Treatment of FGG-Related Diseases and Disorders

Abstract

Disclosed herein is a composition comprising an oligonucleotide that targets FGG.The oligonucleotide can comprise small interfering RNA (siRNA) or antisense oligonucleotide (ASO).Also provided herein is a method for treating psychiatric disorders or pathologies associated with FGG mutation.The method can comprise providing an oligonucleotide that targets FGG to a subject.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 286,393, filed December 6, 2021, which is incorporated herein by reference.

[0002] Incorporation by reference of sequence listing This application is filed with an electronic Sequence Listing, which has been submitted as a file entitled 54462-736601.xml, created on December 3, 2022, and having a size of 5155 kilobytes. The information in the electronic Sequence Listing is incorporated by reference in its entirety. [Background technology]

[0003] Psychiatric and neurological disorders are widespread, increasing, and can affect a wide range of people. Improved medications are needed to treat these disorders. Summary of the Invention

[0004] In some embodiments, disclosed herein are compositions comprising oligonucleotides targeting the fibrinogen gamma gene (FGG). In some embodiments, disclosed herein are compositions comprising oligonucleotides that target FGG and, when administered to a subject in an effective amount, improve a mental disorder measure 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, a mood disorder, an anxiety disorder, an eating disorder, a substance use disorder, a bipolar disorder, a personality disorder, schizophrenia, or a schizoaffective disorder. In some embodiments, the psychiatric disorder measure is selected from the group consisting of Montgomery-Asberg Depression Rating Scale (MADRS) score, Hamilton Depression Rating Scale-17 score, signs and symptoms of anxiety, signs and symptoms of eating disorders, signs and symptoms of substance use disorders, signs and symptoms of post-traumatic stress disorder, signs and symptoms of bipolar disorder, signs and symptoms of schizophrenia, and signs and symptoms of psychosis. In some embodiments, the psychiatric 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), or motor neuron disease (e.g., amyotrophic lateral sclerosis). In some embodiments, the psychiatric disorder measure is selected from the group consisting of cognitive function, CNS amyloid plaques, CNS tau accumulation, CSF beta amyloid 42, CSF tau, CSF phosphorylated tau, Lewy bodies, CSF 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 an alkyl phosphonate, phosphorothioate, methyl phosphonate, phosphorodithioate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphotriester, 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 modified nucleosides. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-O-allyl, a 2'-fluoro, or a 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2',4'-constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, a 2'-deoxyfluoro nucleoside, a 2'-ON-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, a 2'-O-aminopropyl (2'-O-AP) nucleoside, or a 2'-ara-F, or a combination thereof. In some embodiments, the modified nucleosides include one or more 2'-fluoro-modified nucleosides. In some embodiments, the modified nucleosides include 2'-O-alkyl-modified nucleosides. In some embodiments, the oligonucleotide includes 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 the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmitylstearyl, or α-tocopherol, or a combination thereof. In some embodiments, the oligonucleotide comprises a sugar moiety attached at the 3' or 5' end 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. In some embodiments, disclosed herein are compositions comprising oligonucleotides that inhibit expression of FGG, wherein the oligonucleotides comprise siRNA comprising a sense strand and an antisense strand, each strand independently being 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, with respect to the sense strand, any one of the following is true: 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 sense strand comprises any one of the following modification patterns: 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S.In some embodiments, with respect to the antisense strand, any one of the following is true: 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 the following modification patterns: 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. 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 with one or two 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 with one or two 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 with one or two 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 with one or two 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 with one or two 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 with one or two substitutions, additions, or deletions. In some 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 with one or two 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 with one or two 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 to 30 nucleosides in length.In some embodiments, disclosed herein are compositions comprising an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises an ASO of 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. In some embodiments, the composition comprises a pharmaceutically acceptable carrier. Disclosed herein are methods for treating a subject with a neurological or neurological disorder, comprising administering an effective amount of a 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, a mood disorder, an anxiety disorder, an eating disorder, a substance use disorder, a bipolar disorder, a 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), and motor neuron disease (e.g., amyotrophic lateral sclerosis). [Brief explanation of the drawings]

[0005] [Figure 1] Examples of GalNAc ligands are illustrated. [Figure 2] Examples of GalNAc ligands are illustrated. DETAILED DESCRIPTION OF THE INVENTION

[0006] Large-scale human genetic data can improve the success rate of drug discovery and development. Genome-wide association studies (GWAS) can detect associations between genetic variants and traits in population samples. GWAS can improve our understanding of disease biology and inform appropriate treatments. GWAS can utilize genotyping and / or sequencing data and often involve evaluating millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is a case-control study, which involves comparing variant frequencies in cases and controls. If a variant has a significantly different frequency between cases and controls, the variant is said to be associated with disease. Relevant statistics that may be used in GWAS are the p-value as an indicator of statistical significance, the odds ratio (OR) as an indicator of effect size, or the beta coefficient (β) as an indicator of effect size. Researchers often assume an additive genetic model and calculate allelic odds ratios, which indicate that each additional copy of an allele (compared to no copies of that allele) increases (or decreases) the risk of a given disease. An additional concept in the design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obscure which variants are "causative."

[0007] Functional annotation of variants and / or wet-lab experiments can pinpoint causative gene variants identified through GWAS, often leading to the identification of disease-causing genes. Understanding the functional effect of a causative gene variant (e.g., loss of protein function, gain of protein function, increased gene expression, or decreased gene expression) can allow researchers to use the variant as a surrogate for therapeutic modulation of the target gene, providing insight into the potential therapeutic efficacy and safety of therapeutics that modulate that target.

[0008] Identifying such gene-disease associations provides insights into disease biology and can be used to identify novel therapeutic targets for the pharmaceutical industry. To translate therapeutic insights gained from human genetics, disease biology in patients may be exogenously "programmed" to recapitulate observations from human genetics. There are several potential therapeutic modalities that can be added when applying therapeutic targets identified through human genetics to new drugs. These may include well-established therapeutic modalities such as small molecules and monoclonal antibodies, mature modalities such as oligonucleotides, and newer modalities such as gene therapy and gene editing. The choice of therapeutic modality may depend on several factors, including the location of the target (e.g., intracellular, extracellular, or secreted), the relevant tissue (e.g., liver, brain, or nervous tissue), and the relevant indication.

[0009] The fibrinogen gamma chain gene, also known as the fibrinogen gamma gene (FGG), is located on chromosome 4 and encodes the fibrinogen gamma chain (also called the FGG protein). The FGG protein may be the gamma component of fibrinogen. The FGG protein may contain 453 amino acids and have a mass of approximately 51.5 kDa. An example FGG amino acid sequence and further description of FGG are included at uniprot.org under accession number P02679 (last updated September 29, 2021).

[0010] Here, we have shown that genetic variants resulting in the inactivation of FGG confer protective associations against psychiatric and neurological phenotypes. Therefore, inhibition of FGG may serve as a therapeutic agent for the treatment of psychiatric diseases and disorders such as depressive disorders (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 disorder, as well as neurological diseases and disorders such as Alzheimer's disease, dementia, delirium, cognitive decline, vascular dementia, headache, migraine, chronic pain, fibromyalgia, chronic fatigue syndrome (e.g., myalgic encephalomyelitis (ME)), or motor neuron diseases (e.g., amyotrophic lateral sclerosis).

[0011] Disclosed herein is a composition comprising an oligonucleotide that targets FGG.When disclosed about inhibiting or targeting FGG, it is contemplated that some embodiments may include inhibiting or targeting FGG protein or FGG RNA.For example, by using the oligonucleotide described herein to inhibit or target the RNA (e.g., mRNA) encoded by FGG gene, FGG protein can be inhibited or targeted, resulting in less FGG protein being produced by translation of FGG RNA, or FGG protein can be targeted or inhibited by an oligonucleotide that binds or interacts with FGG RNA and reduces the production of FGG protein from FGG RNA.Therefore, targeting FGG can refer to the binding of FGG RNA and the reduction of FGG RNA or protein levels.The oligonucleotide can include small interfering RNA (siRNA) or antisense oligonucleotide (ASO).

[0012] Also provided herein are methods for treating mental disorders, such as psychiatric or neurological disorders or diseases, by providing or administering an oligonucleotide targeting FGG to a subject in need thereof. Administration of the oligonucleotide to the subject may improve psychiatric-related traits, such as the Montgomery-Asberg Depression Rating Scale (MADRS) (e.g., the scale ranges from 0 to 60, with higher scores indicating worsening depressive symptoms), the Hamilton Depression Rating Scale 17-item (e.g., the scale ranges from 0 to 52, with higher scores indicating worsening depressive symptoms), symptoms and signs of anxiety disorders, symptoms and signs of eating disorders, symptoms and signs of substance use disorders, symptoms and signs of post-traumatic stress disorder, symptoms and signs of bipolar disorder, symptoms and signs of schizophrenia, or symptoms and signs of psychosis. Furthermore, administration of an oligonucleotide to a subject may improve neurologically related traits such as cognitive function, amyloid plaques (e.g., accumulation) in the CNS, tau accumulation in the CNS, beta amyloid 42 (e.g., accumulation) in the CSF, tau (e.g., accumulation) in the CSF, phosphorylated tau (e.g., accumulation) in the CSF, Lewy bodies (e.g., accumulation), alpha synuclein (e.g., accumulation) in the CSF, 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.

[0013] I. Composition In some embodiments, compositions comprising oligonucleotides are disclosed herein. In some embodiments, the compositions comprise an oligonucleotide targeting FGG. In some embodiments, the compositions consist of an oligonucleotide targeting FGG. In some embodiments, the oligonucleotide reduces expression of FGG mRNA in a subject. In some embodiments, the oligonucleotide reduces expression of FGG protein in a subject. The oligonucleotide may comprise a small interfering RNA (siRNA) described herein. The oligonucleotide may comprise an antisense oligonucleotide (ASO) described herein. In some embodiments, the compositions described herein are used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to compositions comprising oligonucleotides for use in a method of treating a disorder as described herein. Some embodiments relate to the use of a composition comprising an oligonucleotide in a method of treating a disorder as described herein (e.g., a psychiatric or neurological disorder).

[0014] Some embodiments are disclosed herein as compositions comprising oligonucleotides that target FGG and, when administered to a subject in an effective amount, reduce FGG mRNA or protein levels in a cell (e.g., a hepatocyte or neuron), a body fluid (e.g., blood, serum, plasma, or cerebrospinal fluid (CSF)), a tissue (e.g., brain or liver tissue), or an organ (e.g., brain or liver).

[0015] In some embodiments, the composition comprises an oligonucleotide that targets FGG and, when administered to a subject in an effective amount, reduces FGG mRNA levels in a cell or tissue. In some embodiments, the cell is a liver cell (e.g., a hepatocyte). In some embodiments, the cell is a neuronal cell. In some embodiments, the tissue is liver tissue. In some embodiments, the tissue is neuronal tissue. In some embodiments, the neuronal tissue is CNS tissue. In some embodiments, the neuronal tissue is brain tissue (e.g., neuronal tissue, glial tissue, or endothelial tissue). In some embodiments, the body fluid is CSF. In some embodiments, FGG mRNA levels are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, FGG mRNA levels are reduced by about 10% or more compared to before administration. In some embodiments, FGG mRNA levels are reduced 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% compared to before administration. In some embodiments, the FGG mRNA level is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the FGG mRNA level is reduced by about 10% or less compared to before administration. In some embodiments, the FGG mRNA level is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, or about 90% or less compared to before administration. In some embodiments, the FGG mRNA level is reduced 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 a range defined by any two of the foregoing percentages.

[0016] In some embodiments, the composition comprises an oligonucleotide that targets FGG and, when administered to a subject in an effective amount, reduces FGG protein levels in a cell, body fluid (e.g., CSF), or tissue. In some embodiments, the cell is a liver cell. In some embodiments, the cell is a neuronal cell (e.g., a CNS cell (e.g., a 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 neuronal (e.g., CNS (e.g., brain)) tissue. In some embodiments, the body fluid is CSF. In some embodiments, FGG protein levels are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to pre-administration. In some embodiments, FGG protein levels are reduced by about 10% or more compared to pre-administration. In some embodiments, the FGG protein level is reduced 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% compared to before administration. In some embodiments, the FGG protein level is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the FGG protein level is reduced by about 10% or less compared to before administration. In some embodiments, the FGG protein level is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, or about 90% or less compared to before administration. In some embodiments, FGG protein levels are reduced 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 a range defined by any two of the foregoing percentages.

[0017] In some embodiments, the composition comprises an oligonucleotide that targets FGG and, when administered to a subject in an effective amount, reduces the phenotype of a psychiatric disorder or disease, such as a psychiatric or neurological disorder. The disorder may include a disease. The psychiatric disease or disorder may include a depressive disorder (e.g., major depressive disorder, persistent depressive disorder, treatment-resistant depression, or signs and symptoms of depression), post-traumatic stress disorder, mood disorder, anxiety disorder, eating disorder, substance use disorder, bipolar disorder, personality disorder, schizophrenia, and schizoaffective disorder. The neurological disease or disorder may include Alzheimer's disease, dementia, delirium, cognitive decline, vascular dementia, headache, migraine, chronic pain, fibromyalgia, chronic fatigue syndrome (e.g., myalgic encephalomyelitis (ME)), or motor neuron disease (e.g., amyotrophic lateral sclerosis). For psychiatric / neurological indications, fibrinogen can be reduced to a sufficient degree to have a therapeutic effect on the psychiatric disorder without significantly affecting coagulation parameters such as PT or aPTT.

[0018] In some embodiments, the composition comprises an oligonucleotide that targets FGG and, when administered to a subject in an effective amount, reduces a psychiatric phenotype. The psychiatric phenotype may include a Montgomery-Asberg Depression Rating Scale (MADRS) score. The psychiatric phenotype may include a Hamilton Depression Rating Scale score. The psychiatric phenotype may include signs or symptoms of anxiety. The psychiatric phenotype may include signs or symptoms of an eating disorder. The psychiatric phenotype may include signs or symptoms of a substance use disorder. The psychiatric phenotype may include signs or symptoms of post-traumatic stress disorder. The psychiatric phenotype may include signs or symptoms of bipolar disorder. The psychiatric phenotype may include signs or symptoms of schizophrenia. The psychiatric phenotype may include signs or symptoms of psychosis. In some embodiments, the psychiatric disorder phenotype is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the psychiatric disorder phenotype is reduced by about 10% or more compared to before administration. In some embodiments, the psychiatric disorder phenotype is reduced 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% compared to before administration. In some embodiments, the psychiatric disorder phenotype is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the psychiatric disorder phenotype is reduced by about 10% or less compared to before administration. In some embodiments, the psychiatric disorder phenotype is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, or about 90% or less compared to before administration. In some embodiments, the psychiatric disorder phenotype is reduced 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 a range defined by any two of the foregoing percentages.

[0019] In some embodiments, the composition comprises an oligonucleotide that targets FGG and, when administered to a subject in an effective amount, reduces a neurological disease phenotype. The neurological disease phenotype may include cognitive impairment. The neurological disease phenotype may include amyloid plaques in the central nervous system (CNS). The neurological disease phenotype may include tau accumulation in the CNS. The neurological disease phenotype may include beta-amyloid 42 in the cerebrospinal fluid (CSF). The neurological disease phenotype may include tau in the CSF. The neurological disease phenotype may include phosphorylated tau in the CSF. The neurological disease phenotype may include Lewy bodies. The neurological disease phenotype may include alpha-synuclein in the CSF. The neurological disease phenotype may include a symptom or sign of headache. The neurological disease phenotype may include a symptom or sign of migraine. The neurological disease phenotype may include a symptom or sign of chronic pain. The neurological disease phenotype may include symptoms or signs of fibromyalgia. The neurological disease phenotype may include symptoms or signs of chronic fatigue syndrome (e.g., myalgic encephalomyelitis). The neurological disease phenotype may include symptoms or signs of motor neuron disease (e.g., amyotrophic lateral sclerosis). In some embodiments, the neurological disease phenotype is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the neurological disease phenotype is reduced by about 10% or more compared to before administration. In some embodiments, the neurological disease phenotype is reduced 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% compared to before administration. In some embodiments, the neurological disease phenotype is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the neurological disease phenotype is reduced by about 10% or less compared to before administration, hi some embodiments, the neurological disease phenotype is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, or about 90% or less compared to before administration.In some embodiments, the neurological disease phenotype is reduced 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 a range defined by any two of the foregoing percentages.

[0020] The composition may treat coagulation disorders or blood clotting disorders. The composition may treat thrombophilia. The composition may affect coagulation or clotting time. In some embodiments, the composition comprises an oligonucleotide that reduces fibrinogen. Given that significant knockdown of FGG may lead to prolonged clotting time (e.g., PT, INR, or aPTT) in some cases, FGG siRNA compositions may be useful as anticoagulants, such as for treating or preventing blood coagulation disorders or clotting disorders (e.g., venous thromboembolism, atrial fibrillation). For blood coagulation disorders or clotting disorders, it is useful to significantly reduce fibrinogen sufficiently to prolong clotting time to clinically meaningful levels for these indications. Data are provided herein showing that administration of FGG siRNA can result in knockdown of FGG. Knockdown of FGG can result in reduced circulating fibrinogen. Reduced circulating fibrinogen can result in increased PT, INR, and aPTT. Thus, the compound may be useful for reducing coagulation. Some embodiments relate to compositions comprising oligonucleotides that target FGG and that, when administered to a subject in an effective amount, reduce fibrinogen.

[0021] In some embodiments, prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT) levels remain unchanged compared to administration. In some embodiments, PT, INR, or aPTT increases by about 10% or less compared to before administration. In some embodiments, PT, INR, or aPTT decreases by about 20% or less, about 40% or less, about 80% or less, about 160% or less, about 200% or less, about 300% or less, about 400% or less, or about 600% or less compared to before administration. In some embodiments, PT, INR, or aPTT increases by 5%, 10%, 20%, 40%, 80%, 100%, 200%, 400%, or 600%, or a range defined by any two of the aforementioned percentages.

[0022] A. siRNA In some embodiments, the composition comprises an oligonucleotide targeting FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide targeting FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0023] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, the sense strand being 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 either of the two preceding numbers. The sense strand can be 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that 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 either of the two preceding numbers. The antisense strand can be 14 to 30 nucleosides in length.

[0024] In some embodiments, compositions comprise oligonucleotides that inhibit expression of FGG, wherein the oligonucleotides comprise siRNAs comprising a sense strand and an antisense strand, each strand independently being about 12-30 nucleosides in length, and wherein at least one of the sense and antisense strands 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 substituted with uracil (U). In some embodiments, at least one of the sense and antisense strands comprises 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.

[0025] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises siRNA that comprises sense strand and antisense strand, and the sense strand and 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.

[0026] 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 defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises two 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 defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides.

[0027] 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 defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises two 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 defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides.

[0028] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the siRNA binds to a 19-mer in human FGG mRNA. In some embodiments, the siRNA binds to a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, or 25-mer in human FGG mRNA.

[0029] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, the oligonucleotide comprises an siRNA that comprises a sense strand and an antisense strand, and the siRNA binds to a 17-mer in non-human primate FGG mRNA.In some embodiments, the siRNA binds to a 12-mer, a 13-mer, a 14-mer, a 15-mer, a 16-mer, a 17-mer, a 18-mer, a 19-mer, a 20-mer, a 21-mer, a 22-mer, a 23-mer, a 24-mer or a 25-mer in non-human primate FGG mRNA.

[0030] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to human FGG mRNA and 20 or fewer human off-targets, with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human FGG mRNA and 10 or fewer human off-targets, with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human FGG mRNA and 30 or fewer human off-targets, with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human FGG mRNA and 40 or fewer human off-targets, with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human FGG mRNA and 50 or fewer human off-targets, with no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human FGG mRNA and 10 or fewer human off-targets, with no more than three mismatches in the antisense strand. In some embodiments, the siRNA binds to human FGG mRNA and 20 or fewer human off-targets, with no more than three mismatches in the antisense strand. In some embodiments, the siRNA binds to human FGG mRNA and 30 or fewer human off-targets, with no more than three mismatches in the antisense strand. In some embodiments, the siRNA binds to human FGG mRNA and 40 or fewer human off-targets, with no more than three mismatches in the antisense strand. In some embodiments, the siRNA binds to human FGG mRNA and 50 or fewer human off-targets, with no more than three mismatches in the antisense strand.

[0031] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of FGG, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, the siRNA binding to a human FGG mRNA target site that does not harbor a SNP, and the minor allele frequency (MAF) is 1% or greater (positions 2-18). In some embodiments, the MAF is about 2% or greater, about 3% or greater, about 4% or greater, about 5% or greater, about 6% or greater, about 7% or greater, about 8% or greater, about 9% or greater, about 10% or greater, about 11% or greater, about 12% or greater, about 13% or greater, about 14% or greater, about 15% or greater, about 16% or greater, about 17% or greater, about 18% or greater, about 19% or greater, or about 20% or greater.

