Treatment of MTRES1-associated diseases and disorders

Abstract

Disclosed herein is a composition comprising an oligonucleotide targeting MTRES1. The oligonucleotide may comprise a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein is a method for treating a disease associated with a MTRES1 gene mutation, comprising providing a subject with an oligonucleotide targeting MTRES1.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 211,379, filed June 16, 2021, the entirety of which is incorporated herein by reference. [Background technology]

[0002] Neurological disorders are a common problem, especially in the elderly population. Improved therapeutic agents are needed to treat these disorders. Summary of the Invention

[0003] Described herein is a composition comprising an oligonucleotide that targets MTRES1. Described herein is a composition comprising an oligonucleotide that targets MTRES1 and reduces MTRES1 mRNA or protein levels when administered to a subject in an effective amount. Described herein is a composition comprising an oligonucleotide that targets MTRES1 and reduces central nervous system (CNS) MTRES1 when administered to a subject in an effective amount. In some embodiments, CNS MTRES1 is reduced by about 10% or more compared to before administration. Disclosed herein in some embodiments is a composition comprising an oligonucleotide that targets MTRES1 and improves cognitive function or slows cognitive decline when administered to a subject in an effective amount. In some embodiments, cognitive function is improved by about 10% or more compared to before administration. In some embodiments, cognitive decline is slowed by about 10% or more compared to before administration. Disclosed herein in some embodiments is a composition comprising an oligonucleotide that targets MTRES1 and reduces a marker of neurodegeneration when administered to a subject in an effective amount. In some embodiments, the marker of neurodegeneration comprises a central nervous system (CNS) or cerebrospinal fluid (CSF) marker of neurodegeneration. In some embodiments, the markers of neurodegeneration include measurements of central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) beta-amyloid 42, CSF tau, CSF phospho-tau, CSF or plasma neurofilament light chain (NfL), Lewy bodies, or CSF alpha-synuclein. In some embodiments, the markers of neurodegeneration are reduced by about 10% or more compared to before administration. In some embodiments, disclosed herein are compositions comprising oligonucleotides that target MTRES1 and improve cognitive function when administered to a subject in an effective amount. In some embodiments, the cognitive function is improved by about 10% or more compared to before administration.In some embodiments, disclosed herein is a composition comprising an oligonucleotide that targets MTRES1 and reduces central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) beta-amyloid 42, CSF tau, CSF phospho-tau, Lewy bodies, or CSF alpha-synuclein when administered to a subject in an effective amount. In some embodiments, CNS amyloid plaques, CNS tau accumulation, CSF beta-amyloid 42, CSF tau, CSF phospho-tau, Lewy bodies, or CSF alpha-synuclein are reduced by about 10% or more before administration. 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 linkages include one or more phosphorothioate linkages. 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, or 20 modified internucleoside linkages. In some embodiments, the oligonucleotide includes modified nucleosides. In some embodiments, the modified nucleosides include locked nucleic acids (LNA), hexitol nucleic acids (HLA), cyclohexene nucleic acids (CeNA), 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or combinations thereof. In some embodiments, the modified nucleosides include LNA. In some embodiments, the modified nucleosides include 2',4' constrained ethyl nucleic acids.In some embodiments, the modified nucleosides include 2'-O-methyl nucleosides, 2'-deoxyfluoro nucleosides, 2'-ON-methylacetamide (2'-O-NMA) nucleosides, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleosides, 2'-O-aminopropyl (2'-O-AP) nucleosides, or 2'-ara-F, or combinations 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 lipophilic moiety attached at the 3' or 5' end of the oligonucleotide. In some embodiments, the lipophilic moiety comprises cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. In some embodiments, the lipophilic moiety comprises a C4-C30 hydrocarbon chain. In some embodiments, the lipophilic moiety comprises a lipid. In some embodiments, the lipid comprises myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmitylstearyl, or α-tocopherol, or a combination thereof. 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 an oligonucleotide that inhibits expression of MTRES1, wherein the oligonucleotide comprises 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 comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO:2443. In some embodiments, any one of the following is true for the sense strand: all purines comprise 2'fluoro modified purines, all pyrimidines comprise a mixture of 2'fluoro and 2'methyl modified pyrimidines, all purines comprise 2'methyl modified purines, all pyrimidines comprise a mixture of 2'fluoro and 2'methyl modified pyrimidines, all purines comprise 2'fluoro modified purines, all pyrimidines comprise 2'methyl modified pyrimidines, all pyrimidines comprise 2'fluoro modified pyrimidines, all purines comprise a mixture of 2'fluoro and 2'methyl modified purines, all pyrimidines comprise 2'methyl modified pyrimidines, all purines comprise a mixture of 2'fluoro and 2'methyl modified purines, or all pyrimidines comprise 2'fluoro modified pyrimidines and all purines comprise 2'methyl modified purines. In some embodiments, the sense strand comprises any one of modification patterns 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S.In some embodiments, any one of the following applies to the antisense strand: all purines include 2'fluoro modified purines, all pyrimidines include a mixture of 2'fluoro and 2'methyl modified pyrimidines, all purines include 2'methyl modified purines, all pyrimidines include a mixture of 2'fluoro and 2'methyl modified pyrimidines, all purines include 2'methyl modified purines, all pyrimidines include 2'fluoro modified pyrimidines, all pyrimidines include 2'fluoro modified pyrimidines, all purines include a mixture of 2'fluoro and 2'methyl modified purines, all pyrimidines include 2'methyl modified pyrimidines, all purines include a mixture of 2'fluoro and 2'methyl modified purines, or all pyrimidines include 2'methyl modified pyrimidines and all purines include 2'fluoro modified purines. In some embodiments, the antisense strand includes any one of the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the oligonucleotide comprises a phosphate at the 5' end of the antisense strand. In some embodiments, the oligonucleotide comprises a phosphate mimetic at the 5' end of the antisense strand. In some embodiments, the phosphate mimetic comprises 5'-vinyl phosphate (VP). In some embodiments, the sense strand comprises a nucleic acid sequence of any one of SEQ ID NOs: 1-1140, and the antisense strand comprises a nucleic acid sequence of any one of SEQ ID NOs: 1141-2280. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. Disclosed herein, in some embodiments, is a composition comprising an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising an ASO of about 12-30 nucleosides in length and a nucleoside sequence complementary to about 12-30 contiguous nucleosides of SEQ ID NO: 2443. Some embodiments include a pharma- ceutically acceptable carrier.Disclosed herein, in some embodiments, is a method of treating a subject having a neurological disorder, comprising administering to the subject an effective amount of a composition. In some embodiments, the neurological disorder comprises dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. [Brief description of the drawings]

