’(2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises one or more 2’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises 2’-O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose. In some embodiments, the sugar comprises GalNAc. In some embodiments, the sugar moiety comprises ETL17. In some embodiments, the composition comprises an oligonucleotide that comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 12- 30 nucleosides in length. In some embodiments, the antisense strand is 12-30 nucleosides in length.

[0009] In one aspect, disclosed herein is a composition comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 3690. In some embodiments, any one of the following is true with regard to the sense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O methyl modified purines. In some embodiments, the antisense strand comprises a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length.

[0010] In one aspect, disclosed 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. InAttorney Docket No.54462-754.601 some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In one aspect, disclosed herein is a method of treating a subject having a psychiatric disorder or a neurological disorder, comprising administering an effective amount of a composition described herein. In some embodiments, the method comprises treating a psychiatric disorder that comprises a depressive disorder, persistent depressive disorder, treatment resistant depression, a sign or symptom of depression, post- traumatic stress disorder, mood disorder, anxiety disorders, eating disorder, substance-use disorder, bipolar disorder, personality disorder, schizophrenia, or a schizoaffective disorder.

[0011] In some embodiments, the neurological disorder comprises Alzheimer’s disease, dementia, delirium, cognitive decline, vascular dementia, headache, chronic pain, chronic fatigue syndrome, chronic traumatic encephalopathy, traumatic brain injury, and motor neuron disease.

[0012] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that targets fibrinogen gamma chain (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, and wherein: (i) the sense strand comprises any one of modification patterns 31S to 49S; or (ii) the antisense strand comprises any one of modification patterns 22AS to 41AS. In some embodiments, the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the sugar moiety is attached at a 5’ terminus of the sense strand. In some embodiments, the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose. In some embodiments, the sugar comprises GalNAc. In some embodiments, the sugar moiety comprises ETL17. In some embodiments, the antisense strand is complementary or at least 90% complementary to a portion of SEQ ID NO: 3621. In some embodiments, the sense strand and the antisense strand each have 14 to 30 nucleotides. In some embodiments, the sense strand comprises a nucleoside sequence having at least 85% sequence identity to any one of SEQ ID NOs: 1-1742. In some embodiments, the sense strand comprises the nucleoside sequence of any one of: SEQ ID NOs: 1-1742, or a 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: 1-1742. In some embodiments, the antisense strand comprises a nucleoside sequence having at least 85% sequence identity to any one of SEQ ID NOs: 1743-3484. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of: SEQ ID NOs: 1743-3484, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 1743-3484. In some embodiments, the sense strand comprises the nucleobase sequence of a sense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B, 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B or a nucleobase sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleobase sequence of a sense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B, 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B. In some embodiments, the antisense strand comprises the nucleobase sequence of an antisense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B,Attorney Docket No.54462-754.601 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B, or a nucleobase sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleobase sequence of an antisense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B, 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B. Disclosed herein, in some embodiments, are pharmaceutical compositions comprising a composition described herein, and a pharmaceutically acceptable carrier.

[0013] Disclosed herein, in some embodiments, are methods of treating a mental or neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition (or the siRNA), thereby treating the disorder. In some embodiments, the mental or neurological disorder comprises a neurodegenerative disease. In some embodiments, the mental or neurological disorder is selected from the group consisting of Alzheimer’s disease, dementia, delirium, cognitive decline, vascular dementia, headache, chronic pain, chronic fatigue syndrome, chronic traumatic encephalopathy, traumatic brain injury, and motor neuron disease. In some embodiments, headache comprises migraine. In some embodiments, chronic pain comprises fibromyalgia. In some embodiments, chronic fatigue syndrome comprises myalgic encephalomyelitis. In some embodiments, motor neuron disease comprises amyotrophic lateral sclerosis (ALS). In some embodiments, the mental or neurological disorder comprises a psychiatric disorder. In some embodiments, the psychiatric disorder is selected from the group consisting of post-traumatic stress disorder, mood disorders, anxiety disorders, eating disorders, substance-use disorders, bipolar disorder, personality disorders, schizophrenia and schizoaffective disorders.

[0014] Disclosed herein, in some embodiments, are methods of decreasing fibrinogen or fibrin in a subject’s central nervous system (CNS), comprising administering to the subject an effective amount of an FGG siRNA, thereby decreasing a quantity of fibrinogen or fibrin in the subject’s CNS. In some embodiments, the quantity of fibrinogen or fibrin is decreased by at least 10% relative to a baseline quantity, or by at least 10% relative to a control. In some embodiments, the FGG siRNA is administered to an area of the subject’s body other than the subject’s head or brain. In some embodiments, the quantity of fibrinogen or fibrin comprises a quantity of fibrinogen. In some embodiments, the quantity of fibrinogen or fibrin comprises a quantity of fibrin. In some embodiments, the CNS comprises a brain. In some embodiments, the FGG siRNA is included in a composition described herein. Disclosed herein, in some embodiments, are methods of decreasing fibrinogen or fibrin in a subject’s blood, comprising administering to the subject an effective amount of an FGG siRNA, thereby decreasing a quantity of fibrinogen or fibrin in the subject’s blood. In some embodiments, the quantity of fibrinogen or fibrin is decreased by at least 10% relative to a baseline quantity, or by at least 10% relative to a control. In some embodiments, the FGG siRNA is administered to an area of the subject’s body other than the subject’s head or brain. In some embodiments, the quantity of fibrinogen or fibrin comprises a quantity of fibrinogen. In some embodiments, the quantity of fibrinogen or fibrin comprises a quantity of fibrin. In some embodiments, the blood comprises plasma. In some embodiments, the FGG siRNA is included in a composition described herein. In some embodiments, described herein is a method of treating a subjectAttorney Docket No.54462-754.601 having a neurological disorder or who is at risk for developing the neurological disorder, the method comprising evaluating a subject’s risk for developing a neurological disorder and administering an effective amount of the composition described herein to the subject. In some embodiments, the subject has a genotype at risk for developing Alzheimer’s disease or dementia. In some embodiments, the subject is a heterozygous or homozygous carrier of APOE4. In some embodiments, the subject is a heterozygous or homozygous carrier of FGG rs148685782-G (A108) or FGG rs6063-C (G191). In some embodiments, evaluating a subject’s risk for developing a neurological disorder comprises calculating a polygenic risk score for developing Alzheimer’s disease or dementia. In some embodiments, the subject has a polygenic risk score in the 40thpercentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia. In some embodiments, the subject has a polygenic risk score in the 20thpercentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia. In some embodiments, calculating a polygenic risk score comprises providing genomic data comprising one or more genotypes of the subject, wherein the one or more genotypes is associated with a high risk for developing Alzheimer’s disease or dementia.

[0015] Provided herein are methods comprising administering an oligonucleotide that targets FGG and when administered to a subject in an effective amount reduces fibrinogen or fibrin in the subject. In some embodiments, the fibrinogen or fibrin is reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 75%, or at least 90% relative to baseline. In some embodiments, the fibrinogen or fibrin is reduced by at least 5%-90% relative to baseline. In some embodiments, one or more non-fibrinogen or fibrin coagulation measurements change by no more than 50%, 40%, 30%, 20%, 15%, 10%, 7% 5%, 4% 3%, 2% or no more than 1% relative to baseline. In some embodiments, the fibrinogen or fibrin is reduced without significant change to one or more non-fibrinogen or fibrin coagulation measurements. In some embodiments, the one or more coagulation measurements comprises von Willebrand Factor (VWF) antigen, VWF activity, factor VIII (FVIII), alpha-2 antiplasmin (A2AP), plasminogen activator inhibitor-1 (PAI-1), thrombin- antithrombin complex (TAT), D-dimer (DD), fibrinogen, prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), activated partial thromboplastin time (aPTT), or bleeding time assay. In some embodiments, the subject has a mental or neurological disorder. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG.1 is an example of a GalNAc ligand.

[0017] FIG.2 is an example of a GalNAc ligand.

[0018] FIG.3 includes a chart showing data from an ELISA (A), and a western blot (B) image. DETAILED DESCRIPTION

[0019] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GWAS) detects associations between genetic variants and traits in a population sample and this improves understanding of the biology of disease and provide 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. TheAttorney Docket No.54462-754.601 most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is considered associated with disease. Association statistics used in a GWAS include p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size. Researchers often assume an additive genetic model and calculate an allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.”