[0032] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof with three or four 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 foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises two 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 defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof with one or two additional nucleosides at the 3' end. In some embodiments, a composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1-1742. In any of SEQ ID NOs: 1 to 1742, thymine (T) can be substituted with uracil (U).

[0033] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1743-3484, or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1743-3484, or a nucleic acid sequence thereof with three or four 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 foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises two 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 defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises one, two, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1743-3484, or a nucleic acid sequence thereof with one or two additional nucleosides at the 3' end. In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1743-3484.In any of SEQ ID NOs: 1743 to 3484, thymine (T) can be substituted with uracil (U).

[0034] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof with three or four 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 foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises two 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 defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises one, two, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof with one or two additional nucleosides at the 3' end. In some embodiments, a composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the sense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3713-3748.In any of SEQ ID NOs: 3713 to 3748, thymine (T) can be substituted with uracil (U).

[0035] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3749-3784, or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3749-3784, or a nucleic acid sequence thereof with three or four 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 foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range defined by any two of the foregoing numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises two 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 defined by any two of the foregoing numbers. In some embodiments, the 5' overhang comprises one, two, or more nucleosides. In some embodiments, the 5' overhang comprises two nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3749-3784, or a nucleic acid sequence thereof with one or two additional nucleosides at the 3' end. In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the antisense strand comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 3749-3784.In any of SEQ ID NOs: 3749 to 3784, thymine (T) can be substituted with uracil (U).

[0036] In some embodiments, the sense strand and / or antisense strand comprises a nucleoside sequence that is 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 the sequence of the sense strand and / or antisense strand of any of Tables 3-7. In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of any of the siRNAs in Tables 3-7, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of any of the siRNAs in Tables 3-7, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of any of the siRNAs in Tables 3-7. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) FGG mRNA. The siRNA may contain one or more internucleoside linkages and / or one or more nucleoside modifications.

[0037] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset A, or a nucleic acid sequence thereof having a substitution, addition, or deletion of three or four nucleosides. In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset A, or a nucleic acid sequence thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset A. The siRNA may contain one or more internucleoside linkages and / or one or more nucleoside modifications.

[0038] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset B, or a nucleic acid sequence thereof having a substitution, addition, or deletion of three or four nucleosides. In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset B, or a nucleic acid sequence thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset B. The siRNA may contain one or more internucleoside linkages and / or one or more nucleoside modifications.

[0039] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset C, or a nucleic acid sequence thereof having a substitution, addition, or deletion of three or four nucleosides. In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset C, or a nucleic acid sequence thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset C. The siRNA may contain one or more internucleoside linkages and / or one or more nucleoside modifications.

[0040] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset D, or a nucleic acid sequence thereof having a substitution, addition, or deletion of three or four nucleosides. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset D, or a nucleic acid sequence thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset D. The siRNA may contain one or more internucleoside linkages and / or one or more nucleoside modifications.

[0041] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset E, or a nucleic acid sequence thereof with a substitution, addition, or deletion of three or four nucleosides. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset E, or a nucleic acid sequence thereof with a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset E. The siRNA may contain one or more internucleoside linkages and / or one or more nucleoside modifications.

[0042] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset G, or a nucleic acid sequence thereof having a substitution, addition, or deletion of three or four nucleosides. In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset G, or a nucleic acid sequence thereof having a substitution, addition, or deletion of one or two nucleosides. In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of an siRNA of subset G. The siRNA may contain one or more internucleoside linkages and / or one or more nucleoside modifications.

[0043] In some embodiments, the sense strand comprises a nucleoside sequence that is 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, or 1278. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 352, 1003, 1011, or 1278, or a sense strand sequence thereof with one or two 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, or 1278, and three or four 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, or 1278. The sense strand can comprise any internucleoside bond or nucleoside modification described herein.The sense strand can comprise an overhang (for example, two bases at the 5' or 3' end when paired with the antisense strand).The sense strand can comprise a GalNAc moiety connected at one end (for example, the 5' end).

[0044] 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 its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 352 and three or four 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 linkage or nucleoside modification described herein. The sense strand may include an overhang (e.g., two bases at the 5' or 3' end when paired with the antisense strand). The sense strand may include a GalNAc moiety attached at one of its ends (e.g., the 5' end).

[0045] In some embodiments, the sense strand comprises a nucleoside sequence that is 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 its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003 and three or four 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 linkage or nucleoside modification described herein. The sense strand may include an overhang (e.g., two bases at the 5' or 3' end when paired with the antisense strand). The sense strand may include a GalNAc moiety attached at one of the ends (e.g., the 5' end).

[0046] 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 its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011 and three or four 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 linkage or nucleoside modification described herein. The sense strand may include an overhang (e.g., two bases at the 5' or 3' end when paired with the antisense strand). The sense strand may include a GalNAc moiety attached at one of the ends (e.g., the 5' end).

[0047] 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 its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278 and three or four 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 linkage or nucleoside modification described herein. The sense strand may include an overhang (e.g., two bases at the 5' or 3' end when paired with the antisense strand). The sense strand may include a GalNAc moiety attached at one of the ends (e.g., the 5' end).

[0048] In some embodiments, the antisense strand comprises a nucleoside sequence that is 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 with one or two 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 three or four 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. Antisense strand can comprise any internucleoside bond or nucleoside modification described herein.Antisense strand can comprise overhang (for example, two bases at the 5' or 3' end when paired with sense strand).Antisense strand can comprise a GalNAc moiety connected at one end (for example, 5' or 3' end).

[0049] 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 its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094. The antisense strand may comprise any internucleoside linkage or nucleoside modification described herein. The antisense strand may comprise an overhang (e.g., two bases at the 5' or 3' end when paired with the sense strand). The sense strand may comprise a GalNAc moiety attached at one of the ends.

[0050] 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 its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745. The antisense strand may comprise any internucleoside linkage or nucleoside modification described herein. The antisense strand may comprise an overhang (e.g., two bases at the 5' or 3' end when paired with the sense strand). The sense strand may comprise a GalNAc moiety attached at one of its termini.

[0051] 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 its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753. The antisense strand may comprise any internucleoside linkage or nucleoside modification described herein. The antisense strand may comprise an overhang (e.g., two bases at the 5' or 3' end when paired with the sense strand). The sense strand may comprise a GalNAc moiety attached at one of the ends.

[0052] 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 its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020. The antisense strand may comprise any internucleoside linkage or nucleoside modification described herein. The antisense strand may comprise an overhang (e.g., two bases at the 5' or 3' end when paired with the sense strand). The sense strand may comprise a GalNAc moiety attached at one of the ends.

[0053] In some embodiments, the sense strand comprises a nucleoside sequence that is 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 with one or two 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 three or four 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 can comprise any internucleoside bond or nucleoside modification described herein.The sense strand can comprise an overhang (for example, two bases at the 5' or 3' end when paired with the antisense strand).The sense strand can comprise a GalNAc moiety connected at one end (for example, the 5' end).

[0054] 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 its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3723 and three or four 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 linkage or nucleoside modification described herein. The sense strand may include an overhang (e.g., two bases at the 5' or 3' end when paired with the antisense strand). The sense strand may include a GalNAc moiety attached at one of the ends (e.g., the 5' end).

[0055] 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 its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724. The sense strand may include any internucleoside linkage or nucleoside modification described herein. The sense strand may include an overhang (e.g., two bases at the 5' or 3' end when paired with the antisense strand). The sense strand may include a GalNAc moiety attached at one of the ends (e.g., the 5' end).

[0056] 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 its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726 and three or four 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 linkage or nucleoside modification described herein. The sense strand may include an overhang (e.g., two bases at the 5' or 3' end when paired with the antisense strand). The sense strand may include a GalNAc moiety attached at one of the ends (e.g., the 5' end).

[0057] 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 its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747 and three or four 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 linkage or nucleoside modification described herein. The sense strand may include an overhang (e.g., two bases at the 5' or 3' end when paired with the antisense strand). The sense strand may include a GalNAc moiety attached at one of the ends (e.g., the 5' end).

[0058] In some embodiments, the antisense strand comprises a nucleoside sequence that is 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, or 3783. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3759, 3760, 3762, or 3783, or an antisense strand sequence thereof with one or two 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, or 3783, and three or four 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, or 3783. Antisense strand can comprise any internucleoside bond or nucleoside modification described herein.Antisense strand can comprise overhang (for example, two bases at the 5' or 3' end when paired with sense strand).Antisense strand can comprise a GalNAc moiety connected at one end (for example, 5' or 3' end).

[0059] 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 its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759. The antisense strand may comprise any internucleoside linkage or nucleoside modification described herein. The antisense strand may comprise an overhang (e.g., two bases at the 5' or 3' end when paired with the sense strand). The sense strand may comprise a GalNAc moiety attached at one of its termini.

[0060] 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 its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760. The antisense strand may comprise any internucleoside linkage or nucleoside modification described herein. The antisense strand may comprise an overhang (e.g., two bases at the 5' or 3' end when paired with the sense strand). The sense strand may comprise a GalNAc moiety attached at one of the ends.

[0061] 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 its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762. The antisense strand may comprise any internucleoside linkage or nucleoside modification described herein. The antisense strand may comprise an overhang (e.g., two bases at the 5' or 3' end when paired with the sense strand). The sense strand may comprise a GalNAc moiety attached at one of its termini.

[0062] In some embodiments, the antisense strand comprises a nucleoside sequence that is 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 its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783. The antisense strand may comprise any internucleoside linkage or nucleoside modification described herein. The antisense strand may comprise an overhang (e.g., two bases at the 5' or 3' end when paired with the sense strand). The sense strand may comprise a GalNAc moiety attached at one of its termini.

[0063] B.ASO In some embodiments, the composition comprises an oligonucleotide that inhibits 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 either of the two preceding numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0064] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises an ASO of about 12-30 nucleosides in length and comprises 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 modified nucleosides and / or modified internucleoside linkage modifications, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprises 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.

[0065] C. Modification Pattern In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises modifications including modified nucleosides and / or modified internucleoside linkages. In some embodiments, the oligonucleotide comprises modified internucleoside linkages. In some embodiments, the modified internucleoside linkages comprise alkyl phosphonates, phosphorothioates, methyl phosphonates, phosphorodithioates, alkyl phosphonothioates, phosphoramidates, carbamates, carbonates, phosphate triesters, acetamidates, or carboxymethyl esters, or combinations thereof. In some embodiments, the modified internucleoside linkages comprise one or more phosphorothioate linkages. Phosphorothioates may contain a non-bridging oxygen atom in the phosphate backbone of the oligonucleotide substituted with sulfur. Modified internucleoside linkages can be included in siRNAs or ASOs. Benefits of modified internucleoside linkages can include reduced toxicity or improved pharmacokinetics.

[0066] In some embodiments, a composition comprises an oligonucleotide that inhibits 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 defined by any two of the foregoing numbers. In some embodiments, the oligonucleotide comprises 18 or fewer modified internucleoside linkages. In some embodiments, the oligonucleotide comprises 20 or fewer modified internucleoside linkages. In some embodiments, the oligonucleotide has 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, 20 or more modified internucleoside linkages, 21 or more modified internucleoside linkages, 22 or more modified internucleoside linkages, 23 or more modified internucleoside linkages, 24 or more modified internucleoside linkages, 25 or more modified internucleoside linkages, 26 or more modified internucleoside linkages, 27 or more modified internucleoside linkages, 28 or more modified internucleoside linkages, 29 or more modified internucleoside linkages, 30 or more modified internucleoside linkages, 31 or more modified internucleoside linkages, 32 or more modified internucleoside linkages, 33 or more modified internucleoside linkages, 34 or more modified internucleoside linkages, 35 or more modified internucleoside linkages, 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.

[0067] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), a hexitol nucleic acid (HLA), a cyclohexene nucleic acid (CeNA), a 2'-methoxyethyl, a 2'-O-alkyl, a 2'-O-allyl, a 2'-fluoro, or a 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2',4'-constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises an HLA. In some embodiments, the modified nucleoside comprises a CeNA. In some embodiments, the modified nucleoside comprises a 2'-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl group. In some embodiments, the modified nucleoside comprises a 2'-O-allyl group. In some embodiments, the modified nucleoside comprises a 2'-fluoro group. In some embodiments, the modified nucleoside comprises a 2'-deoxy group. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside, a 2'-deoxyfluoro nucleoside, a 2'-ON-methylacetamide (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, a 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. Advantages of modified nucleosides may include reduced toxicity or improved pharmacokinetics.

[0068] In some embodiments, the oligonucleotide contains 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 defined by any two of the foregoing numbers. In some embodiments, the oligonucleotide contains 19 or fewer modified nucleosides. In some embodiments, the oligonucleotide contains 21 or fewer modified nucleosides. In some embodiments, the oligonucleotide comprises two or more modified nucleosides, three or more modified nucleosides, four or more modified nucleosides, five or more modified nucleosides, six or more modified nucleosides, seven or more modified nucleosides, eight or more modified nucleosides, nine or more modified nucleosides, ten or more modified nucleosides, eleven or more modified nucleosides, twelve or more modified nucleosides, thirteen or more modified nucleosides, fourteen or more modified nucleosides, fifteen or more modified nucleosides, sixteen or more modified nucleosides, seventeen or more modified nucleosides, eighteen or more modified nucleosides, nineteen or more modified nucleosides, twenty or more modified nucleosides, or twenty one or more modified nucleosides.

[0069] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises a moiety attached at the 3' or 5' end of the oligonucleotide. Examples of the moiety 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 at the 5' end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached at the 3' end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached at the 5' end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached at the 3' end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached at the 5' end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached at the 3' end of the ASO.

[0070] 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 the 3' or 5' end of the oligonucleotide. The hydrophobic moiety may comprise a lipid such as a fatty acid. The hydrophobic moiety may comprise a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be nonlinear. The hydrophobic moiety may comprise a lipid moiety or a cholesterol moiety, or a combination thereof.

[0071] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises a lipid attached at the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmitylstearyl, or α-tocopherol, or a combination thereof.

[0072] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may comprise an N-acetylgalactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetylglucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may comprise one, two, three, or more sugar molecules. The sugar moiety may be attached at the 3' or 5' end of the oligonucleotide. The sugar moiety may comprise an N-acetylgalactose moiety. The sugar moiety may comprise an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may comprise an N-acetylglucose moiety. The sugar moiety may comprise an N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may comprise a fucose moiety. The sugar moiety may comprise a mannose moiety. N-acetylglucose, GlcNAc, fucose, or mannose may be beneficial in targeting macrophages because they may target or bind to mannose receptors such as CD206.

[0073] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc can be beneficial for targeting hepatocytes, nerves (e.g., CNS (e.g., brain)), or CSF. The GalNAc moiety can comprise one, two, three, or more GalNAc molecules. The GalNAc moiety can be attached to the 3' or 5' end of the oligonucleotide.

[0074] Non-limiting examples of GalNAc ligands are shown in Figures 1 and 2. In some embodiments, an oligonucleotide is conjugated to the GalNAc ligand of Figure 1. In the GalNAc ligand shown in Figure 1, J indicates the point of attachment to the oligonucleotide. In some embodiments, J is at the 5' end of the oligonucleotide. In some embodiments, J is at the 3' end of the oligonucleotide. In the GalNAc ligand shown in Figure 1, n can be any number. For example, n can be 1 to 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 foregoing integers. In some embodiments, n is 2. In embodiments where n is 2 and the oligonucleotide is connected at J, the GalNAc moiety can be referred to as "GalNAc#1" or "GalNAc1."

[0075] In some embodiments, the oligonucleotide is conjugated to the GalNAc ligand of Figure 2. The wavy line in Figure 1 indicates the point of attachment to the oligonucleotide. In some embodiments, the wavy line is at the 5' end of the oligonucleotide. In some embodiments, the wavy line is at the 3' end of the oligonucleotide. In embodiments where the oligonucleotide is connected by a wavy line, the GalNAc moiety may be referred to as "GalNAc#23" or "GalNAc23."

[0076] The oligonucleotide may contain purines. Examples of purines include adenine (A) or guanine (G), or modified versions thereof. The oligonucleotide may contain pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0077] In some embodiments, the purines of the oligonucleotide comprise 2'-fluoro modified purines. In some embodiments, the purines of the oligonucleotide comprise 2'-O-methyl modified purines. In some embodiments, the 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 can include 2'-O-methyl. Where a 2'-O-methyl modification is described, it is contemplated that a 2'-methyl modification can be included, and vice versa.

[0078] In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines. In some embodiments, the 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.

[0079] In some embodiments, the purines of the oligonucleotide comprise 2'-fluoro modified purines and the pyrimidines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the oligonucleotide comprise 2'-O-methyl modified purines and the pyrimidines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the oligonucleotide comprise 2'-fluoro modified purines and the pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the oligonucleotide comprise 2'-O-methyl modified purines and the pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-fluoro modified pyrimidines and the purines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines and the purines of the oligonucleotide comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-fluoro-modified pyrimidines and the purines of the oligonucleotide comprise 2'-O-methyl-modified purines. In some embodiments, the pyrimidines of the oligonucleotide comprise 2'-O-methyl-modified pyrimidines and the purines of the oligonucleotide comprise 2'-fluoro-modified purines.

[0080] 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.

[0081] In some cases, the oligonucleotide comprises a specific modification pattern. In some embodiments, position 9, counting from the 5' end of the oligonucleotide chain, may have a 2'F modification. In some embodiments, if position 9 of the oligonucleotide chain is a pyrimidine, all purines in the oligonucleotide chain have a 2'OMe modification. In some embodiments, if position 9 is the only pyrimidine between positions 5 and 11 of the sense strand, position 9 is the only position in the oligonucleotide chain that has a 2'F modification. In some embodiments, if position 9 of the oligonucleotide chain and one other base between positions 5 and 11 are pyrimidines, both of these pyrimidines are the only two positions in the oligonucleotide chain that have a 2'F modification. In some embodiments, if position 9 of the oligonucleotide chain and two other bases between positions 5 and 11 are pyrimidines, and these two other pyrimidines are adjacent positions, so that there are no three 2'F modifications in a row, any combination of 2'F modifications can be made to give a total of three 2'F modifications. In some embodiments, if there are more than two pyrimidines between positions 5 and 11 of an oligonucleotide strand, all combinations of pyrimidines with 2'F modifications are possible, with a total of 3-5 2'F modifications, provided that no oligonucleotide strand has three 2'F modifications in a row. In some cases, either oligonucleotide strand of the siRNA contains a modification pattern that conforms to any or all of these strands of the oligonucleotide rules.

[0082] In some embodiments, if position 9 of an oligonucleotide strand is a purine, all purines in the oligonucleotide strand have a 2'OMe modification. In some embodiments, if position 9 is the only purine between positions 5 and 11 of the sense strand, position 9 is the only position in the oligonucleotide strand with a 2'F modification. In some embodiments, if position 9 and one other base between positions 5 and 11 of an oligonucleotide strand are the only purines, both of these purines are the only two positions in the oligonucleotide strand with a 2'F modification. In some embodiments, if position 9 and two other bases between positions 5 and 11 of an oligonucleotide strand are the only purines, and these two other purines are adjacent positions, so there are no three 2'F modifications in a row, any combination of 2'F modifications that results in a total of three 2'F modifications can be made. In some embodiments, if there are more than two purines between positions 5 and 11 of an oligonucleotide strand, all combinations of purines with 2'F modifications with a total of three to five 2'F modifications are possible, provided that there are no three 2'F modifications in a row in the oligonucleotide strand. In some cases, either oligonucleotide strand of the siRNA contains a modification pattern that conforms to any or all of these strands of the oligonucleotide rules.

[0083] In some cases, the 9th position of the oligonucleotide chain can be 2'deoxy.In these cases, 2'F and 2'OMe modifications can occur at other positions of the oligonucleotide chain.In some cases, any oligonucleotide chain of siRNA comprises the modification pattern that conforms to these chains of oligonucleotide rules.

[0084] In some embodiments, position 9 of the sense strand contains a 2'-fluoro-modified pyrimidine. In some embodiments, all purines in the sense strand contain 2'-O-methyl-modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 contain 2'-fluoro-modified pyrimidines, provided that there are not three 2'-fluoro-modified pyrimidines in a row. In some embodiments, odd-numbered positions of the antisense strand contain 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand contain 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand contain 2'-fluoro-modified nucleotides, 2'-O-methyl-modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position 9 of the sense strand comprises a 2'-fluoro-modified pyrimidine, all purines of the sense strand comprise 2'-O-methyl-modified purines, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise 2'-fluoro-modified pyrimidines, provided that there are not three 2'-fluoro-modified pyrimidines in a row, odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides, and even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0085] In some embodiments, position 9 of the sense strand contains a 2'-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand contain 2'-O-methyl-modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 contain 2'-fluoro-modified purines, provided that there are not three 2'-fluoro-modified purines in a row. In some embodiments, odd-numbered positions of the antisense strand contain 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand contain 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand contain 2'-fluoro-modified nucleotides, 2'-O-methyl-modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position 9 of the sense strand comprises a 2'-fluoro-modified purine, all pyrimidines of the sense strand comprise 2'-O-methyl-modified purines, and 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise 2'-fluoro-modified purines, provided that there are no three 2'-fluoro-modified purines in a row; odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides; and even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are no three 2'-fluoro-modified purines in a row. In some embodiments, there are no three 2'-fluoro-modified pyrimidines in a row.