[0004] [Figure 1] 1 is an image of a Western blot of MTRES1 protein. [Diagram 2] 13 is a plot quantifying the Western blot data for MTRES1. [Diagram 3] MTRES1 mRNA blot data. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] 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 the biological understanding of disease and inform appropriate treatments. GWAS can utilize genotyping and / or sequencing data and often involve the evaluation of 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 in cases and controls, the variant is said to be associated with the disease. Association statistics that may be used in GWAS are p-values ​​as an indicator of statistical significance, odds ratios (OR) as an indicator of effect size, or beta coefficients (β) as an indicator of effect size. Researchers often assume an additive genetic model to calculate allelic odds ratios, which indicate that each additional copy of an allele (compared to having 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 "causal."

[0006] Functional annotation of variants and / or wet lab experiments can identify causative gene variants identified through GWAS, often leading to the identification of disease-causing genes. Notably, 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) allows the variant to be used as a surrogate for therapeutic modulation of a target gene, providing insight into the potential therapeutic efficacy and safety of therapeutics that modulate that target.

[0007] Identification of such gene-disease associations provides insight into disease biology and can be used to identify novel therapeutic targets for the pharmaceutical industry. To translate therapeutic insights gained from human genetics, the disease biology in patients needs to be exogenously "programmed" to recapitulate the observations from human genetics. There are several options for therapeutic modalities that can be added when applying therapeutic targets identified by human genetics to new drugs. These may include well-established therapeutic modalities such as small molecule compounds and monoclonal antibodies, mature modalities such as oligonucleotides, as well as new 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., brain), and the relevant indication.

[0008] The MTRES1 gene is located on chromosome 6 and encodes mitochondrial transcription rescue factor 1 (MTRES1), also known as chromosome 6 open reading frame 203 (C6orf203). The MTRES1 gene may also be referred to as the C6orf203 gene. MTRES1 may contain 240 amino acids and have a mass of about 28 kDa. MTRES1 may be expressed in neuronal cells. MTRES1 may be cytoplasmic or intracellular. MTRES1 may be localized to mitochondria in cells. MTRES1 may be involved in mitochondrial transcription regulation. An example of the MTRES1 amino acid sequence, and further description of MTRES1, is included in uniprot.org under the accession number Q9P0P8 (last modified October 1, 2000).

[0009] It has been shown that loss-of-function MTRES1 mutants can prevent neurological diseases.For example, loss-of-function MTRES1 mutants have been associated with a protective association against Alzheimer's disease, family history of Alzheimer's disease, dementia, vascular dementia, anticholinesterase drug use, and delirium.Therefore, inhibition of MTRES1 can serve as a therapeutic agent for the treatment of neurological disorders such as dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease.

[0010] Disclosed herein is a composition comprising an oligonucleotide targeting MTRES1. When the inhibition or targeting of MTRES1 is disclosed, it is contemplated that some embodiments may include inhibiting or targeting MTRES1 protein or MTRES1 RNA. For example, MTRES1 protein can be inhibited or targeted by using the oligonucleotides described herein to inhibit or target RNA (e.g., mRNA) encoded by MTRES1 gene, resulting in less MTRES1 protein produced by translation of MTRES1 RNA, or MTRES1 protein can be targeted or inhibited by oligonucleotides that bind or interact with MTRES1 RNA and reduce the production of MTRES1 protein from MTRES1 RNA. Thus, targeting MTRES1 can refer to the binding of MTRES1 RNA and the reduction of MTRES1 RNA or protein levels. The oligonucleotides can include small interfering RNA (siRNA) or antisense oligonucleotides (ASO). Also provided herein is a method of treating neurological disorders by providing an oligonucleotide targeting MTRES1 to a subject in need of treatment.

[0011] I. Composition In some embodiments, compositions comprising oligonucleotides are disclosed herein. In some embodiments, the compositions comprise an oligonucleotide targeting MTRES1. In some embodiments, the compositions consist of an oligonucleotide targeting MTRES1. In some embodiments, the oligonucleotide reduces MTRES1 mRNA expression in a subject. In some embodiments, the oligonucleotide reduces MTRES1 protein expression in a subject. The oligonucleotide may comprise a small interfering RNA (siRNA) as described herein. The oligonucleotide may comprise an antisense oligonucleotide (ASO) as described herein. In some embodiments, the compositions described herein are used in a method of treating a disorder in a subject in need of treatment. 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 compositions comprising oligonucleotides in a method of treating a disorder as described herein.

[0012] Some embodiments include compositions comprising an oligonucleotide that targets MTRES1 and reduces MTRES1 mRNA or protein levels in a cell, fluid, or tissue when administered to a subject in an effective amount. In some embodiments, the compositions comprise an oligonucleotide that targets MTRES1 and reduces MTRES1 mRNA levels in a cell or tissue when administered to a subject in an effective amount. In some embodiments, the cell is a neural cell, such as a central nervous system (CNS) cell. Some examples of CNS cells include neurons, glia, microglia, astrocytes, or oligodendrocytes. In some embodiments, the tissue is a CNS or brain tissue. In some embodiments, the MTRES1 mRNA level 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 MTRES1 mRNA level is reduced by about 10% or more compared to before administration. In some embodiments, the MTRES1 mRNA 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 MTRES1 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 MTRES1 mRNA level is reduced by about 10% or less compared to before administration. In some embodiments, the MTRES1 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, MTRES1 mRNA 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 by a range defined by any of the aforementioned two percentages.

[0013] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and reduces MTRES1 protein levels in a cell, fluid, or tissue when administered to a subject in an effective amount. In some embodiments, the cell is a neuronal cell, such as a central nervous system (CNS) cell. Some examples of CNS cells include neurons, glia, microglia, astrocytes, or oligodendrocytes. In some embodiments, the tissue is a CNS or brain tissue. In some embodiments, the MTRES1 protein level 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 MTRES1 protein level is reduced by about 10% or more compared to before administration. In some embodiments, the MTRES1 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 MTRES1 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 MTRES1 protein level is reduced by about 10% or less compared to before administration. In some embodiments, the MTRES1 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, the MTRES1 protein 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 of the two percentages mentioned above.