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

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

[0022] 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 by the liver cells such as hepatocytes.

[0023] Here it is shown that genetic variants causing inactivation of FGG resulted in protective associations for psychiatric and neurological phenotypes. Therefore, inhibition of FGG may serve as a therapeutic for treatment of psychiatric diseases and disorders such as depressive disorder (e.g., major depressive disorder, persistent depressive disorder, treatment resistant depression, or signs and symptoms of depression), post-traumatic stress disorder (PTSD), mood disorders, anxiety disorders, eating disorders, substance-use disorders, bipolar disorder, personality disorders, schizophrenia and schizoaffective disorders, and neurological diseases and disorders such as Alzheimer’s disease, dementia, delirium,Attorney Docket No.54462-754.601 cognitive decline, vascular dementia, headache, migraine, chronic pain, fibromyalgia, chronic fatigue syndrome (e.g., myalgic encephalomyelitis (ME)), chronic traumatic encephalopathy, traumatic brain injury, or motor neuron disease (e.g., amyotrophic lateral sclerosis).

[0024] A reduction of liver FGG expression may affect FGG, fibrinogen, or fibrin levels elsewhere in the body. For example, FGG may be expressed in liver cells, secreted into circulation, and accumulate in other tissues or areas of the body such as the central nervous system (CNS) or brain. A reduction in FGG mRNA or protein (e.g., resultant from treatment with a FGG siRNA), may lead to reduced assembly and secretion of fibrinogen by the liver, which may then also reduce the amount of fibrinogen or its degradation product, fibrin, that enters other tissues (e.g., that is able to cross the blood brain barrier and be deposited in the CNS or brain). By this mechanism, siRNAs targeted to FGG in liver may affect psychiatric or neurological disorders or phenotypes. I. COMPOSITIONS

[0025] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets FGG. In some embodiments, the composition consists of an oligonucleotide that targets FGG. In some embodiments, the oligonucleotide reduces FGG mRNA expression in the subject. In some embodiments, the oligonucleotide reduces FGG protein expression in the subject. The oligonucleotide may include a small interfering RNA (siRNA) described herein. The oligonucleotide may include an antisense oligonucleotide (ASO) described herein. In some embodiments, a composition described herein is used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder as described herein. Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder (e.g., psychiatric or neurological) as described herein.

[0026] 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).

[0027] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases FGG mRNA levels in a cell or tissue. In some embodiments, the cell is a liver cell (e.g., hepatocyte). In some embodiments, the cell is a neuron. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is neural tissue. In some embodiments, the neural tissue is CNS tissue. In some embodiments, the neural tissue is brain tissue (e.g., neuronal, glia, or endothelial tissue). In some embodiments, the fluid is CSF. In some embodiments, the FGG mRNA levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared toAttorney Docket No.54462-754.601 prior to administration. In some embodiments, the FGG mRNA levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0028] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases FGG protein levels in a cell, fluid (e.g., CSF) or tissue. In some embodiments, the cell is a hepatocyte. In some embodiments, the cell is a neural cell (e.g., CNS cell (e.g., brain cell)). In some embodiments, the cell is a neuronal cell. In some embodiments, the cell is a glial cell. In some embodiments, the cell is an endothelial cell. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is neural (e.g., CNS (e.g., brain)) tissue. In some embodiments, the fluid is CSF. In some embodiments, the FGG protein levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by about 10% or more, 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. In some embodiments, the FGG protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0029] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount diminishes a mental disorder or disease phenotype, such as a psychiatric disorder or neurological disorder phenotype. A disorder may include a disease. The psychiatric disease or disorder may include depressive disorder (e.g., major depressive disorder, persistent depressive disorder, treatment resistant depression, or signs and symptoms of depression), post-traumatic stress disorder, mood disorders, anxiety disorders, eating disorders, substance-use disorders, bipolar disorder, personality disorders, schizophrenia and schizoaffective disorders. The neurological disease or disorder may include such as Alzheimer’s disease, dementia, delirium, cognitive decline, vascularAttorney Docket No.54462-754.601 dementia, headache, migraine, chronic pain, fibromyalgia, chronic fatigue syndrome (e.g., myalgic encephalomyelitis (ME)), chronic traumatic encephalopathy, traumatic brain injury, or motor neuron disease (e.g., amyotrophic lateral sclerosis). For psychiatric / neurological indications, fibrinogen may be lowered enough to have a therapeutic effect on mental disorders but without significantly affecting coagulation parameters such as PT or aPTT.

[0030] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves (e.g. decreases) a psychiatric disease phenotype. The psychiatric disease phenotype may include a Montgomery-Asberg Depression Rating Scale (MADRS) score. The psychiatric disease phenotype may include a Hamilton Depression Rating Scale score. The psychiatric disease phenotype may include a sign or symptom of anxiety. The psychiatric disease phenotype may include a sign or symptom of an eating disorder. The psychiatric disease phenotype may include a sign or symptom of a substance-use disorder. The psychiatric disease phenotype may include a sign or symptom of post-traumatic stress disorder. The psychiatric disease phenotype may include a sign or symptom of bipolar disorder. The psychiatric disease phenotype may include a sign or symptom of schizophrenia. The psychiatric disease phenotype may include a sign or symptom of psychosis. In some embodiments, the psychiatric disease phenotype is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the psychiatric disease phenotype is improved by about 10% or more, as compared to prior to administration. In some embodiments, the psychiatric disease phenotype is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the psychiatric disease phenotype is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the psychiatric disease phenotype is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the psychiatric disease phenotype is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the psychiatric disease phenotype is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0031] In some embodiments, the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves (e.g. decreases) a neurological disease phenotype. The neurological disease phenotype may include cognitive dysfunction. The neurological disease phenotype may include central nervous system (CNS) amyloid plaques. The neurological disease phenotype may include CNS tau accumulation. The neurological disease phenotype may include cerebrospinal fluid (CSF) or plasma beta-amyloid 42, beta-amyloid 40, or the ratio of beta-amyloid 42 to beta-amyloid 40. The neurological disease phenotype may include CSF or plasma tau. The neurological disease phenotype may include CSF or plasma phospho-tau (such as p-tau217). The neurological diseaseAttorney Docket No.54462-754.601 phenotype may include CSF or plasma neurofilament light chain (NfL). The neurological disease phenotype may include CSF or plasma glial fibrillary acidic protein (GFAP). The neurological disease phenotype may include Lewy bodies. The neurological disease phenotype may include CSF alpha- synuclein. The neurological disease phenotype may include headache symptoms or signs. The neurological disease phenotype may include migraine symptoms or signs. The neurological disease phenotype may include chronic pain symptoms or signs. The neurological disease phenotype may include fibromyalgia symptoms or signs. The neurological disease phenotype may include chronic fatigue syndrome (e.g., myalgic encephalomyelitis) symptoms or signs. The neurological disease phenotype may include motor neuron disease (e.g., amyotrophic lateral sclerosis) symptoms or signs. In some embodiments, the neurological disease phenotype is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the neurological disease phenotype is improved by about 10% or more, as compared to prior to administration. In some embodiments, the neurological disease phenotype is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the neurological disease phenotype is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the neurological disease phenotype is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the neurological disease phenotype is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the neurological disease phenotype is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0032] The composition may treat a clotting or coagulation disorder. The composition may treat thrombophilia. The composition may affect clotting or a clotting time. In some embodiments, the composition comprises an oligonucleotide that decreases Fibrinogen or fibrin. In some cases, a FGG siRNA composition may be useful as an anticoagulant, such as for treatment or prophylaxis of a coagulation or clotting disorders (e.g., venous thromboembolism, atrial fibrillation), given that significant FGG knockdown may lead to a prolonged clotting time (e.g., PT, INR or aPTT). For coagulation or clotting disorders, it is useful to lower Fibrinogen or fibrin significantly enough to prolong clotting times to clinically meaningful levels for these indications. Provided herein are data that show FGG siRNA administration may result in FGG knockdown. FGG knockdown may result in decreased circulating fibrinogen or fibrin. Decreased circulating fibrinogen or fibrin may result in increased PT, INR and aPTT. As such, the compounds may be useful for reducing clotting. Some aspects relate to a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases fibrinogen or fibrin.Attorney Docket No.54462-754.601

[0033] In some embodiments, the prothrombin time (PT), International Normalized Ration (INR) and activated partial thromboplastin time (aPTT) levels are unchanged as compared to administration. In some embodiments, PT, INR or aPTT increases by no more than about 10%, as compared to prior to administration. In some embodiments, PT, INR or aPTT increase by no more than about 20%, no more than about 40%, no more than about 80%, no more than about 160%, no more than about 200%, no more than about 300%, no more than about 400%, or no more than about 600%, as compared to prior to administration. In some embodiments, the PT, INR or aPTT increases by 5%, 10%, 20%, 40%, 80%, 100%, 200%,400% or 600%, or by a range defined by any of the two aforementioned percentages.