[0086] In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2'-fluoro-modified nucleotides. In some embodiments, all pyrimidines at positions 10-21 of the sense strand comprise 2'-O-methyl-modified pyrimidines, and all purines at positions 10-21 of the sense strand comprise 2'-O-methyl-modified purines or 2'-fluoro-modified purines. In some embodiments, odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides, 2'-O-methyl-modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide, positions 5, 7, and 8 of the sense strand comprise 2'-fluoro-modified nucleotides, all pyrimidines at positions 10-21 of the sense strand comprise 2'-O-methyl-modified pyrimidines and all purines at positions 10-21 comprise 2'-O-methyl-modified purines or 2'-fluoro-modified purines, odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides, and even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0087] In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2'-fluoro-modified nucleotides. In some embodiments, all purines at positions 10-21 of the sense strand comprise 2'-O-methyl-modified purines, and all pyrimidines at positions 10-21 comprise 2'-O-methyl-modified pyrimidines or 2'-fluoro-modified pyrimidines. In some embodiments, odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides, 2'-O-methyl-modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide, positions 5, 7, and 8 of the sense strand comprise 2'-fluoro-modified nucleotides, all purines at positions 10-21 of the sense strand comprise 2'-O-methyl-modified purines and all pyrimidines at positions 10-21 comprise 2'-O-methyl-modified pyrimidines or 2'-fluoro-modified pyrimidines, odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides, and even-numbered positions of the antisense strand comprise 2'-fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0088] In some embodiments, the moiety comprises a negatively charged group attached to the 5' end of the oligonucleotide. This may be referred to as a 5'-terminal group. In some embodiments, the negatively charged group is attached to the 5' end of the antisense strand of the siRNA disclosed herein. The 5'-terminal group may be or include 5'-terminal phosphorothioate, 5'-terminal phosphorodithioate, 5'-terminal vinylphosphonate (5'-VP), 5'-terminal methylphosphonate, 5'-terminal cyclopropylphosphonate, or 5'-deoxy-5'-C-malonyl. The 5'-terminal group may include 5'-VP. In some embodiments, the 5'-VP includes trans-vinyl phosphate or cis-vinyl phosphate. The 5'-terminal group may include an extra 5' phosphate. A combination of 5'-terminal groups may be used.

[0089] In some embodiments, the oligonucleotide comprises a negatively charged group. The negatively charged group can aid in cell or tissue penetration. The negatively charged group can be attached to the 5' or 3' end (e.g., the 5' end) of the oligonucleotide. This can be referred to as a terminal group. The terminal group can be or include phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropylphosphonate, or deoxy-C-malonyl. The terminal group can include an extra 5' phosphate, for example, an extra 5' phosphate. A combination of terminal groups can be used.

[0090] In some embodiments, the oligonucleotide comprises a phosphomimetic. In some embodiments, the phosphomimetic comprises a vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises trans-vinyl phosphate. In some embodiments, the vinyl phosphonate comprises cis-vinyl phosphate. Examples of nucleotides that contain vinyl phosphonates are shown below.

[0091] [ka]

[0092] In some embodiments, vinyl phosphonates increase the stability of oligonucleotides. In some embodiments, vinyl phosphonates increase the accumulation of oligonucleotides in tissues. In some embodiments, vinyl phosphonates protect oligonucleotides from exonucleases or phosphatases. In some embodiments, vinyl phosphonates improve the binding affinity of oligonucleotides to siRNA processing machinery.

[0093] In some embodiments, the oligonucleotide comprises one vinyl phosphonate. In some embodiments, the oligonucleotide comprises two vinyl phosphonates. In some embodiments, the oligonucleotide comprises three vinyl phosphonates. In some embodiments, the oligonucleotide comprises four 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.

[0094] 1.Hydrophobic part 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 the 3' or 5' end of the oligonucleotide. The hydrophobic moiety may comprise a lipid such as a fatty acid. The hydrophobic moiety may comprise a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be nonlinear. The hydrophobic moiety may comprise a lipid moiety or a cholesterol moiety, or a combination thereof.

[0095] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises a lipid attached at the 3' or 5' end 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.

[0096] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises a hydrophobic ligand or hydrophobic moiety. In some embodiments, the hydrophobic ligand or hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or hydrophobic moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or hydrophobic moiety is attached at the 3' end of the oligonucleotide. In some embodiments, the hydrophobic ligand or hydrophobic moiety is attached at the 5' end of the oligonucleotide. In some embodiments, the composition comprises a sense strand, wherein the hydrophobic ligand or hydrophobic moiety is attached to the sense strand (e.g., attached to the 5' end of the sense strand or attached to the 3' end of the sense strand). In some embodiments, the composition comprises an antisense strand, wherein the hydrophobic ligand or hydrophobic moiety is attached to the antisense strand (e.g., attached to the 5' end of the antisense strand or attached to the 3' end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or hydrophobic moiety attached to the 3' end or 5' end of the oligonucleotide.

[0097] In some embodiments, the hydrophobic moiety is attached to the oligonucleotide (e.g., the sense strand and / or antisense strand of an siRNA). In some embodiments, the hydrophobic moiety is attached at the 3' end of the oligonucleotide. In some embodiments, the hydrophobic moiety is attached at the 5' end of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety comprises cyclohexanyl.

[0098] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises a lipid attached at the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid is attached at the 3' end of the oligonucleotide. In some embodiments, the lipid is attached at the 5' end 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, docosahexaenoyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid comprises 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.

[0099] In some embodiments, the oligonucleotide comprises aspects of any of the following structures:

[0100] [ka] In some embodiments, the oligonucleotide comprises aspects of any of the following structures:

[0101] [ka] In some embodiments, the oligonucleotide comprises aspects of any of the following structures:

[0102] [ka] In some embodiments, the oligonucleotide comprises any of the following structural features. The oligonucleotide may comprise the entire structure or a lipid portion 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 preceding numbers. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid portion comprises an alcohol or ether.

[0103] In some embodiments, the lipid comprises a fatty acid. In some embodiments, the lipid comprises a lipid shown in Table 1. The exemplary lipid moieties in Table 1 are shown attached at the 5' end of the oligonucleotide, with the 5' terminal phosphate of the oligonucleotide shown with the lipid moiety. In some embodiments, the lipid moieties in Table 1 can be attached at attachment points other than those shown. For example, the attachment point of any of the lipid moieties in the table can be at the 3' end of the oligonucleotide. In some embodiments, lipids are used to target oligonucleotides to non-hepatic cells or non-hepatic tissues.

[0104] [Table 1-1]

[0105] [Table 1-2]

[0106] [Table 1-3]

[0107] In some embodiments, the lipid or lipid moiety contains 16-18 carbons. In some embodiments, the lipid contains 16 carbons. In some embodiments, the lipid contains 17 carbons. In some embodiments, the lipid contains 18 carbons. In some embodiments, the lipid moiety contains 16 carbons. In some embodiments, the lipid moiety contains 17 carbons. In some embodiments, the lipid moiety contains 18 carbons.

[0108] The hydrophobic portion may include a linker comprising a carbocycle. The carbocycle may be six-membered. Some examples of carbocycles include phenyl or cyclohexyl. The linker may include phenyl. The linker may include cyclohexyl. The lipid may be attached to the carbocycle, which may then be attached to a phosphate (e.g., the 5' or 3' phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon and the end of the sense strand are connected to the phenyl or cyclohexyl linker in a 1,4, 1,3, or 1,2 substitution pattern (e.g., para-, meta-, or ortho-phenyl configuration). In some embodiments, the lipid or hydrocarbon and the end of the sense strand are connected to the phenyl or cyclohexyl linker in a 1,4 substitution pattern (e.g., para-phenyl configuration). The lipid may be attached to the carbocycle in a 1,4 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in a 1,3 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in a 1,2 substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in an ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in a para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in a meta orientation relative to the oligonucleotide.

[0109] The lipid portion has the following structure:

[0110] [ka] In some embodiments, the lipid moiety may comprise or consist of the structure:

[0111] [ka] In some embodiments, the lipid moiety comprises or consists of the structure:

[0112] [ka] In some embodiments, the lipid moiety comprises the structure

[0113] [ka] or consists of the above structure. In some embodiments, the dotted line represents a covalent bond. The covalent bond can be between the ends of the sense strand or the antisense strand. For example, the bond can be to the 5' end of the sense strand. In some embodiments, n is 0 to 3. In some embodiments, n is 1 to 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 foregoing numbers. In some embodiments, R comprises or consists of an alkyl group containing 4 to 18 carbons.

[0114] The lipid moiety can be attached at the 5' end of the oligonucleotide. The 5' end can have one phosphate attaching the lipid moiety to the 5' carbon of the oligonucleotide sugar. The 5' end can have two phosphates attaching the lipid moiety to the 5' carbon of the oligonucleotide sugar. The 5' end can have three phosphates attaching the lipid moiety to the 5' carbon of the oligonucleotide sugar. The 5' end can have one phosphate attached to the 5' carbon of the oligonucleotide sugar, where one phosphate is attached to the lipid moiety. The 5' end can have two phosphates attached to the 5' carbon of the oligonucleotide sugar, where one of the two phosphates is attached to the lipid moiety. The 5' end can have three phosphates attached to the 5' carbon of the oligonucleotide sugar, where one of the three phosphates is attached to the lipid moiety. The sugar can include ribose. The sugar can include deoxyribose. The sugar can be modified, such as a 2'-modified sugar (e.g., 2'O-methyl or 2'fluororibose). The 5'-terminal phosphate may contain modifications such as sulfur instead of oxygen, the two 5'-terminal phosphates may contain modifications such as sulfur instead of oxygen, and the three 5'-terminal phosphates may contain modifications such as sulfur instead of oxygen.

[0115] In some embodiments, the oligonucleotide comprises one lipid moiety. In some embodiments, the oligonucleotide comprises two lipid moieties. In some embodiments, the oligonucleotide comprises three lipid moieties. In some embodiments, the oligonucleotide comprises four lipid moieties.

[0116] Some embodiments relate to a method for producing oligonucleotides that contain hydrophobic conjugates.The strategy for producing hydrophobic conjugates can include the use of phosphoramidite reagents based on 6-membered alcohols such as phenol or cyclohexanol.The phosphoramidite can be reacted with nucleotide to connect the nucleotide to hydrophobic moiety, thereby producing hydrophobic conjugates.Some examples of phosphoramidite reagents that can be used to produce hydrophobic conjugates are provided as follows:

[0117] [ka] In some embodiments, n is 1 to 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 foregoing numbers. In some embodiments, R comprises or consists of an alkyl group containing 4 to 18 carbons. Any one of the phosphoramidite reagents can be reacted with the 5' end of an oligonucleotide to generate an oligonucleotide containing a hydrophobic moiety. In some embodiments, the phosphoramidite reagent is reacted with the 5' end of the sense strand of the siRNA. Then, sense strand can be hybridized with antisense strand to form double strand.Hybridization can be carried out by incubating sense strand and antisense strand in solution at a predetermined temperature.The temperature can be gradually lowered.The temperature can include or include the temperature that includes the annealing temperature of sense strand and antisense strand.The temperature can include or include the temperature that is lower than the annealing temperature of sense strand and antisense strand.The temperature can be lower than the melting temperature of sense strand and antisense strand.

[0118] The lipid may be attached to the oligonucleotide by a linker, which may comprise polyethylene glycol (e.g., tetraethylene glycol).

[0119] The modifications described herein can be useful for delivery to cells or tissues, for example, extrahepatic delivery or targeting of oligonucleotide compositions. The modifications described herein can be useful for targeting oligonucleotide compositions to cells or tissues.

[0120] 2.Sugar part In some embodiments, a composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may comprise an N-acetylgalactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetylglucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may comprise one, two, three, or more sugar molecules. The sugar moiety may be attached at the 3' or 5' end of the oligonucleotide. The sugar moiety may comprise an N-acetylgalactose moiety. The sugar moiety may comprise an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may comprise an N-acetylglucose moiety. The sugar moiety may comprise an N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may comprise a fucose moiety. The sugar moiety may comprise a mannose moiety. N-acetylglucose, GlcNAc, fucose, or mannose can be useful for targeting macrophages when they target or bind to mannose receptors such as CD206. The sugar moiety can be useful for binding to or targeting asialoglycoprotein receptors, such as the asialoglycoprotein receptor on hepatocytes. The GalNAc moiety can bind to the asialoglycoprotein receptor. The GalNAc moiety can target hepatocytes.

[0121] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, and the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc can be useful for hepatocyte targeting. The GalNAc moiety can comprise a bivalent or trivalent branched linker. The oligo can be linked to one, two, or three GalNAc molecules via a bivalent or trivalent branched linker. The GalNAc moiety can comprise one, two, three, or more GalNAc molecules. The GalNAc moiety can be linked to the 3' or 5' end of the oligonucleotide.

[0122] In some embodiments, the composition comprises an oligonucleotide that inhibits 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 to the 3' end of the oligonucleotide. In some embodiments, the GalNAc ligand is attached to the 5' end of the oligonucleotide. In some embodiments, the composition comprises a sense strand, wherein the GalNAc ligand is attached to the sense strand (e.g., attached to the 5' end of the sense strand or attached to the 3' end of the sense strand). In some embodiments, the composition comprises an antisense strand, wherein the GalNAc ligand is attached to the antisense strand (e.g., attached to the 5' end of the antisense strand or attached to the 3' end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached at the 3' or 5' end of the oligonucleotide.

[0123] In some embodiments, a composition comprising an oligonucleotide that inhibits expression of FGG is disclosed herein, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety can be comprised in any of the formulas, structures, or GalNAc moieties shown below. In some embodiments, the composition comprises an oligonucleotide represented by formula (I) or (II):

[0124] [ka] or a salt thereof, wherein: 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 between 1 and 20, m is selected from any value between 1 and 20, z is selected from any value between 1 and 3, when z is 3, Y is C; If z is 2, Y is CR 6 and When z is 1, Y is C(R 6 )2, Q is Halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R7)2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 , and C 1-6 C optionally substituted with one or more substituents independently selected from alkyl 3-10 Carbocyclic rings (where C 1-6 The alkyl is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO2, and —NH2. is selected from R 1 teeth, -O-, -S-, -N(R7 )-, -C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 )C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 )2)NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 )2)O-, -OP(OR 7 )N(R 7 )-, and -OPN(R 7 )2NR 7 - is a linker selected from R 2 are respectively, Halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR7 , -OC(O)R 7 , and -S(O)R 7 C optionally substituted with one or more substituents independently selected from 1-6 Alkyl are independently selected from R 3 and R 4 are respectively, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 are independently selected from R 5 are respectively, -OC(O)R 7 , -OC(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)R 7 , -C(O)OR 7 , and -C(O)N(R 7 )2 are independently selected from R 6 are respectively, hydrogen, Halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 , and Halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 C optionally substituted with one or more substituents independently selected from 1-6 Alkyl are independently selected from R 7 are respectively, hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl (each of which is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 10-membered heterocycle; and C 3-10Carbocycles and 3- to 10-membered heterocycles (each of which is selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic rings, 3- to 10-membered heterocyclic rings, and C 1-6 and optionally substituted with one or more substituents independently selected from haloalkyl. are independently selected from

[0125] In some embodiments, each w is independently selected from any value between 1 and 10. In some embodiments, each w is independently selected from any value between 1 and 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value between 1 and 10. In some embodiments, each v is independently selected from any value between 1 and 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value between 1 and 10. In some embodiments, n is selected from any value between 1 and 5. In some embodiments, n is 2. In some embodiments, m is selected from any value between 1 and 10. In some embodiments, m is selected from any value between 1 and 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 halogen, —CN, —NO2, —OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 C optionally substituted with one or more substituents independently selected from 5-6 In some embodiments, Q is a C optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, and —NH. 5-6 In some embodiments, Q is selected from carbocycle. 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, R 1 is -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 )2)NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 )2)O-, -OP(OR 7 )N(R 7 )-, and -OPN(R 7 )2-NR 7 In some embodiments, R 1 is -OP(O)(OR 7)O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, and -OP(OR 7 )O-. In some embodiments, R 1 is -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, and -OP(OR 7 )O-. In some embodiments, R 1 is -OP(O)(OR 7 )O- and -OP(OR 7 )O-. In some embodiments, R 2 is halogen, -OR 7 , -OC(O)R 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , and -S(O)R 7 C substituted with one or more substituents independently selected from 1-3 In some embodiments, R 2 -OR 7 , -OC(O)R 7 , -SR 7 , and -N(R 7 C substituted with one or more substituents independently selected from 1-3 In some embodiments, R 2 -OR 7 and -OC(O)R 7 C substituted with one or more substituents independently selected from1-3 In some embodiments, R 3 is halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -OC(O)R 7 , and -S(O)R 7 In some embodiments, R 3 -OR 7 -SR 7 , -OC(O)R 7 , and -N(R 7 In some embodiments, R 3 -OR 7 - and -OC(O)R 7 In some embodiments, R 4 is halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -OC(O)R 7 , and -S(O)R 7 In some embodiments, R 4 -OR 7 -SR 7 , -OC(O)R 7 , and -N(R 7 In some embodiments, R 4 -OR 7 - and -OC(O)R 7 In some embodiments, R 5 is -OC(O)R 7 , -OC(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, and -N(R 7 )C(O)OR 7 In some embodiments, R 5 is -OC(O)R 7 and -N(R 7)C(O)R 7 In some embodiments, R 7 are hydrogen and halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, and -OC, respectively. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 C optionally substituted with one or more substituents independently selected from a carbocycle or a 3- to 10-membered heterocycle 1-6 In some embodiments, R 7 are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, and -OC, respectively. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 alkyl)2, and -NH(C 1-6 C optionally substituted with one or more substituents independently selected from alkyl 1-6 In some embodiments, R 7 each C optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, and —SH; 1-6 In some embodiments, w is 1, v is 1, n is 2, m is 1 or 2, z is 3, Y is C, and Q is phenyl or cyclohexyl, each of which is independently selected from halogen, —CN, —OH, —SH, —NO, —NH, and C. 1-3 optionally substituted with one or more substituents independently selected from alkyl; 1 is -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, and -OP(OR 7 )O-, and R 2is a C1 alkyl substituted with -OH or -OC(O)CH3, and R 3 is -OH or -OC(O)CH3, and R 4 is -OH or -OC(O)CH3, and R 5 is —NH(O)CH. In some embodiments, the compound is

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] [ka]

[0130] [ka]

[0131] [ka] Includes:

[0132] In some embodiments, the oligonucleotide (J) is linked at the 5' or 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 alkyl phosphonate, phosphorothioate, methyl phosphonate, phosphorodithioate, alkyl phosphonothioate, phosphoramidate, carbamate, carbonate, phosphotriester, 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 the asialoglycoprotein receptor. In some embodiments, the compound targets hepatocytes.

[0133] Some embodiments include the following, where J is an oligonucleotide:

[0134] [ka] J may include one or more additional phosphates or one or more phosphorothioates attached to the oligonucleotide. J may include one or more additional phosphates attached to the oligonucleotide. J may include one or more phosphorothioates attached to the oligonucleotide.

[0135] Some embodiments include the following, where J is an oligonucleotide:

[0136] [ka] J may include one or more additional phosphates or one or more phosphorothioates attached to the oligonucleotide. J may include one or more additional phosphates attached to the oligonucleotide. J may include one or more phosphorothioates attached to the oligonucleotide.

[0137] Some embodiments include the following, where J is an oligonucleotide:

[0138] [ka] J may comprise one or more phosphates or phosphorothioates attached to the oligonucleotide. J may comprise one or more phosphates attached to the oligonucleotide. J may comprise a phosphate attached to the oligonucleotide. J may comprise one or more phosphorothioates attached to the oligonucleotide. J may comprise a phosphorothioate attached to the oligonucleotide.

[0139] Some embodiments include the following, where J is an oligonucleotide:

[0140] [ka] The structure in this compound attached to the oligonucleotide (J) is sometimes referred to as "ETL17" and is an example of a GalNAc moiety. J can include one or more phosphates or phosphorothioates attached to the oligonucleotide. J can include one or more phosphates attached to the oligonucleotide. J can include one or more phosphates attached to the oligonucleotide. J can include one or more phosphorothioates attached to the oligonucleotide. J can include phosphorothioates attached to the oligonucleotide.