[0014] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and reduces a neuropathic phenotype when administered to a subject in an effective amount. The neuropathic disease may include dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. In some embodiments, the neuropathic 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 neuropathic phenotype is reduced by about 10% or more compared to before administration. In some embodiments, the neuropathic 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 neuropathic 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 neuropathic phenotype is reduced by about 10% or less compared to before administration. In some embodiments, the neuropathic 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 neuropathic 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 of the two foregoing percentages.

[0015] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and enhances a protective phenotype against a neurological disorder in a subject when administered to the subject in an effective amount. The neurological disorder may include dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. In some embodiments, the protective phenotype is increased by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the protective phenotype is increased by about 10% or more compared to before administration. In some embodiments, the protective phenotype is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more compared to before administration. In some embodiments, the protective phenotype is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more compared to before administration. In some embodiments, the protective phenotype is increased by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the protective phenotype is increased by about 10% or less compared to before administration. In some embodiments, the protective phenotype is increased 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 before administration. In some embodiments, the protective phenotype is increased by about 200% or less, about 300% or less, about 400% or less, about 500% or less, about 600% or less, about 700% or less, about 800% or less, about 900% or less, or about 1000% or less compared to before administration. In some embodiments, the protective phenotype is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or a range defined by any of the two foregoing percentages.

[0016] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and reduces a marker of neurodegeneration in a subject when administered to the subject in an effective amount. Some examples of markers of neurodegeneration may include central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) beta-amyloid 42, CSF tau, CSF phospho-tau, CSF or plasma neurofilament light chain (NfL), Lewy bodies, or CSF alpha-synuclein. In some embodiments, the marker of neurodegeneration 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 marker of neurodegeneration is reduced by about 10% or more compared to before administration. In some embodiments, the marker of neurodegeneration 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 markers of neurodegeneration are decreased by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, the markers of neurodegeneration are decreased by about 10% or less compared to before administration. In some embodiments, the markers of neurodegeneration are 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, or about 90% or less compared to before administration. In some embodiments, the markers of neurodegeneration are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or a range defined by any of the two percentages mentioned above.

[0017] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and reduces central nervous system (CNS) amyloid plaques in a subject when administered to the subject in an effective amount. In some embodiments, CNS amyloid plaques 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, CNS amyloid plaques are reduced by about 10% or more compared to before administration. In some embodiments, CNS amyloid plaques 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, CNS amyloid plaques are reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, CNS amyloid plaques are reduced by about 10% or less compared to before administration. In some embodiments, CNS amyloid plaques 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, or about 90% or less compared to before administration. In some embodiments, CNS amyloid plaques 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 of the foregoing two percentages.

[0018] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and reduces central nervous system (CNS) tau accumulation in a subject when administered to the subject in an effective amount. In some embodiments, CNS tau accumulation 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, CNS tau accumulation is reduced by about 10% or more compared to before administration. In some embodiments, CNS tau accumulation 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, CNS tau accumulation 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, CNS tau accumulation is reduced by about 10% or less compared to before administration. In some embodiments, CNS tau accumulation 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, CNS tau accumulation 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 of the aforesaid two percentages.

[0019] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and reduces cerebrospinal fluid (CSF) beta-amyloid 42 in a subject when administered to the subject in an effective amount. In some embodiments, CSF beta-amyloid 42 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, CSF beta-amyloid 42 is reduced by about 10% or more compared to before administration. In some embodiments, CSF beta-amyloid 42 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, CSF beta-amyloid 42 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, CSF beta-amyloid 42 is reduced by about 10% or less compared to before administration. In some embodiments, CSF beta-amyloid 42 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, CSF beta-amyloid 42 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 of the two aforementioned percentages.

[0020] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and reduces cerebrospinal fluid (CSF) tau in a subject when administered to the subject in an effective amount. In some embodiments, CSF tau 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, CSF tau is reduced by about 10% or more compared to before administration. In some embodiments, CSF tau 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, CSF tau 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, CSF tau is reduced by about 10% or less compared to before administration. In some embodiments, CSF tau 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, CSF tau 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 of the foregoing two percentages.

[0021] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and reduces cerebrospinal fluid (CSF) tau in a subject when administered to the subject in an effective amount. In some embodiments, CSF phospho-tau 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, CSF phospho-tau is reduced by about 10% or more compared to before administration. In some embodiments, CSF phospho-tau 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, CSF phospho-tau 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, CSF phospho-tau is reduced by about 10% or less compared to before administration. In some embodiments, CSF phospho-tau 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, CSF phospho-tau 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 of the foregoing two percentages.

[0022] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and reduces cerebrospinal fluid (CSF) α-synuclein in a subject when administered to the subject in an effective amount. In some embodiments, CSF α-synuclein 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, CSF α-synuclein is reduced by about 10% or more compared to before administration. In some embodiments, CSF α-synuclein 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, CSF α-synuclein 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, CSF α-synuclein is reduced by about 10% or less compared to before administration. In some embodiments, CSF alpha-synuclein 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, CSF alpha-synuclein 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 of the two foregoing percentages.

[0023] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and reduces Lewy bodies in a subject when administered to the subject in an effective amount. In some embodiments, the Lewy bodies 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, the Lewy bodies are reduced by about 10% or more compared to before administration. In some embodiments, the Lewy bodies 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 Lewy bodies are 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 Lewy bodies are reduced by about 10% or less compared to before administration. In some embodiments, Lewy bodies 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, or about 90% or less compared to before administration. In some embodiments, Lewy bodies 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 of the aforesaid two percentages.

[0024] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and improves cognitive function when administered to a subject in an effective amount. In some embodiments, the cognitive function is increased by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the cognitive function is increased by about 10% or more compared to before administration. In some embodiments, the cognitive function is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more compared to before administration. In some embodiments, the cognitive function is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more compared to before administration. In some embodiments, cognitive function is increased by about 2.5% or less, about 5% or less, or about 7.5% or less compared to before administration. In some embodiments, cognitive function is increased by about 10% or less compared to before administration. In some embodiments, cognitive function is increased 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 before administration. In some embodiments, cognitive function is increased by about 200% or less, about 300% or less, about 400% or less, about 500% or less, about 600% or less, about 700% or less, about 800% or less, about 900% or less, or about 1000% or less compared to before administration. In some embodiments, cognitive function is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or a range defined by any of the aforesaid two percentages.