[0034] The composition may be used to reduce levels of fibrinogen or fibrin. In some embodiments, the fibrinogen or fibrin is reduced while leading to minimal or non-significant changes in other coagulation measurements. In some instances, the fibrinogen or fibrin is reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 75%, or at least 90% relative to baseline without significant change in other coagulation measurements. In some instances, the fibrinogen or fibrin is reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 75%, or at least 90% relative to baseline and one or more non-fibrinogen or fibrin coagulation measurements change by no more than 50%, 40%, 30%, 20%, 15%, 10%, 7% 5%, 4% 3%, 2% or no more than 1% relative to baseline. In some instances, the fibrinogen or fibrin is reduced by 5- 95% 5-90%, 5-80%, 5-70%, 5-50%, 5-40%, 5-30%, 10-90%, 10-80%, 10-70%, 10-50%, 10-30%, 20- 95%, 20-50%, 40-90%, 50-95%, 60-95%, or 70-90% relative to baseline and one or more non-fibrinogen or fibrin coagulation measurements change by no more than 50%, 40%, 30%, 20%, 15%, 10%, 7% 5%, 4% 3%, 2% or no more than 1% relative to baseline. In some instances, the fibrinogen or fibrin is reduced by 5-95% 5-90%, 5-80%, 5-70%, 5-50%, 5-40%, 5-30%, 10-90%, 10-80%, 10-70%, 10-50%, 10-30%, 20-95%, 20-50%, 40-90%, 50-95%, 60-95%, or 70-90% relative to baseline and one or more non- fibrinogen or fibrin coagulation measurements change by 1-75%, 1-50%, 1-40%, 1-30%, 1-20%, 1-15%, 1-10%, 1-%, 1-5%, 1-3%, or 1-2% relative to baseline. In some instances, the fibrinogen or fibrin is reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 75%, or at least 90% relative to baseline and one or more non-fibrinogen or fibrin coagulation measurements change by 1-75%, 1-50%, 1-40%, 1-30%, 1-20%, 1-15%, 1-10%, 1-%, 1-5%, 1-3%, or 1-2% relative to baseline. In some embodiments, coagulation measurements comprises von Willebrand Factor (VWF) antigen, VWF activity, factor VIII (FVIII), alpha- 2 antiplasmin (A2AP), plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex (TAT), D-dimer (DD), fibrinogen, fibrin, prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), activated partial thromboplastin time (aPTT), or bleeding time assay. A. siRNAs

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

[0036] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisenseAttorney Docket No.54462-754.601 strand, wherein the sense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises a sense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The sense strand may be 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The antisense strand may be 14- 30 nucleosides in length.

[0037] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human FGG mRNA sequence such as SEQ ID NO: 3621. In SEQ ID NO: 3621, thymine (T) may be replaced with Uracil (U). In some embodiments, at least one of the sense strand and the antisense strand comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 3621.

[0038] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded RNA duplex. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair.

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

[0040] In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.Attorney Docket No.54462-754.601

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

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

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

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

[0045] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisenseAttorney Docket No.54462-754.601 strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742. In any of SEQ ID NOs: 1-1742, thymine (T) may be replaced with uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-Attorney Docket No.54462-754.601 1742 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an C. In some embodiments, position 1 and position 6, position 1 and 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 C.

[0046] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484. In any of SEQ ID NOs: 1743-3484, thymine (T) may be replaced with uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ IDAttorney Docket No.54462-754.601 NOs: 1743-3484 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 1743-3484 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 1743-3484 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743- 3484 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an C.

[0047] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, theAttorney Docket No.54462-754.601 composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748. In any of SEQ ID NOs: 3713-3748, thymine (T) may be replaced with uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713- 3748 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713- 3748 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713- 3748 is modified to an C.

[0048] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs:Attorney Docket No.54462-754.601 3749-3784 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784. In any of SEQ ID NOs: 3749-3784, thymine (T) may be replaced with uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 3749-3784 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749- 3784 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 1 and position 14,Attorney Docket No.54462-754.601 position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an C.

[0049] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021. In any of SEQ ID NOs: 3879-3941 or 4020-4021, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-Attorney Docket No.54462-754.601 3941 or 4020-4021 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879- 3941 or 4020-4021 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020- 4021 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C.

[0050] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises anAttorney Docket No.54462-754.601 oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023. In any of SEQ ID NOs: 3942-4002 or 4022-4023, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942- 4002 or 4022-4023 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C.Attorney Docket No.54462-754.601

[0051] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in any of Tables 3-7. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any Tables 3-7, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the 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. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. In some embodiments, a sense strand sequence of an siRNA in any one of Tables 3-7 is modified by substitution of the 3’ nucleoside to an A. In some embodiments, a sense strand sequence of an siRNA in any one of Tables 3-6 is modified by substitution of the nucleoside to an A at position 19 (from the 5’ end). In some embodiments, an antisense strand sequence of an siRNA in any one of Tables 3-7 is modified by substitution of the 3’ nucleoside to an U. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0052] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 66B. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 66B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 66B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 66B. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0053] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 79. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA inAttorney Docket No.54462-754.601 Table 79, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 79, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 79. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0054] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in any of Table 83. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any Table 83, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any 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 any 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 internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0055] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 87. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 87, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 87, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 87. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside 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 strandAttorney Docket No.54462-754.601 where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0056] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 93. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 93, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 93, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 93. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0057] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 97. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 97, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 97, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 97. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0058] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 101. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 101, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In someAttorney Docket No.54462-754.601 embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 101, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 101. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0059] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 105. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 105, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 105, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 105. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0060] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 109. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 109, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 109, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 109. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside 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 oneAttorney Docket No.54462-754.601 of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0061] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 113. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 113, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 113, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 113. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside 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.

[0062] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 117. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 117, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 117, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 117. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside 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.

[0063] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 121. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 121, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA inAttorney Docket No.54462-754.601 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 internucleoside 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.

[0064] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 125. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 125, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 125, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 125. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside 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.

[0065] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 166. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 166, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 166, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 166. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside 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 oneAttorney Docket No.54462-754.601 of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0066] In some embodiments, the sense and / or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and / or antisense strand sequence in Table 170. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 170, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 170, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 170. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside 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.

[0067] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A. The siRNA may include one or more internucleoside 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.

[0068] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B. The siRNA may include one or more internucleoside 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 19Attorney Docket No.54462-754.601 (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.

[0069] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand 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.

[0070] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D. The siRNA may include one or more internucleoside 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.

[0071] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E. The siRNA may include one or more internucleoside 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.

[0072] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisenseAttorney Docket No.54462-754.601 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 internucleoside 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.

[0073] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset H, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset H, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset H. The siRNA may include one or more internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand 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.

[0074] In some embodiments, the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 352, 1003, 1011, 1278, or 3785. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 352, 1003, 1011, 1278, or 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, or 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 internucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0075] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 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 internucleoside linkages or nucleoside modifications described herein. The sense strand may include an overhang (e.g., 2 bases on aAttorney Docket No.54462-754.601 5’ or 3’ end when paired with an antisense strand). The sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).

[0076] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1003. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003. The sense strand may include any internucleoside 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).

[0077] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1011. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011. The sense strand may include any internucleoside 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).