[0141] Some embodiments include the following, where the phosphate or "5'" indicates the connection to the oligonucleotide:

[0142] [ka]

[0143] Some embodiments include the following, where the phosphate or "5'" indicates the connection to the oligonucleotide:

[0144] [ka]

[0145] Some embodiments include the following, where J is an oligonucleotide:

[0146] [ka] J may comprise one or more phosphates or phosphorothioates attached to the oligonucleotide. J may comprise one or more phosphates attached to the oligonucleotide. J may comprise a phosphate attached to the oligonucleotide. J may comprise one or more phosphorothioates attached to the oligonucleotide. J may comprise a phosphorothioate attached to the oligonucleotide.

[0147] Some embodiments include the following, where J is an oligonucleotide:

[0148] [ka] The structure in this compound attached to the oligonucleotide (J) is sometimes referred to as "ETL1" and is an example of a GalNAc moiety. J can include one or more phosphates or phosphorothioates attached to the oligonucleotide. J can include one or more phosphates attached to the oligonucleotide. J can include one or more phosphates attached to the oligonucleotide. J can include one or more phosphorothioates attached to the oligonucleotide. J can include one or more phosphorothioates attached to the oligonucleotide.

[0149] 3. siRNA modification patternsIn some embodiments, a composition comprises an oligonucleotide that inhibits expression of FGG, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises the modification pattern 1S:5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 3622), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 2S:5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 3623), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 3S:5'-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 3624), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 4S:5'-NfsnsNfnNfnNfNfNfNfnNfnNfnNfnNfnNfsnsnN-moiety-3' (SEQ ID NO: 3625), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 5S:5'-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-moiety-3' (SEQ ID NO: 3626), where "Nf" is a 2'fluoro-modified nucleoside, "n" is a 2'O-methyl-modified nucleoside, "s" is a phosphorothioate linkage, and N comprises one or more nucleosides. In some embodiments, a moiety in modification pattern 4S or 5S is a lipid moiety. In some embodiments, a moiety in modification pattern 4S or 5S is a sugar moiety.In some embodiments, the sense strand comprises the modification pattern 6S:5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO: 3627), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 7S:5'-nsnsnnNfNfNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 3628), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 8S:5'-nsnsnnnNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 3629), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 9S:5'-nsnsnnnnNfNfNfNfnnnnnnnnnsnsn-3' (SEQ ID NO: 3630), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 10S:5'-nsnsnnNfNfnNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 3785), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0150] In some embodiments, the sense strand comprises the modification pattern 11S:5'-nsnsnnNfnnnNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 3786), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0151] In some embodiments, the sense strand comprises the modification pattern 12S:5'-snnnnNfNfnNfNfnnnnNfnnNfnnsnsn-3' (SEQ ID NO: 3787), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0152] In some embodiments, the sense strand comprises the modification pattern 13S:5'-snnnnNfNfnNfdNnNfNfnnNfnnnnsnsn-3' (SEQ ID NO: 3788), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0153] In some embodiments, the sense strand comprises the modification pattern 14S:5'-snnNfNfnnnnNfnnnnNfnNfNfnnsnsn-3' (SEQ ID NO: 3789), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0154] In some embodiments, the sense strand comprises the modification pattern 15S:5'-snnNfnNfnNfNfdNnNfNfnnNfnnNfnnnnsnsn-3' (SEQ ID NO: 3790), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 16S:5'-snnnnNfNfNfNfNfnnnnnnnsnsn-3' (SEQ ID NO: 3791), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 17S:5'-snnnnnNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 3792), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 18S:5'-snnnnNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 3793), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 19S:5'-snnnnNfnnnNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 3794), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 20S:5'-snnnnnNfNfNfNfNfnnnnnnsnsn-3' (SEQ ID NO: 3795), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the sense strand comprises the modification pattern 21S:5'-snnnnnnNfNfNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 3796), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 22S:5'-snnnnNfNfNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 3797), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 23S:5'-snnnnNfnNfNfdTnnnnnnnnnnsnsn-3' (SEQ ID NO: 3798), where "dT" is deoxythymidine, "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 24S:5'-snnnnNfNfnnNfNfnnnnnnnnnsnsn-3' (SEQ ID NO: 3799), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 25S:5'-snnnnnNfNfnNfnnnnnnnnnnsnsn-3' (SEQ ID NO: 3800), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 26S:5'-snnnnnnNfnNfNfnnnnnnnnnsnsn-3' (SEQ ID NO: 3801), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the sense strand comprises the modification pattern 27S:5'-snnnnnnnNfNfnNfnnnnnnnnsnsn-3' (SEQ ID NO: 3802), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 28S:5'-snnnnnnnnNfnNfnNfnnnnnnsnsn-3' (SEQ ID NO: 3803), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand comprises the modification pattern 29S:5'-snnnnnnNfNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO: 3804), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0155] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of FGG, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, the antisense strand comprising modification pattern 1AS:5'-nsNfsnNfnNfnNfnNfnnnNfnNfnsnsn-3' (SEQ ID NO:3631), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 2AS:5'-nsNfsnnnNfnNfNfNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO:3632), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 3AS:5'-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 3633), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 4AS:5'-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 3634), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 5AS:5'-nsNfsnnnnnnnnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 3635), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 6AS:5'-nsNfsnnnNfnnNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 3636), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the antisense strand comprises the modification pattern 7AS:5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 3637), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 8AS:5'-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3' (SEQ ID NO: 3638), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 9AS:5'-nNfnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 3639), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 10AS:5'-nsNfsnNfnnnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 3805), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 11AS:5'-nsNfsnNfnnNfnnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO:3806), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 12AS:5'-nsNfsndTndNnNfnNfndNnNfndNnNfnsnsn-3' (SEQ ID NO:3807), where "Nf" is a 2' fluoro-modified nucleoside, "dT" is deoxythymidine, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the antisense strand comprises the modification pattern 13AS:5'-nsNfsndTndNnNfnNfndNndTndNndTnsnsn-3' (SEQ ID NO:3808), where "Nf" is a 2' fluoro-modified nucleoside, "dT" is deoxythymidine, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 14AS:5'-nsNfsnnnNfnnnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO:3809), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 15AS:5'-dTsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO:3810), where "Nf" is a 2' fluoro-modified nucleoside, "dT" is deoxythymidine, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 16As:5'-NfsNfsnnnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO:3811), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 17AS:5'-nsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 3812), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 18AS:5'-nsNfsnNfnNfnnnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 3813), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.In some embodiments, the antisense strand comprises the modification pattern 19AS:5'-nsNfsnNfnnNfNfnNfnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 3814), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 20AS:5'-nsNfsnNfnnNfnnnnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 3815), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises the modification pattern 21AS: 5'-nsNfsnnnNfnNfnnnNfnNfnNfnNfnsnsn-3' (SEQ ID NO: 3816), where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0156] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern 1S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 5S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 6S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS.In some embodiments, the sense strand comprises pattern 7S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 9S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 10S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 11S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 12S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS.In some embodiments, the sense strand comprises pattern 13S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 14S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 15S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 16S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 17S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 18S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS.In some embodiments, the sense strand comprises pattern 19S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 20S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 21S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 22S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 23S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 24S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS.In some embodiments, the sense strand comprises pattern 25S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 26S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 27S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 28S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the sense strand comprises pattern 29S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS.

[0157] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises pattern 1AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises pattern 2AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises pattern 3AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises pattern 4AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises pattern 5AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises pattern 6AS.In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises pattern 7AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises pattern 8AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 9AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises pattern 10AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 11AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 12AS.In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 13AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 14AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 15AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 16AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 17AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 18AS.In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 19AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 209AS. In some embodiments, the sense strand comprises the pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S, and the antisense strand comprises the pattern 21AS.

[0158] In some embodiments, the sense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS. In some embodiments, the antisense strand comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, or 29S. In some embodiments, the sense strand or antisense strand comprises modification pattern ASO1.

[0159] In some embodiments, the purines in the sense strand comprise 2'-fluoro modified purines. In some embodiments, the purines in the sense strand comprise 2'-O-methyl modified purines. In some embodiments, the purines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all purines in the sense strand comprise 2'-fluoro modified purines. In some embodiments, all purines in the sense strand comprise 2'-O-methyl modified purines. In some embodiments, all purines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines.

[0160] In some embodiments, the pyrimidines of the sense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, the pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, the pyrimidines of the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all pyrimidines in the sense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, all pyrimidines in the sense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all pyrimidines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines.

[0161] In some embodiments, the purines of the sense strand comprise 2'-fluoro modified purines, and the pyrimidines of the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the sense strand comprise 2'-O-methyl modified purines, and the pyrimidines of the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the sense strand comprise 2'-fluoro modified purines, and the pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the sense strand comprise 2'-O-methyl modified purines, and the pyrimidines of the sense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, the pyrimidines of the sense strand comprise 2'-fluoro modified pyrimidines, and the purines of the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines, and the purines of the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the sense strand comprise 2'-fluoro-modified pyrimidines and the purines of the sense strand comprise 2'-O-methyl-modified purines. In some embodiments, the pyrimidines of the sense strand comprise 2'-O-methyl-modified pyrimidines and the purines of the sense strand comprise 2'-fluoro-modified purines.

[0162] In some embodiments, all purines in the sense strand comprise 2'-fluoro modified purines, and all pyrimidines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the sense strand comprise 2'-O-methyl modified purines, and all pyrimidines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the sense strand comprise 2'-fluoro modified purines, and all pyrimidines in the sense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the sense strand comprise 2'-O-methyl modified purines, and all pyrimidines in the sense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, all pyrimidines in the sense strand comprise 2'-fluoro modified pyrimidines, and all purines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all pyrimidines in the sense strand comprise 2'-O-methyl modified pyrimidines, and all purines in the sense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all pyrimidines in the sense strand comprise 2'-fluoro-modified pyrimidines and all purines in the sense strand comprise 2'-O-methyl-modified purines. In some embodiments, all pyrimidines in the sense strand comprise 2'-O-methyl-modified pyrimidines and all purines in the sense strand comprise 2'-fluoro-modified purines.

[0163] In some embodiments, the purines in the antisense strand comprise 2'-fluoro modified purines. In some embodiments, the purines in the antisense strand comprise 2'-O-methyl modified purines. In some embodiments, the purines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all purines in the antisense strand comprise 2'-fluoro modified purines. In some embodiments, all purines in the antisense strand comprise 2'-O-methyl modified purines. In some embodiments, all purines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines.

[0164] In some embodiments, the pyrimidines of the antisense strand comprise 2'-fluoro-modified pyrimidines. In some embodiments, the pyrimidines of the antisense strand comprise 2'-O-methyl-modified pyrimidines. In some embodiments, the pyrimidines of the antisense strand comprise a mixture of 2'-fluoro- and 2'-O-methyl-modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2'-fluoro-modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2'-O-methyl-modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise a mixture of 2'-fluoro- and 2'-O-methyl-modified pyrimidines.

[0165] In some embodiments, the purines of the antisense strand comprise 2'-fluoro modified purines, and the pyrimidines of the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the antisense strand comprise 2'-O-methyl modified purines, and the pyrimidines of the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the antisense strand comprise 2'-fluoro modified purines, and the pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the antisense strand comprise 2'-O-methyl modified purines, and the pyrimidines of the antisense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, the pyrimidines of the antisense strand comprise 2'-fluoro modified pyrimidines, and the purines of the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines, and the purines of the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the antisense strand comprise 2'-fluoro modified pyrimidines, and the purines of the antisense strand comprise 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines, and the purines of the antisense strand comprise 2'-fluoro modified purines.

[0166] In some embodiments, all purines in the antisense strand comprise 2'-fluoro modified purines, and all pyrimidines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the antisense strand comprise 2'-O-methyl modified purines, and all pyrimidines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the antisense strand comprise 2'-fluoro modified purines, and all pyrimidines in the antisense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all purines in the antisense strand comprise 2'-O-methyl modified purines, and all pyrimidines in the antisense strand comprise 2'-fluoro modified pyrimidines. In some embodiments, all pyrimidines in the antisense strand comprise 2'-fluoro modified pyrimidines, and all purines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all pyrimidines in the antisense strand comprise 2'-O-methyl modified pyrimidines, and all purines in the antisense strand comprise a mixture of 2'-fluoro and 2'-O-methyl modified purines. In some embodiments, all pyrimidines in the antisense strand comprise 2'-fluoro modified pyrimidines, and all purines in the antisense strand comprise 2'-O-methyl modified purines. In some embodiments, all pyrimidines in the antisense strand comprise 2'-O-methyl modified pyrimidines, and all purines in the antisense strand comprise 2'-fluoro modified purines.

[0167] In some embodiments, modified oligonucleotides are disclosed herein.Modified oligonucleotides can be siRNAs that contain modifications to ribose rings and phosphate bonds.Modifications can be specific patterns that maximize cell delivery, stability, and efficiency.siRNAs can also contain vinyl phosphonates and hydrophobic groups.These modifications can aid in delivery to cells or tissues within a subject.Modified oligonucleotides can be used in methods such as therapeutic methods or methods for reducing gene expression.

[0168] In some embodiments, the oligonucleotide comprises a duplex consisting of a 21-nucleotide single strand with 19 base pairs between them. In some embodiments, the duplex comprises a single-stranded 2-nucleotide overhang at the 3' end of each strand. One strand (the antisense strand) is complementary to FGG mRNA. Each end of the antisense strand has one to two phosphorothioate linkages. The 5' end has an optional phosphate mimetic, such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knockdown FGG mRNA or a target protein. In some embodiments, the sense strand has the same sequence as FGG mRNA. In some embodiments, one to two phosphorothioates are present at the 3' end. In some embodiments, one or no phosphorothioates are present at the 5' end. In some embodiments, a 12-25 carbon hydrophobic conjugate is attached at the 5' end via a phosphodiester bond.

[0169] In some cases, the sense strand of any siRNA contains an siRNA with a specific modification pattern. In some embodiments of the modification pattern, position 9, counting from the 5' end of the sense strand, can have a 2'F modification. In some embodiments, if position 9 of the sense strand is a pyrimidine, all purines in the sense strand have a 2'OMe modification. In some embodiments, if position 9 is the only pyrimidine between positions 5 and 11 of the sense strand, position 9 is the only position in the sense strand that has a 2'F modification. In some embodiments, if position 9 of the sense strand and one other base between positions 5 and 11 of the sense strand are pyrimidines, both of these pyrimidines are the only two positions in the sense strand that have a 2'F modification. In some embodiments, if position 9 of the sense strand and two other bases between positions 5 and 11 of the sense strand are pyrimidines, and these two other pyrimidines are adjacent positions, so that there are no three 2'F modifications in a row, any combination of 2'F modifications can be made to give a total of three 2'F modifications. In some embodiments, if there are more than two pyrimidines between positions 5 and 11 of the sense strand, all combinations of pyrimidines with 2'F modifications are possible, with a total of 3-5 2'F modifications, provided that the sense strand does not have three 2'F modifications in a row. In some cases, the sense strand of any siRNA contains a modification pattern that conforms to any or all of these sense strand rules.

[0170] In some embodiments, if position 9 of the sense strand is a purine, all purines in the sense strand have a 2'OMe modification. In some embodiments, if position 9 is the only purine between positions 5 and 11 of the sense strand, then position 9 is the only position in the sense strand with a 2'F modification. In some embodiments, if position 9 of the sense strand and one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions in the sense strand with a 2'F modification. In some embodiments, if position 9 of the sense strand and two other bases between positions 5 and 11 of the sense strand are purines, and these two other purines are adjacent positions, so that there are no three 2'F modifications in a row, then any combination of 2'F modifications that results in a total of three 2'F modifications can be made. In some embodiments, if there are more than two purines between positions 5 and 11 of the sense strand, then all combinations of purines with 2'F modifications that result in a total of three to five 2'F modifications are possible, provided that the sense strand does not have three 2'F modifications in a row. In some cases, either sense strand of the siRNA contains a modification pattern that conforms to any or all of these sense strand rules.

[0171] In some cases, position 9 of the sense strand can be 2'deoxy. In these cases, 2'F and 2'OMe modifications can occur at other positions of the sense strand. In some cases, any sense strand of siRNA contains a modification pattern that conforms to these sense strand rules.

[0172] In some cases, either sense strand of the siRNA contains a modification pattern that fits these sense strand rules.

[0173] In some embodiments, disclosed herein is a composition comprising an oligonucleotide that targets FGG and reduces expression of FGG when administered to a cell, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises a sense strand sequence described herein with at least one internucleoside linkage modified and at least one nucleoside modified, or a sense strand sequence comprising a substitution, addition, or deletion of one or two nucleosides of the oligonucleotide sequence with at least one internucleoside linkage modified and at least one nucleoside modified, and the antisense strand comprises an antisense strand sequence described herein with at least one internucleoside linkage modified and at least one nucleoside modified, or an oligonucleotide sequence comprising a substitution, addition, or deletion of one or two nucleosides of the antisense strand sequence with at least one internucleoside linkage modified and at least one nucleoside modified. Some embodiments relate to a method comprising administering the composition to a subject.

[0174] In some embodiments, the sense and / or antisense strands comprise a nucleoside sequence that is 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 the sense and / or antisense strand sequences of any of Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 66A, or 81. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of any of siRNAs in Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 66A, or 81, or a nucleic acid sequence thereof having three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of any of the siRNAs in Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 66A, or 81, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense and / or antisense strand sequence of any of the siRNAs in Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 66A, or 81. The siRNA may contain the same internucleoside linkage modifications or nucleoside modifications as those in Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 66A, or 81. The siRNA can contain any different internucleoside linkage or nucleoside modifications different from those in Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 66A, or 81. The siRNA can contain some unmodified internucleoside linkages or nucleosides.

[0175] In some embodiments, the sense and / or antisense strands comprise nucleoside sequences that are 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 the sequences of the sense and / or antisense strands of Table 8A. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strands of the siRNAs of Table 8A, or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strands of the siRNAs of Table 8A, or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strands of the siRNAs of Table 8A. The siRNA may comprise the same internucleoside linkage modifications or nucleoside modifications as those in Table 8A. The siRNA may contain any different internucleoside linkage or nucleoside modifications different from those in Table 8 A. The siRNA may contain some unmodified internucleoside linkages or nucleosides.

[0176] In some embodiments, the sense and / or antisense strands comprise nucleoside sequences that are 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 the sequences of the sense and / or antisense strands of Table 8B. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strands of an siRNA of Table 8B, or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strands of an siRNA of Table 8B, or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strands of an siRNA of Table 8B. The siRNA may comprise the same internucleoside linkage modifications or nucleoside modifications as those in Table 8B. The siRNA may contain any different internucleoside linkage or nucleoside modifications different from those in Table 8B. The siRNA may contain some unmodified internucleoside linkages or nucleosides.

[0177] In some embodiments, the sense and / or antisense strands comprise nucleoside sequences that are 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 the sequences of the sense and / or antisense strands of Table 81. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strands of an siRNA in Table 81, or a nucleic acid sequence thereof with three or four nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strands of an siRNA in Table 81, or a nucleic acid sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strands of an siRNA in Table 81. The siRNA may comprise the same internucleoside linkage modifications or nucleoside modifications as those in Table 81. The siRNA may contain any different internucleoside linkage or nucleoside modifications different from those in Table 81. The siRNA may contain some unmodified internucleoside linkages or nucleosides.

[0178] In some embodiments, the sense strand comprises a nucleoside sequence that is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical to any one of SEQ ID NOs: 3591-3594. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3591-3594, or a sense strand sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3591-3594, and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3591-3594. The sense strand may comprise any different internucleoside linkage modifications or nucleoside modifications that are different from those of SEQ ID NOs: 3591-3594. The sense strand may contain some unmodified internucleoside linkages or nucleosides. The sense strand may contain GalNAc1 or another GalNAc moiety.

[0179] In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 3591. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3591 or its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3591 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3591. The sense strand can include any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3591. The sense strand can include some unmodified internucleoside linkages or nucleosides. The sense strand can include GalNAc1 or another GalNAc moiety.

[0180] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3592. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3592 or its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3592 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3592. The sense strand can contain any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3592. The sense strand can contain some unmodified internucleoside linkages or nucleosides. The sense strand can contain GalNAc1 or another GalNAc moiety.

[0181] In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 3593. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3593, or its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3593 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3593. The sense strand can contain any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3593. The sense strand can contain some unmodified internucleoside linkages or nucleosides. The sense strand can contain GalNAc1 or another GalNAc moiety.

[0182] In some embodiments, the sense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 3594. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3594 or its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3594 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3594. The sense strand may contain any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3594. The sense strand may contain some unmodified internucleoside linkages or nucleosides. The sense strand may contain GalNAc1 or another GalNAc moiety.

[0183] 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: 3641-3676. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3641-3676, or a sense strand sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3641-3676, and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3641-3676. The sense strand may comprise any different internucleoside linkage modifications or nucleoside modifications that are different from those of SEQ ID NOs: 3641-3676. The sense strand may contain some unmodified internucleoside linkages or nucleosides. The sense strand may contain GalNAc1 or another GalNAc moiety.