[0025] A. siRNA In some embodiments, the composition comprises an oligonucleotide targeting MTRES1, the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide targeting MTRES1, the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0026] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises 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 in 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 compositions comprise 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 in the range defined by either of the preceding two numbers. The antisense strand can be 14-30 nucleosides in length.

[0027] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, each strand being independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprising a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human MTRES1 mRNA sequence, such as SEQ ID NO: 2443. In some embodiments, at least one of the sense strand and the antisense strand 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: 2443.

[0028] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, each strand being independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprising a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human MTRES1 mRNA sequence, such as SEQ ID NO: 2462. In some embodiments, at least one of the sense strand and the antisense strand 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: 2462.

[0029] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, the sense strand and the antisense strand form a double-stranded RNA duplex. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair.

[0030] 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 series of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a series of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises 2 nucleosides.

[0031] 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 series of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3' overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5' overhang. In some embodiments, the 5' overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a series of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5' overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5' overhang comprises 2 nucleosides.

[0032] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the siRNA binds to a 19-mer in human MTRES1 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 MTRES1 mRNA.

[0033] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, and the siRNA binds to a 17-mer in the non-human primate MTRES1 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 the non-human primate MTRES1 mRNA.

[0034] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, the siRNA binds to human MTRES1 mRNA and 20 or fewer human off-targets, and has no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human MTRES1 mRNA and 10 or fewer human off-targets, and has no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human MTRES1 mRNA and 30 or fewer human off-targets, and has no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human MTRES1 mRNA and 40 or fewer human off-targets, and has no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human MTRES1 mRNA and 50 or fewer human off-targets, and has no more than two mismatches in the antisense strand. In some embodiments, the siRNA binds to human MTRES1 mRNA and 10 or fewer human off-targets, and has no more than three mismatches in the antisense strand. In some embodiments, the siRNA binds to human MTRES1 mRNA and 20 or fewer human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human MTRES1 mRNA and 30 or fewer human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human MTRES1 mRNA and 40 or fewer human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds to human MTRES1 mRNA and 50 or fewer human off-targets, with no more than 3 mismatches in the antisense strand.

[0035] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, the siRNA binds to a human MTRES1 mRNA target site that does not have a SNP, and the minor allele frequency (MAF) is 1% or more (positions 2-18). In some embodiments, the MAF is about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 11% or more, about 12% or more, about 13% or more, about 14% or more, about 15% or more, about 16% or more, about 17% or more, about 18% or more, about 19% or more, or about 20% or more.

[0036] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, the sense strand comprising a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1-1140, or a nucleic acid sequence thereof having 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: 1-1140, or a nucleic acid sequence thereof having 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 stretch 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 series of nucleotides 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: 1-1140, or a nucleic acid sequence thereof with one or two nucleoside additions at the 3' end. In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, the sense strand comprising a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1-1140.

[0037] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, the antisense strand comprising a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1141-2280, or a nucleic acid sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1141-2280, or a nucleic acid sequence thereof having 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 stretch 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 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 stretch of nucleotides 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: 1141-2280, or a nucleic acid sequence thereof having one or two nucleoside additions at the 3' end.In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, the antisense strand comprising a nucleoside sequence comprising or consisting of any one of SEQ ID NOs: 1141-2280.

[0038] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of any one of siRNAs in Tables 2-7, 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 strand and / or antisense strand of any one of siRNAs in Tables 2-7, 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 strand and / or antisense strand of any one of siRNAs in Tables 2-7. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MTRES1 mRNA. The siRNA may comprise 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 the siRNA of Table 11B, 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 strand and / or antisense strand of the siRNA of Table 11B, 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 strand and / or antisense strand of the siRNA of Table 11B. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MTRES1 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications. The siRNA may comprise a moiety such as a lipid moiety or a GalNAc moiety.

[0040] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of the siRNA of Table 13B, or the nucleic acid sequence thereof with 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 the siRNA of Table 13B, or the nucleic acid sequence thereof with 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 the siRNA of Table 13B. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MTRES1 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications. The siRNA may comprise a moiety such as a lipid moiety or a GalNAc moiety.

[0041] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of the siRNA of Table 15B, or the nucleic acid sequence thereof with 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 the siRNA of Table 15B, or the nucleic acid sequence thereof with 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 the siRNA of Table 15B. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MTRES1 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications. The siRNA may comprise a moiety such as a lipid moiety or a GalNAc moiety.

[0042] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of a siRNA of subset A, 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 strand and / or antisense strand of a siRNA of subset A, 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 strand and / or antisense strand of a siRNA of subset A. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MTRES1 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0043] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of a siRNA of subset B, 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 strand and / or antisense strand of a siRNA of subset B, 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 strand and / or antisense strand of a siRNA of subset B. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MTRES1 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0044] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of a siRNA of subset C, 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 strand and / or antisense strand of a siRNA of subset C, 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 strand and / or antisense strand of a siRNA of subset C. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MTRES1 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0045] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of a 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 a 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 a siRNA of subset D. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MTRES1 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0046] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of a siRNA of subset E, 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 strand of a siRNA of subset E, 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 strand of a siRNA of subset E. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MTRES1 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0047] In some embodiments, the siRNA comprises the sequence of the sense and / or antisense strand of an siRNA of subset F, 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 F, 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 F. In some embodiments, the siRNA is cross-reactive with non-human primate (NHP) MTRES1 mRNA. The siRNA may comprise one or more internucleoside linkages and / or one or more nucleoside modifications.

[0048] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 2576. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 2576, at least 80% identical to SEQ ID NO: 2576, at least 85% identical to SEQ ID NO: 2576, at least 90% identical to SEQ ID NO: 2576, or at least 95% identical to SEQ ID NO: 2576. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 2576, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 2576, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2576. The sense strand may comprise any modification or modification pattern described herein. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA includes an antisense strand having a sequence set forth in SEQ ID NO:2638. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2638, at least 80% identical to SEQ ID NO:2638, at least 85% identical to SEQ ID NO:2638, at least 90% identical to SEQ ID NO:2638, or at least 95% identical to SEQ ID NO:2638. In some embodiments, the antisense strand sequence comprises or consists of a sequence of SEQ ID NO:2638, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence of SEQ ID NO:2638, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2638.The antisense strand can include any modification or modification pattern described herein. The antisense strand can include a moiety such as a GalNAc moiety or a lipid moiety.