[0078] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1278. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278. The sense strand may include any internucleoside 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).

[0079] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3785. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785. The sense strand may include any internucleoside 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).Attorney Docket No.54462-754.601

[0080] In some embodiments, the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 2094, 2745, 2753, or 3020. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020. The antisense strand may include any internucleoside 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).

[0081] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2094. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094. The antisense strand may include any internucleoside 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.

[0082] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2745. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745. The antisense strand may include any internucleoside 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.

[0083] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2753. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753. The antisense strand may include any internucleoside linkages or nucleoside modifications described herein. The antisense strandAttorney Docket No.54462-754.601 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.

[0084] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3020. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020. The antisense strand may include any internucleoside 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.

[0085] In some embodiments, the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3723, 3724, 3726, or 3747. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3723, 3724, 3726, or 3747, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3723, 3724, 3726, or 3747, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3723, 3724, 3726, or 3747. The sense strand may include any internucleoside 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).

[0086] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3723. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3723, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3723, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3723. The sense strand may include any internucleoside 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).

[0087] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3724. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724. The sense strand may include anyAttorney Docket No.54462-754.601 internucleoside 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).

[0088] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3726. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726. The sense strand may include any internucleoside 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).

[0089] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3747. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747. The sense strand may include any internucleoside 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).

[0090] In some embodiments, the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3759, 3760, 3762, 3783, or 3790. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3759, 3760, 3762, 3783, or 3790, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3759, 3760, 3762, 3783, or 3790, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3759, 3760, 3762, 3783, or 3790. The antisense strand may include any internucleoside 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).

[0091] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3759. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, theAttorney Docket No.54462-754.601 antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759. The antisense strand may include any internucleoside 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.

[0092] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3760. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760. The antisense strand may include any internucleoside 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.

[0093] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3762. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762. The antisense strand may include any internucleoside 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.

[0094] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3783. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783. The antisense strand may include any internucleoside 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.

[0095] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3790. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790. The antisense strand may include any internucleoside linkages or nucleoside modifications described herein. The antisense strandAttorney Docket No.54462-754.601 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.

[0096] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any sequence of Table 1A. In some embodiments, the siRNA comprises a sense strand sequence as shown in Table 1A. Table 1A. Sense strand sequence examplesAttorney Docket No.54462-754.601

[0097] In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of Table 1A, at least 80% identical to any one of Table 1A, at least 85% identical to of any one of Table 1A, at least 90% identical to any one of Table 1A, or at least 95% identical to any one of Table 1A. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of Table 1A, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of Table 1A, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to Table 1A. The sense strand may comprise a modification pattern described herein. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety.

[0098] In some embodiments, the siRNA comprises an antisense sense strand sequence as shown in Table 1B. Table 1B. Antisense strand sequence examplesAttorney Docket No.54462-754.601

[0099] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of Table 1B. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of Table 1B, at least 80% identical to any one of Table 1B, at least 85% identical to of any one of Table 1B, at least 90% identical to any one of Table 1B, or at least 95% identical to any one of Table 1B. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of Table 1B, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of Table 1B, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to Table 1B. The antisense strand may comprise a modification pattern described herein.

[0100] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 3. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 3. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 3, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisenseAttorney Docket No.54462-754.601 strand comprises a sequence of a sense or antisense strand in Table 3, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 3. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0101] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 4. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 4. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 4, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 4, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 4. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0102] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 5. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 5. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 5, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 5, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 5. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0103] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 6. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 6. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 6, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 6, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisenseAttorney Docket No.54462-754.601 sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 6. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0104] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 7. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 7. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 7, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 7, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 7. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0105] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 8. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 8. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 8, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 8, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 8. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0106] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 9B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 9B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 9B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 9B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strandAttorney Docket No.54462-754.601 sequence in Table 9B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0107] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 9C. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 9C. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 9C, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 9C, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 9C. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0108] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 18B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 18B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 18B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 18B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 18B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0109] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 22B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 22B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 22B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 22B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 22B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.Attorney Docket No.54462-754.601

[0110] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 26B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 26B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 26B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 26B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 26B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0111] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 31B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 31B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 31B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 31B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 31B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0112] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 33B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 33B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 33B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 33B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 33B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0113] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 37B. In someAttorney Docket No.54462-754.601 embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 37B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 37B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 37B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 37B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0114] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 42B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 42B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 42B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 42B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 42B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 42B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 42B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 42B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 42B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 42B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0115] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 47B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand orAttorney Docket No.54462-754.601 antisense strand sequence in Table 47B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 47B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 47B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 47B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0116] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 67B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 67B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 67B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 67B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 67B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0117] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 79B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 79B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 79B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 79B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 79B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0118] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 85. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 85. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 85, or a sequence thereof having 3 or 4Attorney Docket No.54462-754.601 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 85, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 85. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0119] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 89. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 89. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 89, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 89, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 89. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0120] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 93. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 93. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 93, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 93, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 93. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0121] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 97. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 97. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 97, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 97, or a sequence thereof having 1 orAttorney Docket No.54462-754.601 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 97. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0122] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 101. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 101. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 101, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 101, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 101. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0123] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 105. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 105. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 105, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 105, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 105. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0124] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 109. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 109. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 109, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 109, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strandAttorney Docket No.54462-754.601 sequence in Table 109. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0125] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 113. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 113. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 113, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 113, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 113. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0126] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 117. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 117. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 117, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 117, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 117. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0127] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 121. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 121. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 121, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 121, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 121. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.Attorney Docket No.54462-754.601

[0128] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 125. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 125. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 125, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 125, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in 125185. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0129] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 142. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 142. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 142, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 142, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 142. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0130] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 183. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 183. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 183, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 183, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 183. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0131] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 187. In someAttorney Docket No.54462-754.601 embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 187. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 187, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 187, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 187. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.

[0132] In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 190B. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 190B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 190B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 190B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 190B. The sense strand or antisense strand may comprise any modifications described herein. The sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety. B. ASOs

[0133] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0134] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human FGG mRNA sequence such as SEQ ID NO: 3621; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 3621.Attorney Docket No.54462-754.601 C. Modification patterns

[0135] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. A phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur. Modified internucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified internucleoside linkage may include decreased toxicity or improved pharmacokinetics.

[0136] In some embodiments, the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothioates at the 5’ and 3’ ends.

[0137] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside linkages.Attorney Docket No.54462-754.601

[0138] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises the modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises a LNA. In some embodiments, the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises HNA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2'-O-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl group. In some embodiments, the modified nucleoside comprises 2’-O-methoxyethyl. In some embodiments, the modified nucleoside comprises a methoxyethyl. For example, position 4 of the sense strand may comprise a methoxyethyl nucleoside such as a 2’-O- methoxyethyl thymine. In some embodiments, the modified nucleoside comprises 2'-O-methyl. In some embodiments, the modified nucleoside comprises a 2'-O-allyl group. In some embodiments, the modified nucleoside comprises a 2'-fluoro group. In some embodiments, the modified nucleoside comprises a 2'- deoxy group. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'- deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2’- fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2’-O-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an acyclic nucleic acid. In some embodiments, the acyclic nucleic is a glycol nucleic acid. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics.

[0139] In some embodiments, the modified nucleoside comprises a glycol nucleic acid (GNA). A GNA may comprise the following structure:Attorney Docket No.54462-754.601

[0140]

[0141] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure:wherein the base can be any pyrimidine or purine.

[0142] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:are independently an H or a 3’ or 5’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.

[0143] In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises methylphosphonate. An example of a nucleotide that comprises a methylphosphonate is shown below:methylphosphonate 2’-O-Methyl Uridine).Attorney Docket No.54462-754.601

[0144] In some embodiments, the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothioates at the 5’ and 3’ ends.

[0145] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range of nucleosides defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0146] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a moiety attached at a 3’ or 5’ terminus of the oligonucleotide. Examples of moieties include a hydrophobic moiety or a sugar moiety, or a combination thereof. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 5’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5’ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3’ end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 5’ end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 3’ end of the ASO.

[0147] In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In someAttorney Docket No.54462-754.601 embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.