[0184] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3651. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3651 or its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3651 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3651. The sense strand can contain any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3651. The sense strand can contain some unmodified internucleoside linkages or nucleosides. The sense strand can contain GalNAc1 or another GalNAc moiety.

[0185] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3652. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652 or its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652. The sense strand can contain any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3652. The sense strand can contain some unmodified internucleoside linkages or nucleosides. The sense strand can contain GalNAc1 or another GalNAc moiety.

[0186] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3654. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3654 or its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3654 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3654. The sense strand may contain any different internucleoside linkage or nucleoside modifications different from those of SEQ ID NO: 3594. The sense strand may contain some unmodified internucleoside linkages or nucleosides. The sense strand may contain GalNAc1 or another GalNAc moiety.

[0187] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3675. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3675 or its sense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3675 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3675. The sense strand may contain any different internucleoside linkage or nucleoside modifications different from those of SEQ ID NO: 3675. The sense strand may contain some unmodified internucleoside linkages or nucleosides. The sense strand may contain GalNAc1 or another GalNAc moiety.

[0188] In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical to any one of SEQ ID NOs: 3595-3598. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598, or an antisense strand sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598, and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598. The antisense strand may comprise any different internucleoside linkage modifications or nucleoside modifications that are different from those of SEQ ID NOs: 3595-3598. The antisense strand may contain some unmodified internucleoside linkages or nucleosides. The antisense strand may contain a GalNAc moiety.

[0189] In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 3595. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3595, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3595 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3595. The antisense strand may contain any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3595. The antisense strand may contain some unmodified internucleoside linkages or nucleosides. The antisense strand may contain a GalNAc moiety.

[0190] In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 3596. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3596, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3596 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3596. The antisense strand may contain any different internucleoside linkage or nucleoside modifications that are different from those of SEQ ID NO: 3596. The antisense strand may contain some unmodified internucleoside linkages or nucleosides. The antisense strand may contain a GalNAc moiety.

[0191] In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 3597. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597. The antisense strand may contain any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3597. The antisense strand may contain some unmodified internucleoside linkages or nucleosides. The antisense strand may contain a GalNAc moiety.

[0192] In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 3598. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3598, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3598 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3598. The antisense strand may contain any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3598. The antisense strand may contain some unmodified internucleoside linkages or nucleosides. The antisense strand may contain a GalNAc moiety.

[0193] In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical to any one of SEQ ID NOs: 3677-3712. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712, or an antisense strand sequence thereof with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712, and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712. The antisense strand may comprise any different internucleoside linkage modifications or nucleoside modifications that are different from those of SEQ ID NOs: 3677-3712. The antisense strand may contain some unmodified internucleoside linkages or nucleosides. The antisense strand may contain a GalNAc moiety.

[0194] In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 3687. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3687, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3687 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3687. The antisense strand may contain any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3687. The antisense strand may contain some unmodified internucleoside linkages or nucleosides. The antisense strand may contain a GalNAc moiety.

[0195] In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 3688. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688. The antisense strand may contain any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3688. The antisense strand may contain some unmodified internucleoside linkages or nucleosides. The antisense strand may contain a GalNAc moiety.

[0196] In some embodiments, the antisense strand comprises a nucleoside sequence that is at least 85% identical to SEQ ID NO: 3690. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690. The antisense strand may contain any different internucleoside linkage or nucleoside modifications that differ from those of SEQ ID NO: 3690. The antisense strand may contain some unmodified internucleoside linkages or nucleosides. The antisense strand may contain a GalNAc moiety.

[0197] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3747. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3747 or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3747 and three or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3747. The antisense strand may contain any different internucleoside linkage or nucleoside modifications that are different from those of SEQ ID NO: 3747. The antisense strand may contain some unmodified internucleoside linkages or nucleosides. The antisense strand may contain a GalNAc moiety.

[0198] 4. ASO modification pattern In some embodiments, the composition comprises an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).

[0199] In some embodiments, the ASO comprises the modification pattern ASO1:5'-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3' (SEQ ID NO: 3640), where "dN" is any deoxynucleotide, "n" is a 2'O-methyl or 2'O-methoxyethyl modified nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the ASO comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 156S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 28S, 29S, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS.

[0200] D. Formulation In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0201] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer solution. In some embodiments, the pharmaceutically acceptable carrier is saline. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer solution, or saline. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises a liposome, a lipid, a nanoparticle, a protein, a protein-antibody complex, a peptide, cellulose, a nanogel, or a combination thereof.

[0202] II. Methods and Uses In some embodiments, disclosed herein are methods of administering the compositions described herein to a subject. Some embodiments relate to uses of the compositions described herein, such as administering the compositions to a subject.

[0203] Some embodiments relate to methods of treating a disease or disorder (e.g., a mental disorder (e.g., a psychiatric or neurological disorder)) in a subject in need thereof. Some embodiments relate to the use of the compositions described herein in therapeutic methods. Some embodiments comprise administering a composition described herein to a subject suffering from the disorder. In some embodiments, the administration treats the disorder in the subject. In some embodiments, the composition treats the disorder in the subject.

[0204] In some embodiments, treatment includes preventing, inhibiting, or reversing a disorder (e.g., a mental disorder (e.g., a psychiatric or neurological disorder)) in a subject. Some embodiments relate to the use of a composition described herein in a method for preventing, inhibiting, or reversing a disorder. Some embodiments relate to a method for preventing, inhibiting, or reversing a disorder in a subject. Some embodiments include administering a composition described herein to a subject with a disorder. In some embodiments, the administration prevents, inhibits, or reverses the disorder in the subject. In some embodiments, the composition prevents, inhibits, or reverses the disorder in the subject.

[0205] Some embodiments relate to methods of preventing a disorder (e.g., a mental disorder (e.g., a psychiatric or neurological disorder)) in a subject in need thereof. Some embodiments relate to the use of a composition described herein in a method of preventing a disorder. Some embodiments comprise administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject.

[0206] Some embodiments relate to methods of inhibiting a disorder (e.g., a mental disorder (e.g., a psychiatric or neurological disorder)) in a subject in need thereof. Some embodiments relate to the use of a composition described herein in a method of inhibiting a disorder. Some embodiments comprise administering a composition described herein to a subject with the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject.

[0207] Some embodiments relate to methods of reversing a disorder (e.g., a mental disorder (e.g., a psychiatric or neurological disorder)) in a subject in need thereof. Some embodiments relate to the use of a composition described herein in a method of reversing a disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.

[0208] In some embodiments, administration is systemic, in some embodiments, administration is intravenous, in some embodiments, administration is by infusion.

[0209] A. Disability Some embodiments of the methods described herein include treating a disorder in a subject in need thereof. The disorder may include a disease. In some embodiments, the disorder is a psychiatric disorder. In some embodiments, the psychiatric disorder is a psychiatric or neurological disorder. The psychiatric or neurological disorder may include a liver disorder, a brain disorder, a CNS disorder, a CSF disorder, or a combination thereof.

[0210] In some embodiments, the disorder comprises a psychiatric disorder. Non-limiting examples of psychiatric disorders include depressive disorders, such as major depressive disorder, persistent depressive disorder, treatment-resistant depression, and signs or symptoms of depression. Further non-limiting examples of psychiatric disorders include post-traumatic stress disorder, mood disorders, anxiety disorders (e.g., generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, social phobia, etc.), eating disorders, substance use disorders (e.g., alcohol use disorder, prescription drug use disorder, illicit drug use disorder, psychoactive substance use disorder, etc.), bipolar disorder, personality disorder, schizophrenia, and schizoaffective disorder.

[0211] In some embodiments, the disorder is a depressive disorder. Examples of depressive disorders include major depressive disorder, persistent depressive disorder, or treatment-resistant depression. In some embodiments, the depressive disorder comprises or consists of major depressive disorder. In some embodiments, the depressive disorder comprises or consists of persistent depressive disorder. In some embodiments, the depressive disorder comprises or consists of treatment-resistant depression. In some embodiments, the depressive disorder is treatment-resistant depression. Treatment-resistant depression can include depression that does not respond to first-line, second-line, or third-line treatment (e.g., within an acceptable period of time). In some embodiments, the disorder includes signs or symptoms of depression. Exemplary signs or symptoms of depression can include persistent feelings of sadness or loss of interest, loss of motivation, feelings of hopelessness and sadness, anxiety, agitation, and restlessness. An exemplary sign or symptom of depression can be any sign or symptom of depression found in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), which is incorporated herein by reference.

[0212] In some embodiments, the disorder comprises post-traumatic stress disorder (PTSD). Exemplary signs or symptoms of PTSD include recurring, involuntary, disturbing memories of the traumatic event, flashbacks, disturbing dreams or nightmares about the traumatic event, negative thoughts about oneself, others, or the world, memory impairment, difficulty experiencing positive emotions, or emotional numbness. Exemplary signs or symptoms of PTSD may be any of the signs or symptoms of PTSD in DSM-5.

[0213] In some embodiments, the disorder comprises a mood disorder. An exemplary mood disorder comprises dysthymia. In some embodiments, the disorder comprises an anxiety disorder. Exemplary anxiety disorders comprise generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, social phobia, and social anxiety disorder. Signs or symptoms of an anxiety disorder include restlessness, fatigue, difficulty concentrating, and irritability. Exemplary signs or symptoms of an anxiety disorder (e.g., GAD, OCD, etc.) may be any sign or symptom of an anxiety disorder in DSM-5.

[0214] In some embodiments, the disorder comprises an eating disorder. Exemplary eating disorders include anorexia nervosa, bulimia nervosa, and binge eating disorder. Exemplary signs and symptoms of an eating disorder include excessive restriction of food intake, weakness, fear of excessive weight gain, brittle nails or hair, consuming an abnormally large amount of food within a specific period (e.g., a 2-hour period), consuming when not full or hungry, and consuming until uncomfortably full. Exemplary signs or symptoms of an eating disorder may be any of the signs or symptoms of an eating disorder in DSM-5.

[0215] In some embodiments, the disorder comprises a substance use disorder. Exemplary substance use disorders include alcohol use disorder, prescription drug use disorder, illicit drug use disorder, solvent abuse, and "legal high" abuse. Exemplary signs and symptoms of a substance use disorder include having a strong craving for the substance that blocks out other thoughts, needing to take increasing amounts of the substance over time to achieve the same effect, and unsuccessful attempts to quit. Exemplary signs or symptoms of a substance use disorder may be any of the signs or symptoms of a substance use disorder in DSM-5.

[0216] In some embodiments, the disorder comprises bipolar disorder. In some embodiments, bipolar disorder comprises bipolar I disorder. In some embodiments, bipolar disorder comprises bipolar II disorder. In some embodiments, bipolar disorder comprises cyclothymic bipolar disorder. In some embodiments, bipolar disorder comprises bipolar disorder with mixed features. Exemplary signs and symptoms of bipolar disorder include presenting manic episodes and presenting depressive episodes. Exemplary signs or symptoms of bipolar disorder may be any sign or symptom of bipolar disorder in DSM-5.

[0217] In some embodiments, the disorder comprises a personality disorder. Exemplary personality disorders include borderline personality disorder, antisocial personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, and schizoid personality disorder. Exemplary signs or symptoms of personality disorders include impulsiveness, risky behavior, unstable or fragile self-image, mood swings, suicidal thoughts, or self-harm threats. Exemplary signs or symptoms of personality disorders may be any of the signs or symptoms of personality disorders in DSM-5.

[0218] In some embodiments, the disorder comprises schizophrenia. Exemplary signs or symptoms of schizophrenia include delusions, hallucinations, disorganized thinking, and loss of interest or motivation in life. In some embodiments, the signs or symptoms comprise positive symptoms (e.g., hallucinations or delusions). In some embodiments, the signs or symptoms comprise negative symptoms (e.g., loss of interest or blunted affect). Exemplary signs or symptoms of schizophrenia can be any of the signs or symptoms of schizophrenia in DSM-5.

[0219] In some embodiments, the disorder comprises schizoaffective disorder. Exemplary schizoaffective disorders include bipolar schizoaffective disorder and depressive schizoaffective disorder. Exemplary signs or symptoms of schizoaffective disorder include delusions, hallucinations, communication disorders, and bizarre or abnormal behavior. Exemplary signs or symptoms of schizoaffective disorder may be any of the signs or symptoms of schizoaffective disorders in DSM-5.

[0220] In some embodiments, the disorder comprises a neurological disorder. Non-limiting examples of neurological disorders include Alzheimer's disease, dementia, cognitive decline, and vascular dementia. Further non-limiting examples of neurological disorders include headache, migraine (e.g., with aura and / or without aura), chronic pain, fibromyalgia, chronic fatigue syndrome (e.g., myalgic encephalomyelitis), and motor neuron disease (e.g., amyotrophic lateral sclerosis (ALS)).

[0221] In some embodiments, the disorder comprises dementia. In some embodiments, the dementia comprises vascular dementia. In some embodiments, the dementia comprises dementia with Lewy bodies. In some embodiments, the dementia comprises frontotemporal dementia. In some embodiments, the dementia comprises Alzheimer's disease. In some embodiments, the dementia comprises mixed dementia. Exemplary signs or symptoms of dementia include memory loss, difficulty communicating, difficulty with visuospatial awareness, difficulty with reasoning or problem-solving, difficulty with coordination and motor function, and confusion and disorientation.

[0222] In some embodiments, Alzheimer's disease includes early-onset Alzheimer's disease. Early-onset Alzheimer's disease can occur in subjects under the age of 65. In some embodiments, Alzheimer's disease includes late-onset Alzheimer's disease. In some embodiments, Alzheimer's disease includes common Alzheimer's disease. In some embodiments, Alzheimer's disease includes genetic Alzheimer's disease. Exemplary signs or symptoms of Alzheimer's disease include memory loss and increased confusion, inability to learn new things, language difficulties, difficulty organizing or reasoning, shortened attention span, and trouble adapting to new situations.

[0223] In some embodiments, the disorder comprises delirium. Exemplary forms of delirium include hyperactive delirium, hypoactive delirium, and mixed delirium. Exemplary signs or symptoms of delirium include agitation, disorientation, delusional thinking, hallucinations, memory loss, difficulty speaking, and difficulty understanding speech.

[0224] In some embodiments, the disorder comprises cognitive decline. Exemplary forms of cognitive decline include mild cognitive impairment, dementia, primary progressive aphasia, corticobasal degeneration, primary progressive aphasia, and progressive supranuclear palsy. Exemplary signs or symptoms of cognitive decline include forgetfulness, overwhelming emotions, difficulty understanding directions or instructions, inability to organize tasks, and high impulsivity.

[0225] In some embodiments, the disorder comprises headache. In some embodiments, the headache comprises migraine (e.g., with or without aura). Headache may include sinus headache, tension headache, migraine, and cluster headache. Exemplary signs and symptoms of headache include pain (e.g., deep and constant) in the cheekbones, forehead, bridge of the nose, skull, or back of the neck, aura, photophobia, photophobia, and vomiting.

[0226] In some embodiments, the disorder comprises chronic pain. In some embodiments, the chronic pain comprises fibromyalgia. Exemplary signs and symptoms of fibromyalgia include muscle pain, fatigue, depression, anxiety, insomnia, headache, and difficulty concentrating. Exemplary chronic pain disorders include post-operative pain, post-traumatic pain, back pain, cancer pain, arthritis pain, muscle pain, and neuropathic pain (e.g., diabetic neuropathy).

[0227] In some embodiments, the disorder comprises chronic fatigue syndrome (also known as myalgic encephalomyelitis). Exemplary signs and symptoms of chronic fatigue syndrome include extreme fatigue that persists for a long period of time (e.g., at least six months) and cannot be fully explained by an underlying medical condition, fatigue that worsens with physical or mental activity, pain (e.g., in the joints or muscles), fatigue, forgetfulness, anxiety, and depression.

[0228] In some embodiments, the disorder comprises a motor neuron disease. In some embodiments, the motor neuron disease is amyotrophic lateral sclerosis (ALS). Exemplary forms of motor neuron disease include progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), ALS, and primary lateral sclerosis (PLS). Exemplary signs and symptoms of motor neuron disease (e.g., ALS) include difficulty controlling movement (e.g., difficulty walking or performing normal daily activities), muscle weakness, impaired speech intelligibility, difficulty swallowing, muscle spasms and muscle spasms (e.g., of the arms, shoulders, or tongue), and inappropriate crying, laughing, or yawning.

[0229] In some embodiments, the disorder comprises a blood clotting disorder or coagulation disorder. In some embodiments, the blood clotting disorder or coagulation disorder comprises hemophilia, von Willebrand's disease, or a clotting factor deficiency. In some embodiments, the blood clotting disorder or coagulation disorder comprises thrombophilia. In some embodiments, the thrombophilia comprises a congenital thrombophilia. In some embodiments, the thrombophilia comprises an acquired thrombophilia. In some embodiments, the blood clotting disorder or coagulation disorder comprises a hypercoagulable state. In some embodiments, the hypercoagulable state comprises cancer. In some embodiments, the hypercoagulable state comprises atrial fibrillation. In some embodiments, the hypercoagulable state comprises a postoperative period or an immobile state. In some embodiments, the blood clotting disorder or coagulation disorder comprises arterial thrombosis or thromboembolism. In some embodiments, the blood clotting disorder or coagulation disorder comprises venous thrombosis or thromboembolism. In some embodiments, the venous thrombosis comprises deep vein thrombosis. In some embodiments, the venous thrombosis comprises pulmonary embolism. In some embodiments, venous thrombosis comprises thrombophlebitis.

[0230] In some cases, the disorder may be diagnosed by the use of a questionnaire or scoring system. In some cases, the disorder is diagnosed according to DSM-5 criteria. In some cases, the disorder is diagnosed by a medical professional (e.g., a physician, etc.).

[0231] In some embodiments, the disorder includes one or more disorders (e.g., any of the disorders disclosed herein). In some embodiments, the disorder includes two disorders. In some embodiments, the disorder includes three disorders. In some embodiments, the disorder includes four disorders. In some embodiments, the disorder includes five disorders.

[0232] B. Subject Some embodiments of the methods described herein involve treating a subject. Non-limiting examples of subjects include vertebrates, animals, mammals, dogs, cats, cows, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a vertebrate. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a cow. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, mammal, dog, cat, cow, rodent, mouse, rat, primate, or monkey. In some embodiments, the subject is a human.

[0233] In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult (e.g., at least 18 years old). In some embodiments, the subject is 45 years of age or older. In some embodiments, the subject is 50 years of age or older. In some embodiments, the subject is 55 years of age or older. In some embodiments, the subject is 60 years of age or older. In some embodiments, the subject is 65 years of age or older. In some embodiments, the subject is 70 years of age or older. In some embodiments, the subject is 75 years of age or older. In some embodiments, the subject is 80 years of age or older. In some embodiments, the subject is 85 years of age or older.

[0234] In some embodiments, the subject has a body mass index (BMI) of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or greater, or a range defined by any two of the foregoing integers. In some embodiments, the subject is overweight. In some embodiments, the subject has a BMI of 25 or greater. In some embodiments, the subject has a BMI between 25 and 29. In some embodiments, the subject is obese. In some embodiments, the subject has a BMI of 30 or greater. In some embodiments, the subject has a BMI between 30 and 39. In some embodiments, the subject has a BMI between 40 and 50. In some embodiments, the subject has a BMI between 25 and 50.

[0235] In some embodiments, the subject has a personal history of the disorder. In some embodiments, the subject has a family history of the disorder. In some embodiments, the subject is at high risk of suffering from the disorder.

[0236] In some embodiments, the subject suffers from a blood clotting disorder or coagulation disorder. In some embodiments, the blood clotting disorder or coagulation disorder comprises hemophilia, von Willebrand's disease, or a clotting factor deficiency. In some embodiments, the subject suffers from thrombophilia. In some embodiments, the thrombophilia comprises a congenital thrombophilia. In some embodiments, the thrombophilia comprises an acquired thrombophilia. In some embodiments, the subject has a hypercoagulable state. In some embodiments, the hypercoagulable state comprises cancer. In some embodiments, the hypercoagulable state comprises atrial fibrillation. In some embodiments, the hypercoagulable state comprises a postoperative period or an immobile state. In some embodiments, the subject suffers from arterial thrombosis or thromboembolism. In some embodiments, the subject suffers from venous thrombosis or thromboembolism. In some embodiments, the venous thrombosis comprises deep vein thrombosis. In some embodiments, the venous thrombosis comprises pulmonary embolism. In some embodiments, the venous thrombosis comprises thrombophlebitis.