[0049] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 2582. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 2582, at least 80% identical to SEQ ID NO: 2582, at least 85% identical to SEQ ID NO: 2582, at least 90% identical to SEQ ID NO: 2582, or at least 95% identical to SEQ ID NO: 2582. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 2582, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 2582, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2582. The sense strand may comprise any modification or modification pattern described herein. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA includes an antisense strand having a sequence set forth in SEQ ID NO:2644. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2644, at least 80% identical to SEQ ID NO:2644, at least 85% identical to SEQ ID NO:2644, at least 90% identical to SEQ ID NO:2644, or at least 95% identical to SEQ ID NO:2644. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2644, or its antisense strand sequence with one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2644, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2644, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2644.The antisense strand can include any modification or modification pattern described herein. The antisense strand can include a moiety such as a GalNAc moiety or a lipid moiety.

[0050] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 2583. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 2583, at least 80% identical to SEQ ID NO: 2583, at least 85% identical to SEQ ID NO: 2583, at least 90% identical to SEQ ID NO: 2583, or at least 95% identical to SEQ ID NO: 2583. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 2583, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 2583, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2583. The sense strand may comprise any modification or modification pattern described herein. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA includes an antisense strand having a sequence set forth in SEQ ID NO:2645. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2645, at least 80% identical to SEQ ID NO:2645, at least 85% identical to SEQ ID NO:2645, at least 90% identical to SEQ ID NO:2645, or at least 95% identical to SEQ ID NO:2645. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2645, or its antisense strand sequence with one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2645, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2645, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2645.The antisense strand can include any modification or modification pattern described herein. The antisense strand can include a moiety such as a GalNAc moiety or a lipid moiety.

[0051] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in SEQ ID NO:2584. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2584, at least 80% identical to SEQ ID NO:2584, at least 85% identical to SEQ ID NO:2584, at least 90% identical to SEQ ID NO:2584, or at least 95% identical to SEQ ID NO:2584. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO:2584, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO:2584, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2584. The sense strand may comprise any modification or modification pattern described herein. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA includes an antisense strand having a sequence set forth in SEQ ID NO:2646. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2646, at least 80% identical to SEQ ID NO:2646, at least 85% identical to SEQ ID NO:2646, at least 90% identical to SEQ ID NO:2646, or at least 95% identical to SEQ ID NO:2646. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2646, or its antisense strand sequence with one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2646, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2646, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2646.The antisense strand can include any modification or modification pattern described herein. The antisense strand can include a moiety such as a GalNAc moiety or a lipid moiety.

[0052] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in SEQ ID NO:2604. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2604, at least 80% identical to SEQ ID NO:2604, at least 85% identical to SEQ ID NO:2604, at least 90% identical to SEQ ID NO:2604, or at least 95% identical to SEQ ID NO:2604. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO:2604, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO:2604, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2604. The sense strand may comprise any modification or modification pattern described herein. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA includes an antisense strand having a sequence set forth in SEQ ID NO:2666. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2666, at least 80% identical to SEQ ID NO:2666, at least 85% identical to SEQ ID NO:2666, at least 90% identical to SEQ ID NO:2666, or at least 95% identical to SEQ ID NO:2666. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2666, or its antisense strand sequence with one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2666, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO:2666, or its antisense strand sequence with one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2666.The antisense strand can include any modification or modification pattern described herein. The antisense strand can include a moiety such as a GalNAc moiety or a lipid moiety.

[0053] B.ASO In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising 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.

[0054] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an ASO that is about 12-30 nucleosides in length and comprises a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human MTRES1 mRNA sequence, such as SEQ ID NO: 2443, where (i) the oligonucleotide comprises modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharma- ceutically 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: 2443.

[0055] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an ASO that is about 12-30 nucleosides in length and comprises a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human MTRES1 mRNA sequence, such as SEQ ID NO: 2462, where (i) the oligonucleotide comprises modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharma- ceutically 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: 2462.

[0056] C. Modification Pattern In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises modified nucleosides and / or modified internucleoside linkages, and / or (ii) the composition comprises a pharma- ceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification comprising modified nucleosides and / or modified internucleoside linkages. 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, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. The phosphorothioate may comprise a non-bridging oxygen atom in the phosphate backbone of the oligonucleotide that is replaced with sulfur. The modified internucleoside linkage may be comprised in an siRNA or an ASO. Advantages of modified internucleoside linkages may include reduced toxicity or improved pharmacokinetics.

[0057] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MTRES1, 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 series of modified internucleoside linkages 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, or more modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside linkages.

[0058] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising 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 a 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 a 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 the modified nucleoside may include reduced toxicity or improved pharmacokinetics.

[0059] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a series of nucleosides defined by any two of the foregoing numbers. In some embodiments, the oligonucleotide comprises 19 or fewer modified nucleosides. In some embodiments, the oligonucleotide comprises 21 or fewer modified nucleosides. In some embodiments, an oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0060] Some embodiments include oligonucleotides comprising: a sense strand having a 5' end, a 3' end, and a region complementary to the antisense strand; an antisense strand having a 5' end, a 3' end, and a region complementary to the sense strand and a region complementary to an mRNA target; an overhang region at the 3' end of the sense strand having at least three contiguous phosphorothioated nucleotides; and an overhang region at the 3' end of the antisense strand having at least three contiguous phosphorothioated nucleotides.

[0061] Some embodiments include oligonucleotides comprising: a sense strand having a 5' end, a 3' end, and a region complementary to the antisense strand; an antisense strand having a 5' end, a 3' end, and a region complementary to the sense strand and a region complementary to an mRNA target; and an overhang region at the 3' end of the sense strand having at least three contiguous phosphorothioated nucleotides.

[0062] In some embodiments, the oligonucleotide comprises 2-8 oligonucleotides linked via a linker. The linker may be hydrophobic. In some embodiments, the oligonucleotides independently have substantial chemical stabilization (e.g., at least 40% of the constituent bases are chemically modified). In some embodiments, the oligonucleotides independently have complete chemical stabilization (i.e., all of the constituent bases are chemically modified). In some embodiments, the oligonucleotides independently comprise one or more single-stranded phosphorothioated tails each having 2-20 nucleotides. In some embodiments, each single-stranded tail has 8-10 nucleotides.