[0148] In some embodiments, the antisense strand is combination of 2’-fluoro and 2’-O-Methyl modifications. In some embodiments, each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside. In some embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.

[0149] The oligonucleotide may include purines. Examples of purines include adenine (A), guanine (G), or inosine (I), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0150] In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’ -O-methyl and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O- methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, the sense strand may include a 2’ deoxy nucleoside.

[0151] In some embodiments, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’-fluoro- modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.

[0152] In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides areAttorney Docket No.54462-754.601 modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; or all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro.

[0153] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[0154] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or α-tocopherol, or a combination thereof.

[0155] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N- acetyl galactose moiety (e.g., a N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. 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.

[0156] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAcAttorney Docket No.54462-754.601 may be useful for hepatocyte targeting. Since FGG may be secreted by the liver, the decreased FGG quantity in the liver resulting from the liver targeted FGG siRNA may result in a decrease in fibrinogen or FGG protein in circulation, and a related decrease in the central nervous system (CNS) (e.g., brain), or cerebrospinal fluid (CSF). 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.

[0157] Non-limiting examples of GalNAc ligands are shown in FIG.1 and FIG.2. In some embodiments, the oligonucleotide is conjugated to the GalNAc ligand in FIG.1. In the GalNAc ligand shown in FIG.1, J indicates a point of attachment to an oligonucleotide. In some embodiments, J is at a 5’ end of the oligonucleotide. In some embodiments, J is at a 3’ end of the oligonucleotide. In the GalNAc ligand shown in FIG.1, n may be any number. For example, n may be 1-10. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a range defined by any two of the aforementioned integers. In some embodiments, n is 2. In embodiments in which n is 2 and the oligonucleotide is connected at J, the GalNAc moiety may be referred to as “GalNAc#1” or “GalNAc1.”

[0158] In some embodiments, the oligonucleotide is conjugated to the GalNAc ligand in FIG.2. The wavy line in FIG.1 indicates a point of attachment to an oligonucleotide. In some embodiments, the wavy line is at a 5’ end of the oligonucleotide. In some embodiments, the wavy line is at a 3’ end of the oligonucleotide. In embodiments in which the oligonucleotide is connected at the wavy line, the GalNAc moiety may be referred to as “GalNAc#23” or “GalNAc23.”

[0159] The oligonucleotide may include purines. Examples of purines include adenine (A), guanine (G), or inosine (I), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0160] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. 2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’-methyl modification may be included, and vice versa.

[0161] In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.

[0162] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modifiedAttorney Docket No.54462-754.601 pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’- O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O- methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’-fluoro modified purines.

[0163] In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2’-fluoro modified purines.

[0164] In some cases, the oligonucleotide comprises a particular modification pattern. In some embodiments, position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification. In some embodiments, when position 9 of a strand of the oligonucleotide is a pyrimidine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positionsAttorney Docket No.54462-754.601 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0165] In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0166] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.

[0167] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’-fluoro- modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’- fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine; all purines of the sense strand comprises 2’-O- methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’-fluoro-Attorney Docket No.54462-754.601 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.

[0168] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purine, provided there are not three 2’-fluoro-modified purine in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro- modified purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’- fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2’-fluoro-modified purines in a row. In some embodiments, there are not three 2’-fluoro-modified pyrimidines in a row.

[0169] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2’-fluoro-modified purines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O-methyl modified purines or 2’-fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0170] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-Attorney Docket No.54462-754.601 modifed nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide.

[0171] In some embodiments, the moiety includes a negatively charged group attached at a 5’ end of the oligonucleotide. This may be referred to as a 5’-end group. In some embodiments, the negatively charged group is attached at a 5’ end of an antisense strand of an siRNA disclosed herein. The 5’-end group may be or include a 5’-end phosphorothioate, 5’-end phosphorodithioate, 5’-end vinylphosphonate (5’-VP), 5’- end methylphosphonate, 5’-end cyclopropyl phosphonate, or a 5’-deoxy-5’-C-malonyl. The 5’-end group may comprise 5’-VP. In some embodiments, the 5’-VP comprises a trans-vinylphosphonate or cis- vinylphosphonate. The 5’-end group may include an extra 5’ phosphate. A combination of 5’-end groups may be used.

[0172] In some embodiments, the oligonucleotide includes a negatively charged group. The negatively charged group may aid in cell or tissue penetration. The negatively charged group may be attached at a 5’ or 3’ end (e.g., a 5’ end) of the oligonucleotide. This may be referred to as an end group. The end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy-C-malonyl. The end group may include an extra 5’ phosphate such as an extra 5’ phosphate. A combination of end groups may be used.

[0173] In some embodiments, the oligonucleotide includes a phosphate mimic. In some embodiments, the phosphate mimic comprises vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises a trans-vinylphosphonate. In some embodiments, the vinyl phosphonate comprises a cis- vinylphosphonate. An example of a nucleotide that includes a vinyl phosphonate is shown below.Attorney Docket No.54462-754.6015’ vinylphosphonate 2’-O Methyl Uridine

[0174] In some embodiments, the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.

[0175] In some embodiments, the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. 1. Hydrophobic moieties

[0176] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[0177] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof.

[0178] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic ligand or moiety. In some embodiments, the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moietyAttorney Docket No.54462-754.601 s attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide.

[0179] In some embodiments, a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and / or an antisense strand of a siRNA). In some embodiments, a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl. The hydrophobic moiety may include an esterified lipid.

[0180] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid includes a sterol such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12. The lipid moiety may be esterified.

[0181] In some embodiments, the oligonucleotide comprises any aspect 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:Attorney Docket No.54462-754.601some embodiments, the oligonucleotide comprises any aspect of the following structure:aspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid moiety comprises an alcohol or ether.

[0182] In some embodiments, the lipid includes a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 2. The example lipid moieties in Table 2 are shown attached at a 5’ end of an oligonucleotide, in which the 5’ terminal phosphate of the oligonucleotide is shown with the lipid moiety. In some embodiments, a lipid moiety in Table 2 may be attached at a different point of attachment than shown. For example, the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end. In some embodiments, the lipid is used for targeting the oligonucleotide to a non- hepatic cell or tissue. Table 2: Hydrophobic moiety examplesAttorney Docket No.54462-754.601Attorney Docket No.54462-754.601

[0183] In some embodiments, the lipid or lipid moiety includes 16 to 18 carbons. In some embodiments, the lipid includes 16 carbons. In some embodiments, the lipid includes 17 carbons. In some embodiments, the lipid includes 18 carbons. In some embodiments, the lipid moiety includes 16 carbons. In someAttorney Docket No.54462-754.601 embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety includes 18 carbons.

[0184] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration). The lipid may be attached to the carbocycle in the 1,4 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,3 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,2 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.

[0185] The lipid moiety may comprise or consist of the following structurethe lipid moiety comprises the following structure: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,Attorney Docket No.54462-754.601 the connection may be to the 5’ end of the sense strand. In some embodiments, n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons.

[0186] 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.

[0187] In some embodiments, the oligonucleotide includes 1 lipid moiety. In some embodiments, the oligonucleotide includes 2 lipid moieties. In some embodiments, the oligonucleotide includes 3 lipid moieties. In some embodiments, the oligonucleotide includes 4 lipid moieties.

[0188] Some embodiments relate to a method of making an oligonucleotide comprising a hydrophobic conjugate. A strategy for making hydrophobic conjugates may include use of a phosphoramidite reagent based upon a 6-membered ring alcohol such as a phenol or cyclohexanol. The phosphoramidite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, and thereby produce the hydrophobic conjugate. Some examples of phosphoramidite reagents that may be used to produce ahydrophobic conjugate are provided as follows: ,Attorney Docket No.54462-754.601. some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. Any one of the phosphoramidite reagents may be reacted to a 5’ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety. In some embodiments, the phosphoramidite reagents is reacted to a 5’ end of a sense strand of an siRNA. The sense strand may then be hybridized to an antisense strand to form a duplex. The hybridization may be performed by incubating the sense and antisense strands in solution at a given temperature. The temperature may be gradually reduced. The temperature may comprise or include a temperature comprising an annealing temperature for the sense and antisense strands. The temperature may be below or include a temperature below the annealing temperature for the sense and antisense strands. The temperature may be below a melting temperature of the sense and antisense strands.