[0237] C. Baseline Measurements Some embodiments of the methods described herein include obtaining baseline measurements from a subject. In some embodiments, the baseline measurements are baseline measurements of a mental disorder (e.g., a psychiatric or neurological disorder). For example, in some embodiments, the baseline measurements are obtained from a subject before treating the subject. Non-limiting examples of baseline measurements include a baseline measurement of the Montgomery-Asberg Depression Rating Scale (MADRS), a baseline Hamilton Depression Rating Scale 17-item (e.g., the scale ranges from 0 to 52, with higher scores indicating worsening depressive symptoms), baseline anxiety symptoms and / or signs, baseline eating disorder symptoms and / or signs, baseline substance use disorder symptoms and / or signs, baseline post-traumatic stress disorder symptoms and / or signs, baseline bipolar disorder symptoms and / or signs, baseline schizophrenia symptoms and / or signs, and baseline psychosis symptoms and / or signs. In some embodiments, the baseline measurements comprise any of the aspects of Tables 1A-1C and 2A-2B. The baseline measurements may include a baseline fibrinogen measurement, a baseline FGG mRNA measurement, or a baseline FGG protein measurement. The baseline measurements may include a baseline coagulation measurement, a baseline prothrombin time (PT) measurement, a baseline international normalized ratio (INR) measurement, or a baseline activated partial thromboplastin time (aPTT) measurement.

[0238] In some embodiments, the baseline measurements are obtained directly from the subject. In some embodiments, the baseline measurements are obtained by observing the subject. In some embodiments, the baseline measurements are obtained by questioning the subject. In some embodiments, the baseline measurements are obtained by the subject completing a questionnaire.

[0239] In some embodiments, the baseline measurement is a baseline Montgomery-Asberg Depression Rating Scale (MADRS) score. MADRS scores can range from 0 to 60, with higher scores indicating worsening depressive symptoms. The MADRS typically comprises a 10-item diagnostic questionnaire used by psychiatrists to measure the severity of depressive episodes in patients suffering from mood disorders. In some cases, it was designed as an adjunct to the HDRS to more sensitively reflect changes brought about by antidepressants or other forms of treatment. Higher MADRS scores indicate more severe depression than lower scores. Total scores range from 0 to 60. Exemplary cutoff points are as follows: 0-6 points - normal / no symptoms 7-19 points - mild depression 20-34 points - moderate depression, and 34+ points - severe depression.

[0240] In some embodiments, the baseline MADRS score comprises a numerical value, such as a point number. In some embodiments, the numerical value is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60, or a range defined by any two of the foregoing numerical values. In some embodiments, the numerical value is 1-5. In some embodiments, the numerical value is 6-10. In some embodiments, the numerical value is 11-15. In some embodiments, the value is between 16 and 20. In some embodiments, the value is between 21 and 25. In some embodiments, the value is between 26 and 30. In some embodiments, the value is between 31 and 35. In some embodiments, the value is between 36 and 40. In some embodiments, the value is between 41 and 45. In some embodiments, the value is between 46 and 50. In some embodiments, the value is between 51 and 55. In some embodiments, the value is between 56 and 60. In some embodiments, the value is between 1 and 60. In some embodiments, the baseline MADRS score includes a baseline subscore, such as a baseline apparent sadness score, a baseline verbal sadness score, a baseline inner tension score, a baseline decreased sleep score, a baseline decreased appetite score, a baseline difficulty concentrating score, a baseline inhibition score, a baseline emotionless score, a baseline pessimistic thinking score, or a baseline suicidal thinking score. Each baseline subscore can include a value of 0, 1, 2, 3, 4, 5, or 6, or a range of such values. In some embodiments, the baseline MADRS score includes a value at or above a threshold value indicative of a depressive disorder. For example, a subject may be depressed prior to treatment and have a baseline MADRS score of 7 to 60.The subject may have mild depression before treatment and have a baseline MADRS score of 7 to 19. The subject may have moderate depression before treatment and have a baseline MADRS score of 20 to 34. The subject may have severe depression before treatment and have a baseline MADRS score greater than 34. In some embodiments, one or more of the baseline subscores includes a numerical value at or above a threshold numerical value indicative of a depressive disorder.

[0241] In some embodiments, the baseline measure includes a baseline Hamilton Depression Rating Scale (HDRS) score. The HDRS generally includes a multi-item questionnaire that provides an index of depression and is used as a guide to assess recovery. The questionnaire is typically designed for adults and is used to assess the severity of depression by measuring severe mood, guilt, suicidal ideation, insomnia, agitation or psychomotor slowing, anxiety, weight loss, and somatic symptoms. Subjects are typically assessed by a clinician on 17-29 items (depending on the version), scored on a 3- or 5-point Likert scale. In some cases, the HDRS is a 17-item (HDRS 17 ). Other variations may be used, including those containing more than 17 items. For example, in some cases, up to 29 items (HDRS 29 For the 17-item version, a score of 0-7 is generally considered normal, while a score of 20 or greater may indicate moderate or severe depression.

[0242] In some embodiments, the baseline HDRS score comprises a numerical value, such as a point number. In some embodiments, the numerical value is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or a range defined by any two of the foregoing numerical values. In some embodiments, the numerical value is 1-5. In some embodiments, the numerical value is 6-10. In some embodiments, the numerical value is 11-15. In some embodiments, the numerical value is 16-20. In some embodiments, the numerical value is 21-25. In some embodiments, the numerical value is 26 to 30. In some embodiments, the numerical value is 31 to 35. In some embodiments, the numerical value is 36 to 40. In some embodiments, the numerical value is 41 to 45. In some embodiments, the numerical value is 46 to 50. In some embodiments, the numerical value is 51 or 52. In some embodiments, the numerical value is 1 to 50. In some embodiments, the numerical value is 1 to 52. In some embodiments, the baseline HDRS score includes a baseline subscore, such as a baseline depressed mood score, a baseline guilt score, a baseline suicidal ideation score, a baseline difficulty falling asleep score, a baseline difficulty staying asleep score, a baseline early morning sleep disturbance score, a baseline task and interest score, a baseline psychomotor inhibition score, a baseline agitation score, a baseline anxiety score, a baseline somatic anxiety score, a baseline gastrointestinal somatic symptom score, a baseline general somatic symptom score, a baseline genital symptom score, a baseline hypochondriasis score, a baseline weight loss score, or a baseline illness insight score. The baseline subscore may include 0, 1, or 2, or any such range of values. The baseline subscore may include 0, 1, 2, 3, or 4, or any such range of values.In some embodiments, baseline HDRS score comprises a numerical value that is at or above the threshold value that indicates depressive disorder.For example, an HDRS score of 20 or above may indicate moderate to severe depression.In some cases, the subject is depressed before treatment, and the HDRS score is above 19.In some cases, the subject is mildly depressed before treatment, and the HDRS score is above 7.In some embodiments, baseline subscore comprises a numerical value that is at or above the threshold value that indicates depressive disorder.

[0243] In some embodiments, the baseline measure is a baseline anxiety measure. The baseline anxiety measure can include a baseline assessment of anxiety signs or symptoms (e.g., baseline anxiety signs or symptoms). Examples of anxiety signs or symptoms include stress (e.g., stress disproportionate to the impact of an event), worry (e.g., inability to ignore worries), or restlessness. In some cases, anxiety symptoms include one or more behavioral symptoms, such as hypervigilance, irritability, or restlessness. In some cases, anxiety symptoms include one or more cognitive symptoms, such as difficulty concentrating, racing thoughts, or unwanted thoughts. In some cases, anxiety symptoms include one or more systemic symptoms, such as fatigue or excessive sweating. In some cases, anxiety symptoms include excessive worry, fear, a feeling that something bad is about to happen, insomnia, nausea, palpitations, or trembling. In some embodiments, the symptoms include one or more panic attacks. The baseline assessment can include the degree, frequency, duration, or intensity of anxiety or anxiety symptoms. The baseline assessment may include the time since the anxiety or symptoms were experienced. The baseline assessment may include the frequency with which the anxiety or symptoms are experienced.

[0244] In some embodiments, the baseline measure is a baseline eating disorder measure. In some embodiments, the baseline measure is a baseline eating disorder sign or symptom. Examples of eating disorders include anorexia, bulimia, binge eating disorder, pica, rumination disorder, or avoidant eating disorder. In some embodiments, the eating disorder comprises anorexia nervosa. In some embodiments, the eating disorder comprises bulimia. In some embodiments, the eating disorder comprises binge eating. In some embodiments, the eating disorder comprises pica. The baseline eating disorder measure can include a baseline assessment of an eating disorder sign or symptom (e.g., baseline eating disorder sign or symptom). Some examples of symptoms of eating disorders, including anorexia nervosa, include being significantly underweight compared to people of similar age and height, having very restrictive eating patterns, having a strong fear of weight gain or continuing weight-avoidance behaviors despite being underweight, a persistent pursuit of thinness and not wanting to maintain a healthy weight, having perceptions of weight or shape that significantly affect self-esteem, having a distorted body image, or denial of the seriousness of being underweight. Baseline assessments can include the extent, frequency, duration, or intensity of the eating disorder, or the extent, frequency, duration, or intensity of experiencing eating disorder symptoms. Baseline assessments can include the time since the eating disorder began, or the time since experiencing eating disorder symptoms. Baseline assessments can include the frequency of the eating disorder, or the frequency of experiencing eating disorder symptoms.

[0245] In some embodiments, the baseline measure is a baseline substance use measure. In some embodiments, the baseline substance use measure includes a baseline determination of the level of addiction to an addictive substance. Examples of addictive substances include alcohol, anxiolytics, sedatives, caffeine, cannabis (e.g., including marijuana or synthetic cannabinoids), hallucinogens (e.g., LSD, phencyclidine, or psilocybin), inhalants (e.g., paint thinner or some glues), opioids (e.g., fentanyl, morphine, or oxycodone), stimulants (e.g., amphetamine or cocaine), tobacco, or anabolic steroids. The baseline determination of the level of addiction to an addictive substance may include a questionnaire or assessment. The baseline determination of the level of addiction to an addictive substance may include the time since the addictive substance was taken. The baseline determination of the level of addiction to an addictive substance may include the frequency of taking the addictive substance. The baseline assessment may include the extent, frequency, duration, or intensity of having a substance use disorder or the extent, frequency, duration, or intensity of experiencing symptoms of a substance use disorder. The baseline assessment may include the time since having a substance use disorder or the time since experiencing symptoms of a substance use disorder. The baseline assessment may include the frequency of having a substance use disorder or the frequency of experiencing symptoms of a substance use disorder. The baseline assessment may include signs or symptoms of a substance use disorder. Exemplary signs and symptoms may include regularly (e.g., daily) wanting to use the substance, having intense urges to use the substance, needing more of the substance to obtain the effects previously obtained, and continuing to use the substance despite knowing that use of the substance causes problems in normal life activities.

[0246] In some embodiments, the baseline measure comprises a baseline post-traumatic stress disorder (PTSD) measure. In some embodiments, the baseline PTSD measure comprises a baseline determination of PTSD severity level. The baseline assessment of PTSD signs or symptoms may comprise the number of PTSD signs or symptoms. The baseline determination of PTSD severity level may comprise the time since the last PTSD flashback (e.g., reliving the traumatic event as if it were happening again), nightmare, or severe anxiety. The baseline assessment may comprise the frequency of PTSD-related flashbacks, nightmares, or severely anxious events. The baseline assessment may comprise the severity of PTSD signs or symptoms. The baseline assessment may comprise the frequency of PTSD signs or symptoms. Exemplary signs and symptoms of PTSD may include intrusive memories (e.g., recurring, involuntary, upsetting memories of the traumatic event), extreme mental distress or physical reactions to reminders of the traumatic event, trying to avoid thinking or talking about the traumatic event, avoiding places, activities, or people that remind one of the event, feelings of hopelessness, difficulty remembering, difficulty maintaining intimate relationships, and feeling a loss of interest in activities previously found enjoyable.

[0247] In some embodiments, the baseline measure comprises a baseline bipolar disorder measure. In some embodiments, the baseline bipolar disorder measure is a sign or symptom of bipolar disorder. The baseline assessment of a sign or symptom of bipolar disorder may comprise the frequency of a sign or symptom of bipolar disorder. The baseline assessment of a sign or symptom of bipolar disorder may comprise the severity of a sign or symptom of bipolar disorder. The baseline assessment of a sign or symptom of bipolar disorder may comprise the number of signs or symptoms of bipolar disorder. Exemplary signs or symptoms of bipolar disorder include any of the signs or symptoms of bipolar disorder disclosed herein, including a manic episode (e.g., experiencing increased activity, energy, or agitation, excessive happiness and self-esteem, a decreased need for sleep, racing thoughts, distractibility, and decreased ability to control impulses) and a major depressive episode (e.g., experiencing a depressed mood, a marked lack of interest or happiness, fatigue or loss of energy, feelings of guilt or worthlessness, decreased ability to think or concentrate).

[0248] In some embodiments, the baseline measures include baseline schizophrenia measures. In some embodiments, the baseline schizophrenia measures are signs or symptoms of schizophrenia. The baseline assessment of signs or symptoms of schizophrenia may include the frequency of signs or symptoms of schizophrenia. The baseline assessment of signs or symptoms of schizophrenia may include the severity of signs or symptoms of schizophrenia. The baseline assessment of signs or symptoms of schizophrenia may include the number of signs or symptoms of schizophrenia. Exemplary signs and symptoms of schizophrenia may include delusions, hallucinations, disorganized thinking and speech, disorganized or abnormal motor behavior, and negative symptoms (e.g., social withdrawal, anhedonia, loss of motivation, decreased sense of purpose, loss of interest in activities, flat affect, lack of eye contact, and hypoactivity).

[0249] In some embodiments, the baseline measure comprises a baseline psychosis measure. In some embodiments, the baseline psychosis measure is a baseline sign or symptom of psychosis (e.g., a baseline psychosis sign or symptom). The baseline assessment of psychosis signs or symptoms may include the frequency of psychosis signs or symptoms. The baseline assessment of psychosis signs or symptoms may include the severity of psychosis signs or symptoms. The baseline assessment of psychosis signs or symptoms may include the number of psychosis signs or symptoms. Exemplary signs and symptoms of psychosis may include difficulty concentrating, depressed mood, anxiety, excessive distrust, delusions, and hallucinations.

[0250] In some embodiments, the baseline measurement includes a baseline measurement of a neurological disorder. Non-limiting examples of baseline measurements of a neurological disorder include a baseline measurement of cognitive function, a baseline measurement of amyloid plaques (e.g., accumulation) in the CNS, a baseline measurement of tau accumulation in the CNS, a baseline measurement of beta-amyloid 42 (e.g., accumulation) in the CSF, a baseline measurement of tau (e.g., accumulation) in the CSF, a baseline measurement of phosphorylated tau (e.g., accumulation) in the CSF, a baseline measurement of Lewy bodies (e.g., accumulation), or a baseline measurement of alpha-synuclein (e.g., accumulation) in the CSF. Further non-limiting examples of baseline measurements include a baseline measurement of headache signs and / or symptoms, a baseline measurement of migraine symptoms and / or symptoms, a baseline measurement of chronic pain symptoms and / or symptoms, a baseline measurement of fibromyalgia symptoms and / or symptoms, a baseline measurement of chronic fatigue syndrome (ME) symptoms and / or symptoms, and a baseline measurement of motor neuron disease (e.g., ALS) symptoms and / or symptoms.

[0251] In some embodiments, the baseline measurement includes a baseline CNS amyloid plaque accumulation measurement. Exemplary CNS amyloid plaque accumulation measurements include the total amount of amyloid plaques in the CNS (e.g., brain) and the concentration of amyloid plaques in a region of the CNS (e.g., brain). CNS amyloid plaque accumulation can be measured in any suitable manner, including, but not limited to, measuring CNS amyloid plaques using immunoprecipitation mass spectrometry, blood tests, cerebrospinal fluid tests, and measuring CNS amyloid plaques using imaging (e.g., amyloid PET scan(s)).

[0252] In some embodiments, the baseline measurement includes baseline tau (e.g., CNS or CSF) accumulation. Exemplary tau (e.g., CNS or CSF) accumulation measurements can include the total amount of tau accumulation in the CNS (e.g., brain or CSF) and the concentration of tau in a region of the CNS (e.g., brain or CSF). Tau (e.g., CNS or CSF) accumulation can be measured in any suitable manner, including, but not limited to, imaging (e.g., tau PET scan), blood tests, and cerebrospinal fluid tests.

[0253] In some embodiments, the baseline measurement includes baseline CSF β-amyloid 42 accumulation. Exemplary CSF β-amyloid 42 accumulation measurements may include total β-amyloid 42 accumulation in the CNS (e.g., CSF) and the concentration of β-amyloid 4 in a region of the CNS (e.g., CSF). CSF β-amyloid 4 accumulation may be measured in any suitable manner, including, but not limited to, imaging (e.g., PET scan), blood tests, and cerebrospinal fluid tests.

[0254] In some embodiments, the baseline measurement includes baseline CSF β-amyloid 42 accumulation. Exemplary CSF β-amyloid 42 accumulation measurements may include total β-amyloid 42 accumulation in the CNS (e.g., CSF) and the concentration of β-amyloid 4 in a region of the CNS (e.g., CSF). CSF β-amyloid 4 accumulation may be measured in any suitable manner, including, but not limited to, imaging (e.g., PET scan), blood tests, and cerebrospinal fluid tests.

[0255] In some embodiments, the baseline measurement includes baseline phosphorylated tau accumulation (e.g., in CSF). Exemplary measurements of phosphorylated tau (e.g., 181) accumulation (e.g., in CSF) may include the total amount of phosphorylated tau accumulation in the CNS (e.g., CSF or brain) and the concentration of phosphorylated tau (e.g., in CSF) in a region of the CNS (e.g., CSF or brain). Phosphorylated tau (CSF phosphorylated tau) accumulation can be measured in any suitable manner, including, but not limited to, imaging (e.g., PET scan), blood test, and cerebrospinal fluid test.

[0256] In some embodiments, the baseline measurement includes baseline Lewy body accumulation. Exemplary measurements of Lewy body accumulation include the total amount of Lewy body accumulation in the CNS (e.g., brain) and the concentration of Lewy bodies in a region of the CNS (e.g., brain). Lewy body accumulation can be measured in any suitable manner, including, but not limited to, imaging (e.g., PET scan, MRI, CT scan, fluorodeoxyglucose PET scan, or single-photon emission computed tomography (SPECT)), blood tests, and cerebrospinal fluid tests.

[0257] In some embodiments, the baseline measurement includes baseline alpha-synuclein accumulation (e.g., in the CSF). Exemplary measurements of alpha-synuclein accumulation (e.g., in the CSF) may include the total amount of alpha-synuclein accumulation in the CNS (e.g., in the CSF or brain) and the concentration of alpha-synuclein in a region of the CNS (e.g., in the CSF). Alpha-synuclein (CSF alpha-synuclein) accumulation may be measured in any suitable manner, including, but not limited to, imaging (e.g., PET scan), blood tests, cerebrospinal fluid tests, and biopsy tests (e.g., Syn-One tests).

[0258] In some embodiments, the baseline measurement is a baseline cognitive function measurement. The baseline cognitive function measurement can be obtained directly from the subject. For example, the subject can be administered a test. The test can include a cognitive test such as the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), or the Mini-Cog. The test can include an assessment of basic cognitive functions such as memory, language, executive frontal lobe function, motor apraxia, visuospatial ability, behavior, mood, orientation, or attention. The baseline cognitive function measurement can include a score. The baseline cognitive function measurement can indicate mild cognitive impairment or severe cognitive impairment. The baseline cognitive function measurement can indicate neurological disorders.

[0259] In some embodiments, the baseline measurement is a baseline amyloid plaque measurement. The baseline amyloid plaque measurement may include a central nervous system (CNS) amyloid plaque measurement. In some embodiments, the baseline amyloid plaque measurement includes a baseline concentration or amount. The baseline amyloid plaque measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The baseline amyloid plaque measurement may be performed by biopsy. The baseline amyloid plaque measurement may be performed using a spinal tap (e.g., where the baseline amyloid plaque measurement includes a baseline cerebrospinal fluid (CSF) amyloid plaque measurement). In some embodiments, the baseline amyloid plaque measurement is obtained by an assay such as an immunoassay. Baseline beta amyloid plaque measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease.

[0260] In some embodiments, the baseline measurement is a baseline β-amyloid 42 measurement. The baseline β-amyloid 42 measurement may include a cerebrospinal fluid (CSF) β-amyloid 42 measurement. In some embodiments, the baseline β-amyloid 42 measurement includes a baseline concentration or amount. The baseline β-amyloid 42 measurement may be performed by biopsy. The baseline β-amyloid 42 measurement may be performed using a spinal tap (e.g., where the baseline β-amyloid 42 measurement includes a baseline CSF β-amyloid 42 measurement). In some embodiments, the baseline β-amyloid 42 measurement is obtained by an assay such as an immunoassay. The baseline β-amyloid 42 measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease.