[0063] In certain embodiments, the compound (e.g., the moiety attached to the oligonucleotide) comprises three properties: (1) a branched structure, (2) complete metabolic stabilization, and (3) the presence of a single-stranded tail that includes a phosphorothioate linker. In certain embodiments, the compound has two or three branches. The increase in the overall size of the branched structure promotes increased uptake. Furthermore, without being bound to a particular theory of activity, multiple adjacent branches (e.g., two or three) allow each branch to act in concert, thus dramatically enhancing the rate of internalization, transport, and release. The compound may include the oligonucleotides described herein as part of the compound.

[0064] In certain embodiments, the compounds comprise the following characteristics: (1) two or more branched oligonucleotides linked via a non-natural linker; (2) are substantially chemically stabilized, e.g., greater than 40%, optimally 100%, of the oligonucleotide are chemically modified (e.g., RNA-free and optionally DNA-free); and (3) a phosphorothioated single oligonucleotide containing at least 3, optimally 5-20 phosphorothioated linkages.

[0065] In some embodiments, the oligonucleotide comprises a phosphate at the 5' end. In some embodiments, the oligonucleotide comprises a phosphate at the 3' end. In some embodiments, the oligonucleotide comprises a phosphate mimetic at the 5' end. In some embodiments, the oligonucleotide comprises a phosphate mimetic at the 3' end.

[0066] 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.

[0067] In some embodiments, the purines of the oligonucleotide include 2'fluoro modified purines. In some embodiments, the purines of the oligonucleotide include 2'-O-methyl modified purines. In some embodiments, the purines of the oligonucleotide include a mixture of 2'fluoro and 2'-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide include 2'fluoro modified purines. In some embodiments, all purines of the oligonucleotide include 2'-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide include 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] In some cases, the oligonucleotide comprises a specific modification pattern. In some embodiments, position 9, counting from the 5' end of the oligonucleotide strand, may have a 2'F modification. In some embodiments, if position 9 of the oligonucleotide strand is a pyrimidine, all purines in the oligonucleotide 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 oligonucleotide strand that has a 2'F modification. In some embodiments, if position 9 of the oligonucleotide strand and only one other base between positions 5 and 11 are pyrimidines, both of these pyrimidines are the only two positions in the oligonucleotide strand that have a 2'F modification. In some embodiments, if position 9 of the oligonucleotide strand and only two other bases between positions 5 and 11 are pyrimidines, and these two other pyrimidines are adjacent positions, so there are not three 2'F modifications in a row, any combination of 2'F modifications can be made that gives 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 having 2'F modifications with a total of 3-5 2'F modifications are possible, 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 fits any or all of these strands of the oligonucleotide rules.

[0072] In some embodiments, if position 9 of the 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, then position 9 is the only position in the oligonucleotide strand with a 2'F modification. In some embodiments, if position 9 of the oligonucleotide strand and one other base between positions 5 and 11 are 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 of the oligonucleotide strand and two other bases between positions 5 and 11 are only purines, and these two other purines are in adjacent positions, and therefore there are no three 2'F modifications in a row, any combination of 2'F modifications that gives 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 oligonucleotide strand, then all combinations of purines with 2'F modifications with a total of three to five 2'F modifications are possible, provided that the oligonucleotide strand does not have 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.

[0073] In some cases, the 9th position of the oligonucleotide strand can be 2'deoxy.In these cases, 2'F and 2'OMe modifications can occur at other positions of the oligonucleotide strand.In some cases, either oligonucleotide strand of siRNA comprises a modification pattern that fits these strands of the oligonucleotide rules.

[0074] In some embodiments, position 9 of the sense strand comprises a 2'fluoro modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2'-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise 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 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 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.

[0075] In some embodiments, position 9 of the sense strand comprises a 2'fluoro modified purine. In some embodiments, all pyrimidines of the sense strand comprise a 2'-O-methyl modified purine. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2'fluoro modified purine, provided that there are not three 2'fluoro modified purines in a row. In some embodiments, odd-numbered positions of the antisense strand comprise a 2'-O-methyl modified nucleotide. In some embodiments, even-numbered positions of the antisense strand comprise a 2'fluoro modified nucleotide and an unmodified deoxyribonucleotide. In some embodiments, even-numbered positions of the antisense strand comprise a 2'fluoro modified nucleotide, a 2'-O-methyl modified nucleotide, and an unmodified deoxyribonucleotide. 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 pyrimidines, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise 2'fluoro modified purines, provided that there are not three 2'fluoro modified purines in a row, odd positions of the antisense strand comprise 2'-O-methyl modified nucleotides, and even positions of the antisense strand comprise 2'fluoro modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2'fluoro modified purines in a row. In some embodiments, there are not three 2'fluoro modified pyrimidines in a row.

[0076] 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 a 2'fluoro modified nucleotide. In some embodiments, all pyrimidines at positions 10-21 of the sense strand comprise a 2'-O-methyl modified pyrimidine and all purines at positions 10-21 of the sense strand comprise a 2'-O-methyl modified purine or a 2'fluoro modified purine. In some embodiments, odd-numbered positions of the antisense strand comprise a 2'-O-methyl modified nucleotide. In some embodiments, even-numbered positions of the antisense strand comprise a 2'fluoro modified nucleotide and an unmodified deoxyribonucleotide. In some embodiments, even-numbered positions of the antisense strand comprise a 2'fluoro modified nucleotide, a 2'-O-methyl modified nucleotide, and an unmodified deoxyribonucleotide. In some embodiments, position 9 of the sense strand comprises unmodified deoxyribonucleotides, 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.

[0077] 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 a 2'fluoro modified nucleotide. In some embodiments, all purines at positions 10-21 of the sense strand comprise a 2'-O-methyl modified purine and all pyrimidines at positions 10-21 comprise a 2'-O-methyl modified pyrimidine or a 2'fluoro modified pyrimidine. In some embodiments, odd-numbered positions of the antisense strand comprise a 2'-O-methyl modified nucleotide. In some embodiments, even-numbered positions of the antisense strand comprise a 2'fluoro modified nucleotide and an unmodified deoxyribonucleotide. In some embodiments, even-numbered positions of the antisense strand comprise a 2'fluoro modified nucleotide, a 2'-O-methyl modified nucleotide, and an unmodified deoxyribonucleotide. In some embodiments, position 9 of the sense strand comprises unmodified deoxyribonucleotides, 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.