[0189] The lipid may be attached to the oligonucleotide by a linker. The linker may include a polyethyleneglycol (e.g., tetraethyleneglycol).

[0190] The modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition. The modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue. 2. Sugar moieties

[0191] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N- acetyl galactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3’ or 5’Attorney Docket No.54462-754.601 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.

[0192] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting. The GalNAc moiety may include a bivalent or 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.

[0193] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide.

[0194] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (I) or (II):or a salt thereof, whereinAttorney Docket No.54462-754.601 J is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR6, or if z is 1, Y is C(R6)2; Q is selected from: C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, -S(O)R7, and C1-6 alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2; R1is a linker selected from: -O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-, -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, - N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, -SP(O)(OR7)O-, - OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, - OP(O)(S-)O-, -OP(O)(O-)S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-; each R2is independently selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; R3and R4are each independently selected from: -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7,-N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R5is independently selected from: -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7,-N(R7)C(O)N(R7)2, - N(R7)C(O)OR7, -C(O)R7, -C(O)OR7, and -C(O)N(R7)2; each R6is independently selected from: hydrogen; halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7,- N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7,- N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7;Attorney Docket No.54462-754.601 each R7is independently selected from: hydrogen; C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, - O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocycle, and 3- to 10- membered heterocycle; and C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, - NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl.

[0195] In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, - OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O-)S-, - OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, -OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2-NR7. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O- )S-, and -OP(OR7)O-. In some embodiments, R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, and -OP(OR7)O-. In some embodiments, R1is selected from - OP(O)(OR7)O- and -OP(OR7)O-. In some embodiments, R2is selected from C1-3alkyl substituted with one or more substituents independently selected from halogen, -OR7, -OC(O)R7, -SR7, -N(R7)2, -C(O)R7, and -S(O)R7. In some embodiments, R2is selected from C1-3alkyl substituted with one or more substituents independently selected from -OR7, -OC(O)R7, -SR7, and -N(R7)2. In some embodiments, R2is selected from C1-3alkyl substituted with one or more substituents independently selected from -OR7and -Attorney Docket No.54462-754.601 OC(O)R7. In some embodiments, R3is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7.In some embodiments, R3is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R3is selected from -OR7- and -OC(O)R7. In some embodiments, R4is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7. In some embodiments, R4is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R4is selected from -OR7- and -OC(O)R7. In some embodiments, R5is selected from -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, and -N(R7)C(O)OR7. In some embodiments, R5is selected from -OC(O)R7and -N(R7)C(O)R7. In some embodiments, each R7is independently selected from: hydrogen; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O- C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocycle, or 3- to 10-membered heterocycle. In some embodiments, each R7is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, - NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, and -NH(C1-6 alkyl). In some embodiments, each R7is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, and C1-3 alkyl; R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, and - OP(OR7)O-; R2is C1 alkyl substituted with -OH or -OC(O)CH3;Attorney Docket No.54462-754.601Attorney Docket No.54462-754.601Attorney Docket No.54462-754.601Attorney Docket No.54462-754.601Attorney Docket No.54462-754.601Attorney Docket No.54462-754.601

[0196] In some embodiments, the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified internucleoside linkages. In some embodiments, the one or more modified internucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets a hepatocyte.

[0197] Some embodiments include the following, where J is the oligonucleotide:Attorney Docket No.54462-754.601include 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.

[0198] 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.Attorney Docket No.54462-754.601

[0199] 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.

[0200] Some embodiments include the following, where J is the oligonucleotide:. The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” and isAttorney Docket No.54462-754.601 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.

[0201] Some embodiments include the following, where the phosphate or “5’” indicates a connection to the oligonucleotide:

[0202] Some embodiments include the following, where the phosphate or “5’” indicates a connection to the oligonucleotide:

[0203] Some embodiments include the following, where J is the oligonucleotide:Attorney Docket No.54462-754.601include 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.

[0204] Some embodiments include the following, where J is the oligonucleotide:. The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include aAttorney Docket No.54462-754.601 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.

[0205] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (III), (IV), or (V):Formula IV, orAttorney Docket No.54462-754.601Formula V, or a salt thereof, wherein J is an oligonucleotide; each w is independently selected from any value from 0 to 20; v is independently selected from any value from 0 to 20; each n is selected from any value from 0 to 20; each m is selected from any value from 0 to 20; each p is selected from any value from 0 to 1; each w is selected from any value from 0 to 20; t is selected from any value from 0 to 1; x is selected from any value from 0 to 1; r is selected from any value from 0 to 20; u is selected from any value from 0 to 20; Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, - C(O)N(R7)2, -N(R7)C(O)R7,-N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, - S(O)R7, and C1-6alkyl, wherein the C1-6alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2; R1is a linker selected from: -O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-,-N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, - SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O-)O-, -SP(O)(O-)O-, - OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O-)S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-;Attorney Docket No.54462-754.601 each R7is independently selected from: hydrogen, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6alkyl, -S-C1-6alkyl, -N(C1-6alkyl)2, -NH(C1-6alkyl), C3-10carbocycle, and 3- to 10-membered heterocycle, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl.

[0206] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0207] 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.

[0208] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:Attorney Docket No.54462-754.601.

[0209] 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.

[0210] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:.

[0211] 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 orAttorney Docket No.54462-754.601 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.

[0212] Provided herein are sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides:

[0213] The structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide. In some instances, 2-4 GalNAc moieties are attached oligonucleotide. The placement of the GalNAc moieties in some instances is at the 3’ or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K may in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instancesAttorney Docket No.54462-754.601 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.

[0214] Provided herein are sugar moieties comprising the following structure, where R is an oligonucleotide:Attorney Docket No.54462-754.601Attorney Docket No.54462-754.601orAttorney Docket No.54462-754.601.

[0215] The structure in this compound attached to the oligonucleotide (R) in some instances is referred to as H1, H2, H3, H4, H5, H6, H7, or H9, and are examples of GalNAc moieties. R in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. R in some instances comprises one or more phosphates linking to the oligonucleotide. R in some instances comprises a phosphate linking to the oligonucleotide. R in some instances comprises one or more phosphorothioates linking to the oligonucleotide. R in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0216] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:. The structure in this compound attached to the oligonucleotide (J) may be referred to as “K2GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.Attorney Docket No.54462-754.601

[0217] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is S or O:. The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0218] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:Attorney Docket No.54462-754.601. The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0219] Provided herein are sugar moieties comprising the following structure, where J or K comprises an oligonucleotide:Attorney Docket No.54462-754.601

[0220] The structures in these compounds in some instances are attached to the oligonucleotide (J or K), referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties. In some instances, 2-4 GalNAc moieties are attached oligonucleotide. The placement of the GalNAc moieties may be at the 3’ or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0221] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:Attorney Docket No.54462-754.601.

[0222] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “THA,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0223] Provided herein are sugar moieties comprising the following structure, where Nu is an oligonucleotide:

[0224] The structure in this compound attached to the oligonucleotide (Nu) in some instances is referred to as “L-9” and is an example of a GalNAc moiety. Nu in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. Nu in some instances comprises one or more phosphates linking to the oligonucleotide. Nu in some instances comprises a phosphate linking toAttorney Docket No.54462-754.601 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.

[0225] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0226] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Sirius GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0227] Provided herein are sugar moieties comprising the following structures, where J is an oligonucleotide:Attorney Docket No.54462-754.601

[0228] The structures in this compound attached to the oligonucleotide (J) in some instances are referred to as GLS-5 and GLS-15 and are examples of GalNAc moieties. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0229] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:Attorney Docket No.54462-754.601

[0230] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Olix GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0231] Provided herein are sugar moieties comprising the following structure, where J and J’ is an oligonucleotide or a GalNAc moiety:

[0232] The structure in this compound attached to the oligonucleotide or a GalNAc moiety (J or J’) in some instances is referred to as “GalNAc G1b,” and is an example of a GalNAc moiety. J or J’ in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphates linking to the oligonucleotide. J or J’ in some instances comprises a phosphate linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0233] Provided herein are sugar moieties comprising the following structure, where B is a nucleic acid base, and J and J’ is an oligonucleotide or a GalNAc moiety:Attorney Docket No.54462-754.601

[0234] The structure in this compound attached to the oligonucleotide or a GalNAc moiety (J or J’) in some instances is referred to as “1gT3,” and is an example of a GalNAc moiety. J or J’ in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphates linking to the oligonucleotide. J or J’ in some instances comprises a phosphate linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0235] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is an optional linker:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “5gn2c6,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. X is a carbon or heteroatom linker to J. In some instances, the heteroatom in linker X is an N or O.