[0261] In some embodiments, the baseline measurement is a baseline tau measurement. In some embodiments, the baseline tau measurement comprises a baseline concentration or amount. The baseline tau measurement may be performed on a biopsy. In some embodiments, the baseline tau measurement is obtained by an assay such as an immunoassay. The baseline tau measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

[0262] In some embodiments, the baseline tau measurement is a baseline central nervous system (CNS) tau measurement. The baseline tau measurement may include a baseline total tau measurement. The baseline tau measurement may include a baseline non-phosphorylated tau measurement. The baseline tau measurement may include a baseline phosphorylated tau (phospho-tau) measurement. In some embodiments, the baseline tau measurement is a baseline tau accumulation measurement. In some embodiments, the baseline tau measurement is a baseline CNS tau accumulation measurement. The baseline CNS tau accumulation measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

[0263] Baseline tau measurements can include cerebrospinal fluid (CSF) tau measurements. Baseline CSF tau measurements can be performed after the use of spinal tap. Baseline CSF tau measurements can indicate neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.

[0264] Baseline CSF tau measurement can include baseline CSF phosphorylated tau measurement.Baseline CSF phosphorylated tau measurement can include the amount of phosphorylated tau relative to total tau or non-phosphorylated tau.For example, baseline CSF phosphorylated tau measurement can include phosphorylated tau / tau ratio.Baseline CSF phosphorylated tau measurement can indicate neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.

[0265] In some embodiments, the baseline measurement is a baseline Lewy body measurement. The baseline Lewy body measurement may include a central nervous system (CNS) Lewy body measurement. In some embodiments, the baseline Lewy body measurement includes a baseline concentration or amount. The baseline Lewy body measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. Baseline beta Lewy body measurements may be indicative of dementia.

[0266] In some embodiments, the baseline measurement is a baseline alpha-synuclein measurement. The baseline alpha-synuclein measurement may include a cerebrospinal fluid (CSF) alpha-synuclein measurement. In some embodiments, the baseline alpha-synuclein measurement comprises a baseline concentration or amount. The baseline alpha-synuclein measurement may be performed by biopsy. The baseline alpha-synuclein measurement may be performed using a spinal tap (e.g., where the baseline alpha-synuclein measurement includes a baseline CSF alpha-synuclein measurement). In some embodiments, the baseline alpha-synuclein measurement is obtained by an assay such as an immunoassay. The baseline alpha-synuclein measurement may be indicative of a neurodegenerative disease such as Parkinson's disease. The baseline alpha-synuclein measurement may be indicative of dementia.

[0267] In some embodiments, the baseline headache measure is a baseline headache measure. In some embodiments, the baseline headache measure is a baseline headache sign or symptom measure. In some embodiments, the baseline headache measure is a baseline migraine (e.g., with or without aura) measure. In some embodiments, the baseline headache measure is a measure of the frequency of headache signs or symptoms. In some embodiments, the baseline headache measure is a measure of the severity of headache signs or symptoms. In some embodiments, the baseline headache measure is the number of headache signs or symptoms. Exemplary signs and symptoms of headache include pain (e.g., deep and constant) in the cheekbones, forehead, bridge of the nose, skull, or back of the neck, aura, photophobia, phonophobia, and vomiting.

[0268] In some embodiments, the baseline measure is a baseline chronic pain measure. In some embodiments, the baseline chronic pain measure is a baseline fibromyalgia measure. In some embodiments, the baseline chronic pain measure is a baseline chronic pain sign or symptom measure. In some embodiments, the baseline chronic pain measure is a measure of the frequency of chronic pain signs or symptoms. In some embodiments, the baseline chronic pain measure is a measure of the severity of chronic pain signs or symptoms. In some embodiments, the baseline chronic pain measure is the number of chronic pain signs or symptoms. Exemplary signs and symptoms of fibromyalgia include muscle pain, fatigue, depression, anxiety, insomnia, headache, and difficulty concentrating. Exemplary chronic pain disorders include post-surgical pain, post-traumatic pain, back pain, cancer pain, arthritic pain, muscle pain, and neuropathic pain (e.g., diabetic neuropathy).

[0269] In some embodiments, the baseline measure is a baseline chronic fatigue syndrome (also known as myalgic encephalomyelitis) measure. In some embodiments, the baseline chronic fatigue syndrome measure is a baseline chronic fatigue syndrome sign or symptom measure. In some embodiments, the baseline chronic fatigue syndrome measure is a measure of headache sign or symptom frequency. In some embodiments, the baseline chronic fatigue syndrome measure is a measure of chronic fatigue syndrome sign or symptom severity. In some embodiments, the baseline chronic fatigue syndrome n measure is the number of chronic fatigue syndrome signs or symptoms. Exemplary signs and symptoms of chronic fatigue syndrome include extreme fatigue that persists for a long period of time (e.g., at least 6 months) and cannot be fully explained by an underlying medical condition, fatigue that worsens with physical or mental activity, pain (e.g., in the joints or muscles), fatigue, forgetfulness, anxiety, and depression.

[0270] In some embodiments, the baseline measure is a baseline motor neuron disease measure. In some embodiments, the baseline motor neuron disease measure is an amyotrophic lateral sclerosis (ALS) measure. In some embodiments, the baseline motor neuron disease measure is a baseline motor neuron disease sign or symptom measure. In some embodiments, the baseline motor neuron disease measure is a measure of the frequency of motor neuron disease signs or symptoms. In some embodiments, the baseline motor neuron disease measure is a measure of the severity of motor neuron disease signs or symptoms. In some embodiments, the baseline motor neuron disease measure is the number of motor neuron disease signs or symptoms. Exemplary forms of motor neuron disease include progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), ALS, and primary lateral sclerosis (PLS). Exemplary signs and symptoms of motor neuron disease include difficulty controlling movement (e.g., difficulty walking or performing normal daily activities), muscle weakness, decreased speech intelligibility, difficulty swallowing, and muscle spasms and cramps (e.g., in the arms, shoulders, or tongue).

[0271] In some embodiments, the baseline measurement is a baseline fibrinogen level. In some embodiments, the baseline measurement is a baseline circulating fibrinogen level.

[0272] In some embodiments, the baseline measurement is a baseline coagulation or blood clotting measurement. In some embodiments, the baseline measurement is a baseline clotting time measurement. In some embodiments, the baseline measurement is a baseline prothrombin time (PT). In some embodiments, the baseline measurement is a baseline international normalized ratio (INR). In some embodiments, the baseline measurement is a baseline activated partial thromboplastin time (apTT).

[0273] In some cases, the disorder (baseline measurement) can be diagnosed or measured by using a questionnaire or scoring system. In some cases, the disorder is diagnosed according to DSM-5 criteria. In some cases, the disorder is diagnosed by a medical professional (e.g., a doctor, etc.).

[0274] The baseline measurement may include a baseline FGG protein measurement or a baseline FGG mRNA measurement.

[0275] The baseline measurements may include any one or more of the baseline measurements disclosed herein.

[0276] In some embodiments, the baseline measurements are obtained directly from the subject. The baseline measurements are obtained by observation, for example, by observation of the subject or tissue of the subject. In some embodiments, the baseline measurements are obtained non-invasively using an imaging device. In some embodiments, the baseline measurements are obtained invasively using an imaging device.

[0277] In some embodiments, the baseline measurement is obtained on a sample from the subject. In some embodiments, the baseline measurement is obtained on one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay, such as an immunoassay, a colorimetric assay, or a fluorescent assay, on a sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescent assay, or a chromatographic (e.g., HPLC) assay. In some embodiments, the baseline measurement is obtained by PCR.

[0278] In some embodiments, the baseline measurement is a baseline FGG protein measurement. In some embodiments, the baseline FGG protein measurement comprises a baseline FGG protein level. In some embodiments, the baseline FGG protein level is expressed as mass or percentage of FGG protein per sample weight. In some embodiments, the baseline FGG protein level is expressed as mass or percentage of FGG protein per sample volume. In some embodiments, the baseline FGG protein level is expressed as mass or percentage of FGG protein per total protein in the sample. In some embodiments, the baseline FGG protein measurement is a baseline tissue FGG protein measurement. In some embodiments, the baseline FGG protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescent assay. In some embodiments, the baseline FGG protein level is measured in the whole body. In some embodiments, the baseline FGG protein level is measured in the brain. In some embodiments, the baseline FGG protein level is measured in the liver. In some embodiments, the baseline FGG protein level is measured in the blood.

[0279] In some embodiments, the baseline measurement is a baseline FGG mRNA measurement. In some embodiments, the baseline FGG mRNA measurement comprises a baseline FGG mRNA level. In some embodiments, the baseline FGG mRNA level is measured in the liver. In some embodiments, the baseline FGG mRNA level is expressed as the amount or percentage of FGG mRNA per sample weight. In some embodiments, the baseline FGG mRNA level is expressed as the amount or percentage of FGG mRNA per sample volume. In some embodiments, the baseline FGG mRNA level is expressed as the amount or percentage of FGG mRNA per total mRNA in the sample. In some embodiments, the baseline FGG mRNA level is expressed as the amount or percentage of FGG mRNA per total nucleic acid in the sample. In some embodiments, the baseline FGG mRNA level is expressed relative to another mRNA level, such as the mRNA level of a housekeeping gene in the sample. In some embodiments, the baseline FGG mRNA measurement comprises a baseline tissue FGG mRNA measurement. In some embodiments, the baseline FGG mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay. In some embodiments, the PCR comprises quantitative PCR (qPCR). In some embodiments, the PCR comprises reverse transcription of the FGG mRNA.

[0280] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, a baseline measurement is obtained in a sample obtained from the subject. In some embodiments, the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein. In some embodiments, the baseline measurement is obtained in a sample obtained from the subject prior to administration of a composition to the subject. In some embodiments, the sample is obtained from the subject in a fasting state. In some embodiments, the sample is obtained from the subject after an overnight fasting period. In some embodiments, the sample is administered to the subject in a fed state.

[0281] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, the sample comprises blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole blood sample. In some embodiments, the blood is fractionated or centrifuged. In some embodiments, the sample comprises plasma. In some embodiments, the sample is a plasma sample. In some embodiments, the sample can be a plasma sample. In some embodiments, the sample comprises serum. In some embodiments, the sample is a serum sample. In some embodiments, the sample can be a serum sample. In some embodiments, the sample is a CSF sample. In some embodiments, the sample is a CSF sample. In some embodiments, the sample is a CNS sample. In some embodiments, the sample comprises a CNS sample.

[0282] In some embodiments, the sample comprises tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the tissue is liver tissue or brain tissue. For example, baseline FGG mRNA measurements or baseline FGG protein measurements may be obtained in a brain or liver sample obtained from a patient. In some embodiments, the tissue comprises neural tissue. In some embodiments, the tissue comprises neural tissue. In some embodiments, the tissue comprises neurons. In some embodiments, the tissue comprises glial cells. In some embodiments, the tissue comprises epithelial cells. In some embodiments, the tissue comprises liver tissue. The liver may comprise hepatocytes. In some embodiments, the tissue comprises brain tissue. In some embodiments, the sample comprises CSF fluid.

[0283] In some embodiments, the sample comprises a cell. In some embodiments, the sample comprises a cell. In some embodiments, the cell comprises a liver cell (e.g., a hepatocyte) or a brain cell. In some embodiments, the cell is a liver cell. In some embodiments, the liver cell is a hepatocyte. In some embodiments, the cell is a 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 epithelial cell. In some embodiments, the cell is a vasculature cell.

[0284] D.Effects In some embodiments, the composition or administration of the composition affects a measurement, such as a mental disorder (e.g., a psychiatric or neurological disorder) measurement. In some embodiments, the composition or administration of the composition affects a measurement, such as a psychometric measurement (e.g., a Montgomery-Asberg Depression Rating Scale (MADRS) score, a Hamilton Depression Rating Scale (HDRS) score, signs or symptoms of anxiety, signs or symptoms of an eating disorder, signs or symptoms of a substance use disorder, signs or symptoms of post-traumatic stress disorder (PTSD), signs or symptoms of bipolar disorder, signs or symptoms of schizophrenia, or signs or symptoms of psychosis). In some embodiments, the composition or administration of the composition affects a measurement, such as a psychometric measurement, compared to a baseline measurement. In some embodiments, administration of the composition affects a measurement of any of the aspects of Tables 1A-1C and 2A-2B. The measurement may include a fibrinogen measurement, an FGG mRNA measurement, or an FGG protein measurement. The measurements may include coagulation measurements, prothrombin time (PT) measurements, international normalized ratio (INR) measurements, or activated partial thromboplastin time (aPTT) measurements.

[0285] In some embodiments, the composition or administration of the composition affects a neurological measure (e.g., cognitive decline, amyloid plaques (e.g., accumulation) in the CNS, tau accumulation in the CNS, beta-amyloid 42 (e.g., accumulation) in the CSF, tau (e.g., accumulation) in the CSF, phosphorylated tau (e.g., accumulation) in the CSF, Lewy bodies (e.g., accumulation), alpha-synuclein (e.g., accumulation) in the CSF, signs or symptoms of headache, signs or symptoms of migraine, signs or symptoms of chronic pain, signs or symptoms of fibromyalgia, signs or symptoms of chronic fatigue (ME), signs or symptoms of motor neuron disease, or signs or symptoms of ALS). In some embodiments, the composition or administration of the composition affects a measure, such as a neurological measure, as compared to a baseline measure.

[0286] In some embodiments, the measured value indicates that the disorder has been treated. In some embodiments, the measured value indicates that the severity of the disorder has been reduced. In some embodiments, the measured value indicates that the severity of a sign or symptom of the disorder has been reduced. In some embodiments, the measured value indicates that the frequency of a sign or symptom of the disorder has been reduced.

[0287] Some embodiments of the methods described herein include obtaining a measurement from a subject. For example, the measurement may be obtained from the subject after treating the subject. In some embodiments, the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after administering the composition to the subject. In some embodiments, the measurement is indicative of the disorder being treated.

[0288] In some embodiments, the measurements are obtained directly from the subject. In some embodiments, the measurements are obtained non-invasively using an imaging device. In some embodiments, the measurements are obtained in a second sample from the subject. In some embodiments, the measurements are obtained in one or more histological tissue sections. In some embodiments, the measurements are obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurements are obtained by an assay such as an assay described herein. In some embodiments, the assay is an immunoassay, a colorimetric assay, a fluorescent assay, a chromatographic (e.g., HPLC) assay, or a PCR assay. In some embodiments, the measurements are obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescent assay, or a chromatographic (e.g., HPLC) assay. In some embodiments, the measurements are obtained by PCR. In some embodiments, the measurements are obtained by histology. In some embodiments, the measurements are obtained by observation. In some embodiments, additional measurements are made in a third sample, a fourth sample, a fifth sample, etc.

[0289] In some embodiments, measurements are obtained within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after administration of the composition. In some embodiments, measurements are obtained within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the composition. In some embodiments, measurements are obtained within 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years after administration of the composition. In some embodiments, measurements are obtained 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after administration of the composition. In some embodiments, measurements are obtained 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the composition. In some embodiments, measurements are obtained 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years after administration of the composition.

[0290] In some embodiments, the composition reduces the measurement compared to a baseline measurement. For example, an adverse phenotype of a psychiatric or neurological disorder may be reduced by administration of the composition. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline measurement. In some embodiments, the measurement is reduced by about 10% or more compared to the baseline measurement. In some embodiments, the measurement is reduced 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, or about 90% or more compared to the baseline measurement. In some embodiments, the measurement is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline measurement. In some embodiments, the measurement is reduced by about 10% or less compared to the baseline measurement. In some embodiments, the measurement is decreased by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to the baseline measurement, hi some embodiments, the measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0291] In some embodiments, the composition increases the measurement compared to a baseline measurement. For example, a protective phenotype of a psychiatric or neurological disorder may be increased upon administration of the composition. In some embodiments, the increase is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement increases by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline measurement. In some embodiments, the measurement increases by about 10% or more compared to the baseline measurement. In some embodiments, the measurement increases 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, or about 90% or more compared to the baseline measurement. In some embodiments, the measurement increases by about 100% or more, about 250% or more, about 500% or more, about 750% or more, or about 1000% or more compared to the baseline measurement. In some embodiments, the measurement increases by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline measurement. In some embodiments, the measurement increases by about 10% or less compared to the baseline measurement. In some embodiments, the measurement increases by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% or less compared to the baseline measurement. In some embodiments, the measurement increases by about 100%, about 250%, about 500%, about 750%, or about 1000% or less compared to the baseline measurement. In some embodiments, the measurement increases by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or a range defined by any two of the foregoing percentages.

[0292] In some embodiments, the measured value is a baseline Montgomery-Asberg Depression Rating Scale (MADRS) score. In some embodiments, the MADRS score comprises a numerical value, such as a point value. In some embodiments, the numerical value is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60, or a range defined by any two of the foregoing numerical values. In some embodiments, the numerical value is 0. In some embodiments, the number is between 1 and 5. In some embodiments, the number is between 6 and 10. In some embodiments, the number is between 11 and 15. In some embodiments, the number is between 16 and 20. In some embodiments, the number is between 21 and 25. In some embodiments, the number is between 26 and 30. In some embodiments, the number is between 31 and 35. In some embodiments, the number is between 36 and 40. In some embodiments, the number is between 41 and 45. In some embodiments, the number is between 46 and 50. In some embodiments, the number is between 51 and 55. In some embodiments, the number is between 56 and 60. In some embodiments, the number is between 0 and 60. In some embodiments, the MADRS score includes subscores such as an outward sadness score, a verbal sadness score, an inner tension score, a decreased sleep score, a decreased appetite score, difficulty concentrating score, an inhibition score, an inability to feel emotion score, a pessimistic thinking score, or a suicidal thoughts score. Each subscore can comprise a value of 0, 1, 2, 3, 4, 5, or 6, or a range of such values. In some embodiments, the MADRS score comprises a value below a threshold value indicative of a depressive disorder. In some embodiments, the subscore comprises a value below a threshold value indicative of a depressive disorder.

[0293] In some embodiments, the composition reduces the MADRS score compared to the baseline MADRS score. In some embodiments, the reduction in the MADRS score is obtained by observing and / or questioning the subject after administering the composition to the subject. In some embodiments, the MADRS score is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline MADRS score. In some embodiments, the MADRS score is reduced by about 10% or more compared to the baseline MADRS score. In some embodiments, the MADRS score is reduced 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, or about 90% or more compared to the baseline MADRS score. In some embodiments, the MADRS score is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline MADRS score. In some embodiments, the MADRS score is reduced by about 10% or less compared to the baseline MADRS score. In some embodiments, the MADRS score is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to the baseline MADRS score, hi some embodiments, the MADRS score is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages. In some embodiments, the MADRS score is reduced by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 56, 57, 58, 59, or 60 points compared to the baseline MADRS score, or a range of points defined by any two of the foregoing points compared to the baseline MADRS score.In some embodiments, the MADRS score decreases by 1 to 5 points. In some embodiments, the MADRS score decreases by 6 to 10 points. In some embodiments, the MADRS score decreases by 11 to 15 points. In some embodiments, the MADRS score decreases by 16 to 20 points. In some embodiments, the MADRS score decreases by 21 to 25 points. In some embodiments, the MADRS score decreases by 26 to 30 points. In some embodiments, the MADRS score decreases by 31 to 35 points. In some embodiments, the MADRS score decreases by 36 to 40 points. In some embodiments, the MADRS score decreases by 41 to 45 points. In some embodiments, the MADRS score decreases by 46 to 50 points. In some embodiments, the MADRS score decreases by 51 to 55 points. In some embodiments, the MADRS score decreases by 56 to 60 points.

[0294] In some embodiments, after using oligonucleotide treatment, the MADRS score of the subject is reduced, and thereby the MADRS score of the subject changes from severe depression to mild or moderate depression, or normal, non-depressed symptoms.For example, the MADRS score of the subject can be less than 35 after treatment.In some embodiments, the MADRS score changes from moderate depression to mild depression, or normal, non-depressed symptoms.For example, the MADRS score of the subject can be less than 20 after treatment.In some embodiments, the MADRS score changes from mild depression to normal, non-depressed symptoms.For example, the MADRS score of the subject can be less than 7 after treatment.

[0295] In some embodiments, the measurement is a Hamilton Depression Rating Scale (HDRS) score. In some embodiments, the HDRS score comprises a numerical value, such as a point value. In some embodiments, the numerical value is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or a range defined by any two of the foregoing numerical values. In some embodiments, the numerical value is 0. In some embodiments, the numerical value is 1-5. In some embodiments, the numerical value is 6-10. In some embodiments, the numerical value is 11-15. In some embodiments, the numerical value is 16 to 20. In some embodiments, the numerical value is 21 to 25. In some embodiments, the numerical value is 26 to 30. In some embodiments, the numerical value is 31 to 35. In some embodiments, the numerical value is 36 to 40. In some embodiments, the numerical value is 41 to 45. In some embodiments, the numerical value is 46 to 50. In some embodiments, the numerical value is 0 to 50. In some embodiments, the HDRS score includes subscores such as a depressed mood score, a guilt score, a suicidal ideation score, a sleep onset score, a sleep disturbance score, an early morning sleep disturbance score, a work and interest score, a psychomotor retardation score, a irritability score, an anxiety score, a somatic anxiety score, a gastrointestinal somatic symptom score, a general somatic symptom score, a genital symptom score, a hypochondriasis score, a weight loss score, or an illness awareness score. Subscores can include numerical values ​​of 0, 1, or 2, or ranges of such values. Subscores can include numerical values ​​of 0, 1, 2, 3, or 4, or ranges of such values. In some embodiments, the HDRS score comprises a value below the threshold value that indicates a depressive disorder.For example, a score of less than 20 may indicate the absence of moderate or severe depression.In some embodiments, the subscore comprises a value below the threshold value that indicates a depressive disorder.