[0078] 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' end 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'-end group may be or include a 5'-end phosphorothioate, a 5'-end phosphorodithioate, a 5'-end vinyl phosphonate (5'-VP), a 5'-end methyl phosphonate, a 5'-end cyclopropyl phosphonate, or a 5'-deoxy-5'-C-malonyl. The 5'-end group may include a 5'-VP. In some embodiments, the 5'-VP includes a trans-vinyl phosphate or a cis-vinyl phosphate. The 5'-end group may include an extra 5' phosphate. A combination of 5'-end groups may be used.

[0079] 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, vinyl phosphonate, methyl phosphonate, cyclopropyl phosphonate, or deoxy-C-malonyl. The terminal group can include an extra 5' phosphate, e.g., an extra 5' phosphate. A combination of terminal groups can be used.

[0080] In some embodiments, the oligonucleotide comprises a phosphomimetic. In some embodiments, the phosphomimetic comprises a vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises a trans-vinyl phosphate. In some embodiments, the vinyl phosphonate comprises a cis-vinyl phosphate. Examples of nucleotides that contain vinyl phosphonates are shown below.

[0081] [ka]

[0082] 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.

[0083] 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.

[0084] 1.Hydrophobic part In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising a moiety attached to the 3' or 5' end of the oligonucleotide. Exemplary moieties include a hydrophobic moiety, or a sugar moiety, or a combination thereof. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to the 5' end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to the 3' end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to the 5' end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to the 3' end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to the 5' end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to the 3' end of the ASO.

[0085] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, and the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety can be attached to the 3' end or the 5' end of the oligonucleotide. The hydrophobic moiety can comprise a lipid, such as a fatty acid. The hydrophobic moiety can comprise a hydrocarbon. The hydrocarbon can be linear. The hydrocarbon can be non-linear. The hydrophobic moiety can comprise a lipid moiety or a cholesterol moiety, or a combination thereof.

[0086] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising a lipid attached to 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.

[0087] In some embodiments, the oligonucleotide comprises a lipophilic moiety attached at the 3' or 5' end of the oligonucleotide. In some embodiments, the lipophilic moiety comprises cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine, or combinations thereof. The lipophilic moiety may comprise a steroid such as cholesterol. The lipophilic moiety may comprise retinoic acid. The lipophilic moiety may comprise cholic acid. The lipophilic moiety may comprise adamantane acetic acid. The lipophilic moiety may comprise 1-pyrene butyric acid. The lipophilic moiety may comprise dihydrotestosterone. The lipophilic moiety may comprise 1,3-bis-O(hexadecyl)glycerol. The lipophilic moiety may comprise geranyloxyhexanol. The lipophilic moiety may comprise hexadecylglycerol. The lipophilic moiety may comprise borneol. The lipophilic moiety may comprise menthol. The lipophilic moiety may comprise 1,3-propanediol. The lipophilic moiety may comprise a heptadecyl group. The lipophilic moiety may comprise palmitic acid. The lipophilic moiety may comprise myristic acid. The lipophilic moiety may comprise O3-(oleoyl)lithocholic acid. The lipophilic moiety may comprise O3-(oleoyl)cholenic acid. The lipophilic moiety may comprise ibuprofen. The lipophilic moiety may comprise naproxen. The lipophilic moiety may comprise dimethoxytrityl. The lipophilic moiety may comprise phenoxazine.

[0088] In some embodiments, the lipophilic moiety comprises a hydrocarbon chain. The hydrocarbon chain can include or consist of a C4-C30 hydrocarbon chain. In some embodiments, the lipophilic moiety comprises a lipid.

[0089] In some embodiments, oligonucleotide comprises one or more lipophilic monomers containing one or more lipophilic moieties, which are conjugated to one or more positions on at least one strand of oligonucleotide, optionally via linker or carrier.For example, some embodiments provide an oligonucleotide comprising an antisense strand complementary to a target gene, a sense strand complementary to said antisense strand, and one or more lipophilic monomers containing one or more lipophilic moieties, which are conjugated to one or more positions on at least one strand, optionally via linker or carrier.In some embodiments, the lipophilicity of lipophilic moiety is greater than 0, as measured by octanol-water partition coefficient logP.

[0090] In some embodiments, the lipophilic moiety is an aliphatic, cyclic, such as alicyclic, or polycyclic, such as polyalicyclic, compound, such as a steroid (e.g., sterol), a straight or branched chain aliphatic hydrocarbon, or an aromatic. Exemplary lipophilic moieties may include lipids, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. Suitable lipophilic moieties may further include those containing a saturated or unsaturated C4-C30 hydrocarbon chain (e.g., C4-C30 alkyl or alkenyl) and an optional functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne. The functional group may be useful for attaching the lipophilic moiety to an oligonucleotide. In some embodiments, the lipophilic moiety contains a saturated or unsaturated C6-C18 hydrocarbon chain (e.g., linear C6-C18 alkyl or alkenyl). In some embodiments, the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain (e.g., linear C16 alkyl or alkenyl). In some embodiments, the lipophilic moiety contains two or more carbon-carbon double bonds.

[0091] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, and the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety can be attached to the 3' end or the 5' end of the oligonucleotide. The hydrophobic moiety can comprise a lipid, such as a fatty acid. The hydrophobic moiety can comprise a hydrocarbon. The hydrocarbon can be linear. The hydrocarbon can be non-linear. The hydrophobic moiety can comprise a lipid moiety or a cholesterol moiety, or a combination thereof.

[0092] In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising a lipid attached to the 3' or 5' end of the oligonucleotide, in some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithochloyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof.

[0093] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising 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, the hydrophobic ligand or hydrophobic moiety is attached at the sense strand (e.g., attached at the 5' end of the sense strand or attached at the 3' end of the sense strand). In some embodiments, the composition comprises an antisense strand, the hydrophobic ligand or hydrophobic moiety is attached at the antisense strand (e.g., attached at the 5' end of the antisense strand or attached at the 3' end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or hydrophobic moiety attached at the 3' end or 5' end of the oligonucleotide.

[0094] In some embodiments, the hydrophobic moiety is attached to the oligonucleotide (e.g., the sense strand and / or the 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.

[0095] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising a lipid attached to 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, docosahexaenyl, 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.