[0236] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:Attorney Docket No.54462-754.601The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “[Gal-6]s[Gal-6]s[Gal-6],” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0237] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Janssen,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphatesAttorney Docket No.54462-754.601 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.

[0238] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Arbutus,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. 3. siRNA modification patterns

[0239] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern 1S: 5’-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 2S: 5’-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn- 3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 3S: 5’-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In someAttorney Docket No.54462-754.601 embodiments, the sense strand comprises modification pattern 4S: 5’-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-moiety-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 5S: 5’-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-moiety-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the 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. In some embodiments, the sense strand comprises modification pattern 6S: 5’-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 7S: 5’-nsnsnnNfNfNfNfNfnnnnnnnnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 8S: 5’-nsnsnnnNfNfNfNfnnnnnnnnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 9S: 5’-nsnsnnnnNfNfNfNfnnnnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 10S: 5'- nsnsnnNfNfnNfNfnnnnnnnnnnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 11S: 5'-nsnsnnNfnnnNfnnnnnnnnnnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 12S: 5'-snnnnNfNfnNfNfnnnnNfnnNfnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 13S: 5'- snnnnNfNfnNfdNnNfNfnnNfnnnnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 14S: 5'-snnNfNfnnnnNfnnnnNfnNfNfnnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 15S: 5'-snnNfnNfnNfNfdNnNfNfnnNfnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 16S: 5'- snnnnNfnNfNfNfNfnnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments,Attorney Docket No.54462-754.601 the sense strand comprises modification pattern 17S: 5'-snnnnnNfNfNfNfnnnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 18S: 5'-snnnnNfNfnNfNfnnnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 19S: 5'-snnnnNfnnnNfnnnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 20S: 5'-snnnnnNfNfNfNfnNfnnnnnnnnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 21S: 5'- snnnnnnNfNfNfNfNfnnnnnnnnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 22S: 5'-snnnnNfNfnNfNfnNfnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 23S: 5'-snnnnNfnNfNfdTnnnnnnnnnnsnsn-3', wherein “dT” is deoxythymidine, “Nf” is a 2’- fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 24S: 5'- snnnnNfNfnnNfNfnnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 25S: 5'-snnnnnNfNfnNfnnnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 26S: 5'-snnnnnnNfnNfNfnnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 27S: 5'-snnnnnnnNfNfnNfnnnnnnnnsnsn- 3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 28S: 5'-snnnnnnnnNfnNfnNfnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 29S: 5'-snnnnnnnNfNfNfNfnnnnnnnnsnsn- 3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 30S: 5'- snnnnmnNfNfNfNfnnnnmnnnnnnsnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 31S: 5'-snnnnmnNfNfNfNfnnnmnnnnnnnsnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modifiedAttorney Docket No.54462-754.601 nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 32S: 5'-snnnnmnNfNfNfNfntmnnnnnnnnsnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 33S: 5'-snnnnnmNfNfNfNfnnnmnnnnnnnsnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 34S: 5'-snnnnmnNfNfNfNfnnnnnnmnnnnsnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 35S: 5'-snnnnmnNfNfNfNfnnnnnmnnnnnsnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 36S: 5'-snnnnmnNfNfNfNfnnnntmnnnnnsnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 37S: 5'-snnnnmNfnNfNfNfNfnnnmnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 38S: 5'-snnnnmnNfNfNfNfnnmnnnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 39S: 5'-snnnnNfnNfNfNfdnnnnnnnnnnsnsn-3’, wherein “Nf” is a 2’- fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 40S: 5'- snnnnnNfnnNfnNfnnnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 41S: 5'-snnnnNfnnNfNfNfNfnnnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 42S: 5'-snnnnNfNfNfNfNfnnnnnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 43S: 5'-snnnnNfnnNfNfnNfnnnnnnnnsnsn- 3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 44S: 5'-snnnnmNfnNfNfNfNfnntmnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl-modified nucleoside,Attorney Docket No.54462-754.601 and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 45S: 5'-snnnnmnNfNfNfNfnnntmnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 46S: 5'-snnnnmnNfNfNfNfnntmnnnnnnnsnsn-3’, wherein “Nf” is a 2’- fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl- modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 47S: 5'-snnnnNfNfnnNfnNfnnnnnnnnsnsn-3’, wherein “Nf” is a 2’- fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 48S: 5'- snnnnnnNfNfNfNfnnnnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 49S: 5'-snnnnNfnNfnNfnnnnnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 50S: 5'-snnnnnnNfNfNfNfnnnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 51S: 5'- snnnmnNfNfNfNfnnnnmnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 52S: 5'-snnnnNfnNfNfNfdNnnnnnnnnnsnsn-3’, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 53S: 5'- snnnnNfnNfNfNfdTnnnnnnnnnsnsn-3’, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 54S: 5'-snnnnNfnNfnNfNfnnnnnnnnnsnsn-3’, “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 55S: 5'- snnnnNfnnNfNfnnnnnnnnnnsnsn-3’, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 56S: 5'-snnnnNfnnnNfNfnnnnnnnnnsnsn-3’, “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.

[0240] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern 1AS: 5’-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is aAttorney Docket No.54462-754.601 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 2AS: 5’-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 3AS: 5’-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 4AS: 5’-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 5AS: 5’-nsNfsnnnnnnnnnnnNfnNfnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 6AS: 5’-nsNfsnnnNfnnNfnnnnNfnNfnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 7AS: 5’-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 8AS: 5’-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 9AS: 5’-nNfnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 10AS: 5'- nsNfsnNfnnnNfnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 11AS: 5'-nsNfsnNfnnNfnnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 12AS: 5'-nsNfsndTndNnNfnNfndNnNfndNnNfnsnsn-3' , wherein “Nf” is a 2’- fluoro-modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 13AS: 5'-nsNfsndTndNnNfnNfndNndTndNndTnsnsn-3' , wherein “Nf” is a 2’- fluoro-modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 14AS: 5'-nsNfsnnnNfnnnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 15AS: 5'-Attorney Docket No.54462-754.601 dTsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 16As: 5'- NfsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 17AS: 5'- nsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 18AS: 5'-nsNfsnNfnNfnnnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 19AS: 5'-nsNfsnNfnnNfNfnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 20AS: 5'- nsNfsnNfnnNfnnnnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 21AS: 5'-nsNfsnnnNfnNfnnnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 22AS: 5’-nsNfsnNfnnNfnnNfnNfnNfnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 23AS: 5'- nsNfsnnnNfnNfnNfnNfnNfnNfnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 24AS: 5'-nsNfsnnnNfnNfnNfnNfnNfnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 25AS: 5'-nsNfsnnNfnNfnnNfnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 26AS: 5'- nsNfsnnNfnNfNfnnnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 27AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 28AS: 5'-nsNfsnnnNfNfnnNfnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 29AS: 5'-Attorney Docket No.54462-754.601 nsNfsnnnNfNfnnnnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 30AS: 5'-nsNfsnnNfnNfNfnNfnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 31AS: 5'-nsNfsnnNfnNfnnNfnnnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 32AS: 5'- nsNfsnnNfnNfNfnNfnnnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 33AS: 5’-nsNfsnnnnNfnnnnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 34AS: 5’-nsNfsnnNfnNfnNfnnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 35AS: 5’- nsNfsnNfnnNfnnnnNfnNfnNfnNfsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 36AS: 5’-nsNfsnNfnnNfnnnnNfnNfnNfnsNfsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 37AS: 5’-nsNfsnNfnnNfnnnnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 38AS: 5’- nsNfsnNfnnNfnnnnNfnNfnNfsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 39AS: 5’-nsNfsnNfnnNfnnNfnNfnNfnNfnNfsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 40AS: 5’-nsNfsnNfnnNfnnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-meth...