[0296] In some embodiments, the composition reduces the HDRS score compared to the baseline HDRS score. In some embodiments, the reduction in HDRS score is obtained by observing and / or questioning the subject after administering the composition to the subject. In some embodiments, the HDRS score is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline HDRS score. In some embodiments, the HDRS score is reduced by about 10% or more compared to the baseline HDRS score. In some embodiments, the HDRS score is reduced 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, or about 90% or more compared to the baseline HDRS score. In some embodiments, the HDRS score is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline HDRS score. In some embodiments, the HDRS score is reduced by about 10% or less compared to the baseline HDRS score. In some embodiments, the HDRS score is reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to the baseline HDRS score. In some embodiments, the HDRS score is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages. In some embodiments, the HDRS score is reduced by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 56, 57, 58, 59, or 60 points compared to the baseline HDRS score, or a range defined by any two of the foregoing numbers compared to the baseline HDRS score.In some embodiments, the HDRS score decreases by 1 to 5 points. In some embodiments, the HDRS score decreases by 6 to 10 points. In some embodiments, the HDRS score decreases by 11 to 15 points. In some embodiments, the HDRS score decreases by 16 to 20 points. In some embodiments, the HDRS score decreases by 21 to 25 points. In some embodiments, the HDRS score decreases by 26 to 30 points. In some embodiments, the HDRS score decreases by 31 to 35 points. In some embodiments, the HDRS score decreases by 36 to 40 points. In some embodiments, the HDRS score decreases by 41 to 45 points. In some embodiments, the HDRS score decreases by 46 to 50 points. In some embodiments, the HDRS score decreases by 51 to 55 points. In some embodiments, the HDRS score decreases by 56 to 60 points.

[0297] In some embodiments, after using oligonucleotide treatment, the HDRS score of the subject is reduced, and thereby the HDRS score of the subject changes from severe depression to mild or moderate depression, or normal, non-depressed symptoms.In some embodiments, the HDRS score changes from moderate depression to mild depression, or normal, non-depressed symptoms.For example, the HDRS score of the subject can be less than 20 after treatment.In some embodiments, the HDRS score changes from mild depression to normal, non-depressed symptoms.For example, the HDRS score of the subject can be less than 8 after treatment.

[0298] In some embodiments, the measure is an anxiety measure. The anxiety measure can include an assessment of anxiety symptoms. In some embodiments, the anxiety symptom includes stress, worry, or restlessness. In some cases, the anxiety symptom includes one or more behavioral symptoms, such as hypervigilance, irritability, or restlessness. In some cases, the anxiety symptom includes one or more cognitive symptoms, such as difficulty concentrating, racing thoughts, or unwanted thoughts. In some cases, the anxiety symptom includes one or more general symptoms, such as fatigue or excessive sweating. In some cases, the anxiety symptom includes excessive worry, fear, a feeling that something bad is about to happen, insomnia, nausea, palpitations, or trembling. In some embodiments, the symptom includes one or more panic attacks. The anxiety measure can include a questionnaire or assessment. The assessment can include the degree, frequency, duration, or intensity of anxiety or anxiety symptoms. The anxiety measure can include the time since experiencing anxiety or the time since experiencing anxiety symptoms. The anxiety measure can include the frequency of feeling anxious or the frequency of experiencing anxiety symptoms. In some embodiments, the composition reduces the anxiety measure compared to a baseline anxiety measure. For example, the composition can reduce the anxiety measure by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0299] In some embodiments, the measure is an eating disorder measure. Examples of eating disorders include anorexia, bulimia, binge eating disorder, pica, rumination disorder, or avoidant eating disorder. In some embodiments, the eating disorder includes anorexia nervosa. In some embodiments, the eating disorder includes binge eating. In some embodiments, the eating disorder includes pica. The eating disorder measure can include an assessment of eating disorder symptoms. Some examples of eating disorder symptoms, including anorexia nervosa, include being very low in weight compared to people of similar age and height, having very restrictive eating patterns, having a strong fear of weight gain despite being low in weight or continuing to behave in a way that avoids weight gain, a persistent pursuit of thinness and not wanting to maintain a healthy weight, perceptions of weight or shape significantly impacting self-esteem, distorted body image, or denial of the significance of being underweight. The eating disorder measure can include a questionnaire or assessment. The assessment may include the degree, frequency, duration, or intensity of the eating disorder or symptoms. The eating disorder measure may include the time since the eating disorder (e.g., binding, purging, or fasting) began. The eating disorder measure may include the frequency of the eating disorder. In some embodiments, the composition reduces the eating disorder measure compared to a baseline eating disorder measure. For example, the composition may reduce the eating disorder measure by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0300] In some embodiments, the measure is a substance use measure. In some embodiments, the substance use measure includes determining the level of addiction to an addictive substance. Examples of addictive substances include alcohol, anxiolytics, sedatives, caffeine, cannabis (e.g., including marijuana or synthetic cannabinoids), hallucinogens (e.g., LSD, phencyclidine, or psilocybin), inhalants (e.g., paint thinner or some glues), opioids (e.g., fentanyl, morphine, or oxycodone), stimulants (e.g., amphetamine or cocaine), tobacco, or anabolic steroids. The substance abuse measure may include the time since the onset of a substance use disorder or the time since experiencing symptoms of a substance use disorder. The substance abuse measure may include the frequency of having a substance use disorder or the frequency of experiencing symptoms of a substance use disorder. The determination of the level of addiction to an addictive substance may include a questionnaire or assessment. The substance abuse measure or assessment may include the degree, frequency, duration, or intensity of the substance use disorder or symptoms. Determining the level of addiction to an addictive substance may include the time since ingesting the addictive substance. Determining the level of addiction to an addictive substance may include the frequency of ingesting the addictive substance. In some embodiments, the composition reduces a substance abuse measure compared to a baseline substance abuse measure. For example, the composition may reduce a substance abuse measure by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0301] In some embodiments, the measurement is a PTSD measurement. In some embodiments, the measurement of PTSD includes determining the severity level of PTSD. The assessment of PTSD signs or symptoms may include the number of PTSD signs or symptoms. The determination of PTSD severity level may include the time since the last PTSD flashback (e.g., reliving the traumatic event as if it were happening again), nightmare, or severe anxiety. The assessment may include the frequency of PTSD-related flashbacks, nightmares, or severely anxious events. The assessment may include the severity of PTSD signs or symptoms. The assessment may include the frequency of PTSD signs or symptoms. Exemplary signs and symptoms of PTSD may include intrusive memories (e.g., recurring, involuntary, upsetting memories of the traumatic event), extreme mental distress or physical reactions to reminders of the traumatic event, avoiding thoughts or conversations about the traumatic event, avoiding places, activities, or people that remind one of the event, feelings of hopelessness, difficulty remembering, difficulty maintaining intimate relationships, and feeling a loss of interest in activities previously enjoyed. In some embodiments, the composition reduces a PTSD measure compared to a baseline substance abuse measure. For example, the composition may reduce a PTSD measure by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0302] In some embodiments, the measure is a bipolar disorder measure. In some embodiments, the bipolar disorder measure is a sign or symptom of bipolar disorder. The assessment of signs or symptoms of bipolar disorder can include the frequency of signs or symptoms of bipolar disorder. The assessment of signs or symptoms of bipolar disorder can include the severity of signs or symptoms of bipolar disorder. The assessment of signs or symptoms of bipolar disorder can include the number of signs or symptoms of bipolar disorder. Exemplary signs or symptoms of bipolar disorder include any of the signs or symptoms of bipolar disorder disclosed herein, including a manic episode (e.g., experiencing increased activity, energy, or agitation, excessive happiness and self-esteem, a decreased need for sleep, flight of ideas, distractibility, and decreased impulse control) and a major depressive episode (e.g., experiencing a depressed mood, a significant lack of interest or happiness, fatigue or loss of energy, feelings of guilt or worthlessness, and a decreased ability to think or concentrate). In some embodiments, the composition reduces a bipolar disorder measure compared to a baseline substance abuse measure, e.g., the composition may reduce a bipolar disorder measure by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0303] In some embodiments, the measure comprises a schizophrenia measure. In some embodiments, the schizophrenia measure is a sign or symptom of schizophrenia. The assessment of a sign or symptom of schizophrenia may include the frequency of a sign or symptom of schizophrenia. The assessment of a sign or symptom of schizophrenia may include the severity of a sign or symptom of schizophrenia. The assessment of a sign or symptom of schizophrenia may include the number of signs or symptoms of schizophrenia. Exemplary signs and symptoms of schizophrenia may include delusions, hallucinations, disorganized thinking and speech, disorganized or abnormal motor behavior, and negative symptoms (e.g., social withdrawal, anhedonia, loss of motivation, decreased sense of purpose, loss of interest in activities, flat affect, lack of eye contact, and hypoactivity). In some embodiments, the composition reduces a schizophrenia measure compared to a baseline substance abuse measure. For example, the composition may reduce a schizophrenia measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0304] In some embodiments, the measure comprises a psychosis measure. In some embodiments, the psychosis measure is a sign or symptom of psychosis. The assessment of psychosis signs or symptoms may include the frequency of psychosis signs or symptoms. The assessment of psychosis signs or symptoms may include the severity of psychosis signs or symptoms. The assessment of psychosis signs or symptoms may include the number of psychosis signs or symptoms. Exemplary signs and symptoms of psychosis may include difficulty concentrating, depressed mood, anxiety, excessive distrust, delusions, and hallucinations. In some embodiments, the composition reduces a schizophrenia measure compared to a baseline psychosis measure. For example, the composition may reduce a psychosis measure by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0305] In some embodiments, the measurement comprises a measurement of a neurological disorder. Non-limiting examples of neurological disorder measurements include a measurement of cognitive function, a measurement of amyloid plaques (e.g., accumulation) in the CNS, a measurement of tau accumulation in the CNS, a measurement of beta-amyloid 42 (e.g., accumulation) in the CSF, a measurement of tau (e.g., accumulation) in the CSF, a measurement of phosphorylated tau (e.g., accumulation) in the CSF, a measurement of Lewy bodies (e.g., accumulation), or a measurement of alpha-synuclein (e.g., accumulation) in the CSF. Further non-limiting examples of measurements include a measurement of headache signs and / or symptoms, a measurement of migraine symptoms and / or symptoms, a measurement of chronic pain symptoms and / or symptoms, a measurement of fibromyalgia symptoms and / or symptoms, a measurement of chronic fatigue syndrome (ME) symptoms and / or symptoms, and a measurement of motor neuron disease (e.g., ALS) symptoms and / or symptoms. In some embodiments, the composition reduces a neurological disorder measurement compared to a baseline neurological disorder measurement. For example, the composition may reduce a neurological impairment measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0306] In some embodiments, the measurement is a cognitive function measurement. The cognitive function measurement can be obtained directly from the subject. For example, the subject can be administered a test. The test can include a cognitive test such as the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), or the Mini-Cog. The test can include an assessment of basic cognitive functions such as memory, language, executive frontal lobe function, motor apraxia, visuospatial ability, behavior, mood, orientation, or attention. The cognitive function measurement can include a score. The cognitive function measurement can indicate the absence of cognitive impairment. In some embodiments, the cognitive function measurement indicates mild cognitive impairment, and the baseline cognitive function measurement indicates severe cognitive impairment. The cognitive function measurement can indicate a neurological disorder.

[0307] In some embodiments, the composition increases a cognitive function measure compared to a baseline cognitive function measure. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the cognitive function measure increases by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline cognitive function measure. In some embodiments, the cognitive function measure increases by about 10% or more compared to the baseline cognitive function measure. In some embodiments, the cognitive function measure increases 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, or about 90% or more compared to the baseline cognitive function measure. In some embodiments, the cognitive function measure increases by about 100% or more, about 250% or more, about 500% or more, about 750% or more, or about 1000% or more compared to the baseline cognitive function measure. In some embodiments, the cognitive function measure increases by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline cognitive function measure. In some embodiments, the cognitive function measure increases by about 10% or less compared to the baseline cognitive function measure. In some embodiments, the cognitive function measure increases by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to the baseline cognitive function measure. In some embodiments, the cognitive function measure increases by about 100% or less, about 250% or less, about 500% or less, about 750% or less, or about 1000% or less compared to the baseline cognitive function measure. In some embodiments, the cognitive function measure is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or a range defined by any two of the foregoing percentages.

[0308] In some embodiments, the measurement is an amyloid plaque measurement. The amyloid plaque measurement may include a central nervous system (CNS) amyloid plaque measurement. In some embodiments, the amyloid plaque measurement includes concentration or amount. The amyloid plaque measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The amyloid plaque measurement may be performed by biopsy. The amyloid plaque measurement may be performed using a spinal tap (e.g., where the amyloid plaque measurement includes cerebrospinal fluid (CSF) amyloid plaque measurement). In some embodiments, the amyloid plaque measurement is obtained by an assay such as an immunoassay. The beta amyloid plaque measurement may indicate the therapeutic effect of an oligonucleotide on a neurodegenerative disease such as Alzheimer's disease.

[0309] In some embodiments, the composition reduces amyloid plaque measurements compared to baseline amyloid plaque measurements. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the amyloid plaque measurements are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to baseline amyloid plaque measurements. In some embodiments, the amyloid plaque measurements are reduced by about 10% or more compared to baseline amyloid plaque measurements. In some embodiments, the amyloid plaque measurements are reduced 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, or about 90% or more compared to baseline amyloid plaque measurements. In some embodiments, the amyloid plaque measurements are reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to baseline amyloid plaque measurements. In some embodiments, amyloid plaque measurements are reduced by about 10% or less compared to baseline amyloid plaque measurements. In some embodiments, amyloid plaque measurements are reduced by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to baseline amyloid plaque measurements. In some embodiments, amyloid plaque measurements are reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0310] In some embodiments, the measurement is a tau measurement. In some embodiments, the tau measurement comprises a concentration or amount. The tau measurement may be performed on a biopsy. In some embodiments, the tau measurement is obtained by an assay such as an immunoassay. The beta tau measurement may indicate the therapeutic effect of an oligonucleotide on a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

[0311] In some embodiments, the tau measurement is a central nervous system (CNS) tau measurement. The tau measurement may include a total tau measurement. The tau measurement may include a non-phosphorylated tau measurement. The tau measurement may include a phosphorylated tau (phospho-tau) measurement. In some embodiments, the tau measurement is a tau accumulation measurement. In some embodiments, the tau measurement is a CNS tau accumulation measurement. The CNS tau accumulation measurement may indicate the therapeutic effect of an oligonucleotide on a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

[0312] In some embodiments, the composition reduces CNS tau accumulation measurements compared to baseline CNS tau accumulation measurements. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the CNS tau accumulation measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to baseline CNS tau accumulation measurements. In some embodiments, the CNS tau accumulation measurement is reduced by about 10% or more compared to baseline CNS tau accumulation measurements. In some embodiments, the CNS tau accumulation measurement is reduced 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, or about 90% or more compared to baseline CNS tau accumulation measurements. In some embodiments, the CNS tau accumulation measurement is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to baseline CNS tau accumulation measurements. In some embodiments, the CNS tau accumulation measure is reduced by no more than about 10% compared to the baseline CNS tau accumulation measure. In some embodiments, the CNS tau accumulation measure is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% compared to the baseline CNS tau accumulation measure. In some embodiments, the CNS tau accumulation measure is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the foregoing percentages.

[0313] The tau measurement may include cerebrospinal fluid (CSF) tau measurement. The CSF tau measurement may be performed after the use of a spinal tap. The CSF tau measurement may indicate the therapeutic effect of oligonucleotides on neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.

[0314] In some embodiments, the composition reduces CSF tau measurements compared to baseline CSF tau measurements. ...

Claims

1. and targeting FGG, which, when administered to a subject in an effective amount, reduces or eliminates a measure, sign, or symptom of a neurological or psychiatric disorder compared to baseline. a) measurements of cognitive function, amyloid plaques, tau accumulation, beta-amyloid 42, tau, phosphorylated tau, Lewy bodies, alpha-synuclein, or measurements, signs, or symptoms of Alzheimer's disease, dementia, delirium, cognitive decline, vascular dementia, headache, migraine, chronic pain, fibromyalgia, chronic fatigue syndrome, or motor neuron disease; or b) Montgomery-Asberg Depression Rating Scale score, Hamilton Depression Rating Scale score, or any measure, sign, or symptom of a depressive disorder, post-traumatic stress disorder, mood disorder, anxiety disorder, eating disorder, substance use disorder, bipolar disorder, personality disorder, schizophrenia, schizoaffective disorder, or psychosis 10. A composition comprising an oligonucleotide that improves a measurement, sign, or symptom of a neurological or psychiatric disorder in a subject, comprising:

2. The composition of claim 1, wherein the neurological disorder includes Alzheimer's disease, dementia, delirium, cognitive decline, vascular dementia, headache, chronic pain, chronic fatigue syndrome, or motor neuron disease.

3. The composition of claim 1, wherein the psychiatric disorder comprises a depressive disorder, post-traumatic stress disorder, a mood disorder, an anxiety disorder, an eating disorder, a substance use disorder, a bipolar disorder, a personality disorder, schizophrenia, schizoaffective disorder, or psychosis.

4. A composition comprising an oligonucleotide that targets FGG and reduces fibrinogen when administered to a subject in an effective amount.

5. The composition described in claim 4, wherein the subject has a coagulation disorder or blood clotting disorder, thrombophilia, or venous thromboembolism.

6. The composition described in claim 1 or 4, wherein the oligonucleotide comprises a modified internucleoside linkage.

7. The composition of claim 1 or 4, wherein the oligonucleotide comprises modified nucleosides, and 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.

8. The composition of claim 1, wherein the oligonucleotide comprises a sugar moiety attached at the 3' or 5' end of the oligonucleotide.

9. The composition of claim 8, wherein the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose.

10. The composition described in claim 1 or 4, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, each strand independently being 12 to 30 nucleosides in length.

11. A composition comprising an oligonucleotide that inhibits expression of FGG, wherein the oligonucleotide comprises: a) an siRNA comprising a sense strand and an antisense strand, each strand independently being about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprising a nucleoside sequence comprising 12-30 contiguous nucleosides of SEQ ID NO: 3621; or b) an antisense oligonucleotide (ASO) having a length of 12 to 30 nucleosides and comprising a nucleoside sequence complementary to 12 to 30 contiguous nucleosides of SEQ ID NO: 3621; A composition comprising:

12. Regarding the sense strand: all purines include 2'-fluoro modified purines and all pyrimidines include a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines; all purines include 2'-O-methyl modified purines and all pyrimidines include a mixture of 2'-fluoro and 2'-O-methyl modified pyrimidines; all purines include 2'-fluoro modified purines and all pyrimidines include 2'-O-methyl modified pyrimidines; All pyrimidines include 2'-fluoro modified pyrimidines and all purines include a mixture of 2'-fluoro and 2'-O-methyl modified purines, or 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 include 2'-fluoro modified pyrimidines and all purines include 2'-O-methyl modified purines Either one of the following applies, or 12. The composition of claim 11, wherein the antisense strand comprises a mixture of 2'-fluoro and 2'-O-methyl modified nucleosides.

13. The composition of any one of claims 1, 4, or 11, further comprising a pharmaceutically acceptable carrier.

14. A composition comprising an oligonucleotide that modulates expression of FGG for use in a method of treating a subject having a neurological or psychiatric disorder, said method comprising administering to said subject an effective amount of said composition, said oligonucleotide comprising: a) an siRNA comprising a sense strand and an antisense strand, each strand independently being about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprising a nucleoside sequence comprising 12-30 contiguous nucleosides of SEQ ID NO: 3621; or b) an antisense oligonucleotide (ASO) having a length of 12 to 30 nucleosides and comprising a nucleoside sequence complementary to 12 to 30 contiguous nucleosides of SEQ ID NO: 3621; A composition comprising:

15. The composition of claim 14, wherein the neurological disorder comprises Alzheimer's disease, dementia, delirium, cognitive decline, vascular dementia, headache, chronic pain, chronic fatigue syndrome, and motor neuron disease, or the psychiatric disorder comprises depressive disorder, post-traumatic stress disorder, mood disorder, anxiety disorder, eating disorder, substance use disorder, bipolar disorder, personality disorder, schizophrenia or schizoaffective disorder, or psychosis.