Claims

Attorney Docket No.54462-754.601 CLAIMS What is claimed is:

1. A composition comprising an oligonucleotide that targets fibrinogen gamma chain (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, and wherein: (a) the sense strand comprises a modification pattern selected from the group consisting of: 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S; or (b) the antisense strand comprises a modification pattern selected from the group consisting of: 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS; and (c) wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “dN” is a deoxy-modified nucleoside, and “s” is a phosphorothioate linkage.

2. The composition of claim 1, wherein the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide.

3. The composition of claim 2, wherein the sugar moiety is attached at a 5’ terminus of the sense strand.

4. The composition of claim 2 or 3, wherein the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose.

5. The composition of claim 4, wherein the sugar comprises GalNAc.

6. The composition of claim 5, wherein the sugar moiety comprises ETL17.

7. The composition of any one of the aforementioned claims, wherein the antisense strand is complementary or at least 90% complementary to a portion of SEQ ID NO: 3621.

8. The composition of any one of the aforementioned claims, wherein the sense strand and the antisense strand each have 14 to 30 nucleotides.

9. The composition of any one of the aforementioned claims, wherein the sense strand comprises a nucleoside sequence having at least 85% sequence identity to any one of SEQ ID NOs: 1-1742.

10. The composition of any one of the aforementioned claims, wherein the sense strand comprises the nucleoside sequence of any one of: SEQ ID NOs: 1-1742, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.

11. The composition of any one of the aforementioned claims, wherein the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 1-1742.Attorney Docket No.54462-754.601 12. The composition of any one of the aforementioned claims, wherein the antisense strand comprises a nucleoside sequence having at least 85% sequence identity to any one of SEQ ID NOs: 1743- 3484.

13. The composition of any one of the aforementioned claims, wherein the antisense strand comprises the nucleoside sequence of any one of: SEQ ID NOs: 1743-3484, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.

14. The composition of any one of the aforementioned claims, wherein the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 1743-3484.

15. The composition of any one of the aforementioned claims, wherein the sense strand comprises the nucleobase sequence of a sense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B, 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B or a nucleobase sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.

16. The composition of any one of the aforementioned claims, wherein the sense strand comprises the nucleobase sequence of a sense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B, 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B.

17. The composition of any one of the aforementioned claims, wherein the antisense strand comprises the nucleobase sequence of an antisense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B, 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B, or a nucleobase sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.

18. The composition of any one of the aforementioned claims, wherein the antisense strand comprises the nucleobase sequence of an antisense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B, 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B.

19. A pharmaceutical composition comprising the composition of any one of the aforementioned claims, and a pharmaceutically acceptable carrier.

20. A method of treating a mental or neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1-18 or the pharmaceutical composition of claim 19, thereby treating the disorder.

21. The method of claim 20, wherein the mental or neurological disorder comprises a neurodegenerative disease.

22. The method of claim 20, wherein the mental or neurological disorder is selected from the group consisting of Alzheimer’s disease, dementia, delirium, cognitive decline, vascular dementia, headache, chronic pain, chronic fatigue syndrome, chronic traumatic encephalopathy, traumatic brain injury, and motor neuron disease.Attorney Docket No.54462-754.601 23. The method of claim 22, wherein headache comprises migraine.

24. The method of claim 22, wherein chronic pain comprises fibromyalgia.

25. The method of claim 22, wherein chronic fatigue syndrome comprises myalgic encephalomyelitis 26. The method of claim 22, wherein motor neuron disease comprises amyotrophic lateral sclerosis (ALS).

27. The method of claim 20, wherein the mental or neurological disorder comprises a psychiatric disorder.

28. The method of claim 27, wherein the psychiatric disorder is selected from the group consisting of post-traumatic stress disorder, mood disorders, anxiety disorders, eating disorders, substance-use disorders, bipolar disorder, personality disorders, schizophrenia and schizoaffective disorders.

29. A method of decreasing fibrinogen or fibrin measurement in a subject, comprising administering to the subject an effective amount of an FGG siRNA, thereby decreasing a quantity of fibrinogen or fibrin in the subject.

30. The method of any one of claims 20-29, wherein fibrinogen or fibrin measurement is decreased by at least 10% relative to a baseline quantity, or by at least 10% relative to a control.

31. The method of claim 30, wherein the fibrinogen or fibrin measurement comprises circulating fibrinogen measurement or CNS fibrinogen measurement.

32. The method of any one of claims 20-31, wherein the FGG siRNA is administered to an area of the subject’s body other than the subject’s head or brain.

33. The method of any one of claims 20-32, wherein fibrinogen or fibrin measurement comprises a quantity of fibrinogen.

34. The method of any one of claims 20-33, wherein fibrinogen or fibrin measurement comprises a quantity of fibrin.

35. The method of any one of claims 20-34, wherein the CNS comprises a brain.

36. The method of any one of claims 20-35, wherein the FGG siRNA is included in the composition of any one of claims 1-19.

37. A composition comprising an oligonucleotide of any one of claims 1-19 that targets FGG and when administered to a subject in an effective amount improves a marker of neurodegeneration.

38. The composition of claim 37, wherein the marker of neurodegeneration comprises a central nervous system (CNS), cerebrospinal fluid (CSF) or plasma marker of neurodegeneration.

39. The composition of claim 37, wherein the marker of neurodegeneration comprises a measurement of amyloid plaques, tau accumulation, beta-amyloid 42, beta-amyloid 40, the ratio of beta- amyloid 42 to beta-amyloid 40, tau, phospho-tau, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Lewy bodies, or alpha-synuclein.

40. The composition of any one of claims 37-39, wherein the marker of neurodegeneration is improved by about 10% or more, as compared to prior to administration.

41. A method of treating a subject having a neurological disorder or who is at risk for developing the neurological disorder, the method comprising evaluating a subject’s risk for developing aAttorney Docket No.54462-754.601 neurological disorder and administering an effective amount of the composition of any one of claims 1-19 to the subject.

42. The method of claim 41, wherein the subject has a genotype at risk for developing Alzheimer’s disease or dementia.

43. The method of claim 42, wherein the subject is a heterozygous or homozygous carrier of APOE4.

44. The method of claim 42, wherein the subject is a heterozygous or homozygous carrier of FGG rs148685782-G (A108) or FGG rs6063-C (G191).

45. The method of any one of claims 41-44, wherein evaluating a subject’s risk for developing a neurological disorder comprises calculating a polygenic risk score for developing Alzheimer’s disease or dementia.

46. The method of claim 45, wherein the subject has a polygenic risk score in the 40thpercentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia.

47. The method of claim 45, wherein the subject has a polygenic risk score in the 20thpercentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia.

48. The method of claim 45, wherein calculating a polygenic risk score comprises providing genomic data comprising one or more genotypes of the subject, wherein the one or more genotypes is associated with a high risk for developing Alzheimer’s disease or dementia.

49. A method comprising administering an oligonucleotide of any one of claims 1-19 that targets FGG and when administered to a subject in an effective amount reduces fibrinogen in the subject.

50. The method of claim 49, wherein fibrinogen is reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 75%, or at least 90% relative to baseline.

51. The method of claim 49, wherein fibrinogen is reduced by at least 5%-90% relative to baseline.

52. The method of any one of claims 49-51, wherein one or more non-fibrinogen coagulation measurements change by no more than 50%, 40%, 30%, 20%, 15%, 10%, 7%, 5%, 4% 3%, 2% or no more than 1% relative to baseline.

53. The method of any one of claims 49-51, wherein fibrinogen is reduced without significant change to one or more non-fibrinogen coagulation measurements.

54. The method of claim 52 or 53, wherein the one or more coagulation measurements comprises von Willebrand Factor (VWF) antigen, VWF activity, factor VIII (FVIII), alpha-2 antiplasmin (A2AP), plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex (TAT), D- dimer (DD), fibrinogen, prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), activated partial thromboplastin time (aPTT), or bleeding time assay.

55. The method of any one of claims 49-54, wherein the subject has a mental or neurological disorder.

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