[0096] In some embodiments, the oligonucleotide comprises aspects of any of the following structures:

[0097] [ka] In some embodiments, the oligonucleotide comprises aspects of any of the following structures:

[0098] [ka] In some embodiments, the oligonucleotide comprises aspects of any of the following structures:

[0099] [ka] In some embodiments, the oligonucleotide comprises any of the following structures. The oligonucleotide may comprise the entire structure or may comprise 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 of carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the lipid portion comprises an alcohol or ether.

[0100] In some embodiments, the lipid comprises a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 1. The exemplary lipid moieties in Table 1 are shown attached to the 5' end of the oligonucleotide, and the 5' terminal phosphate of the oligonucleotide is shown with the lipid moiety. In some embodiments, the lipid moieties in Table 1 can be attached to a different attachment point than shown. For example, the attachment point of any of the lipid moieties in the table can be at the 3' oligonucleotide end. In some embodiments, lipids are used to target oligonucleotides to non-hepatic cells or tissues.

[0101] [Table 1-1]

[0102] [Table 1-2]

[0103] 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.

[0104] The hydrophobic portion may include a linker that includes 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., 5' or 3' phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon and the end of the sense strand are connected to a 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 a phenyl or cyclohexyl linker in a 1,4 substitution pattern (e.g., paraphenyl 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.

[0105] The lipid portion has the following structure:

[0106] [ka] In some embodiments, the lipid moiety may comprise or consist of the structure:

[0107] [ka] In some embodiments, the lipid moiety comprises or consists of the structure:

[0108] [ka] In some embodiments, the lipid moiety comprises or consists of the structure:

[0109] [ka] or consists of the structure above. In some embodiments, the dotted line indicates 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 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the preceding numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing from 4 to 18 carbons.

[0110] The lipid moiety may be attached to the 5' end of the oligonucleotide. The 5' end may have one phosphate attaching the lipid moiety to the 5' carbon of the oligonucleotide's sugar. The 5' end may have two phosphates attaching the lipid moiety to the 5' carbon of the oligonucleotide's sugar. The 5' end may have three phosphates attaching the lipid moiety to the 5' carbon of the oligonucleotide's sugar. The 5' end may have one phosphate attached to the 5' carbon of the oligonucleotide's sugar, where one phosphate is attached to the lipid moiety. The 5' end may have two phosphates attached to the 5' carbon of the oligonucleotide's sugar, where one of the two phosphates is attached to the lipid moiety. The 5' end may have three phosphates attached to the 5' carbon of the oligonucleotide's sugar, where one of the three phosphates is attached to the lipid moiety. The sugar may include ribose. The sugar may include deoxyribose. The sugar may be modified, such as a 2' modified sugar (e.g., 2'O-methyl or 2'fluororibose). The 5' end phosphate may include a modification, such as a sulfur instead of an oxygen. The two phosphates at the 5' end may contain modifications such as sulfur instead of oxygen. The three phosphates at the 5' end may contain modifications such as sulfur instead of oxygen.

[0111] 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.

[0112] Some embodiments relate to a method for making oligonucleotides that contain hydrophobic conjugates.The strategy for making hydrophobic conjugates can include the use of phosphoramidite reagents based on 6-membered alcohols such as phenol or cyclohexanol.The phosphoramidite can react with nucleotides to bind the nucleotides to hydrophobic moieties, thereby producing hydrophobic conjugates.Some examples of phosphoramidite reagents that can be used to produce hydrophobic conjugates are provided as follows:

[0113] [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 preceding numbers of carbons. 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 to the 5' end of the oligonucleotide to generate an oligonucleotide containing a hydrophobic moiety. In some embodiments, the phosphoramidite reagent is reacted to the 5' end of the sense strand of the siRNA. Then, the sense strand can be hybridized with the antisense strand to form a double strand.Hybridization can be performed by incubating the sense strand and the antisense strand in a 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 the sense strand and the antisense strand.The temperature can include or include the temperature that is lower than the annealing temperature of the sense strand and the antisense strand.The temperature can be lower than the melting temperature of the sense strand and the antisense strand.

[0114] The lipid may be attached to the oligonucleotide by a linker, which may include polyethylene glycol (e.g., tetraethylene glycol).

[0115] The modifications described herein can be useful for delivery, e.g., extrahepatic delivery or targeting, of oligonucleotide compositions to cells or tissues. The modifications described herein can be useful for targeting oligonucleotide compositions to cells or tissues.

[0116] 2.Sugar part In some embodiments, a composition comprises an oligonucleotide that inhibits expression of MTRES1, 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 to 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-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 useful for targeting macrophages if they target or bind to a mannose receptor, such as CD206. The sugar moiety may be useful for binding to or targeting an asialoglycoprotein receptor, such as the asialoglycoprotein receptor of hepatocytes. The GalNAc moiety may bind to an asialoglycoprotein receptor. The GalNAc moiety may target hepatocytes.

[0117] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, 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.

[0118] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprising 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, 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, 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' end or 5' end of the oligonucleotide.

[0119] In some embodiments, disclosed herein is a composition comprising an oligonucleotide that inhibits expression of MTRES1, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be comprised in any of the formulas, structures, or GalNAc moieties shown below. In some embodiments, the GalNAc moiety may be comprised in any of the formulas (I) or (II):

[0120] [ka] or a salt thereof, wherein J is an oligonucleotide; Each w is independently selected from any value of 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 or When z is 1, Y is C(R 6 ) 2 and Q is halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 , and C 1-6 C optionally substituted with one or more substituents independently selected from alkyl 3-10 Carbocyclic ring (where C 1-6 Alkyl is a halogen, -CN, -OH, -SH, -NO 2 , and -NH 2and optionally substituted with one or more substituents independently selected from R 1 -O-, -S-, -N(R 7 )-, C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 )C(O)O-, C(O)O-, -OC(O)-, -S(O)-, -S(O) 2 -, -OS(O) 2 -,-OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O-)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 -, wherein the linker is selected from R 2 are halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 C optionally substituted with one or more substituents independently selected from 1-6 independently selected from alkyl, 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 -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, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 , and Halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 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 , -NH 2 , =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 a carbocycle, and a 3- to 10-membered heterocycle; and C 3-10 Carbocycles and 3- to 10-membered heterocycles, each of which is independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 haloalkyl). 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, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 In some embodiments, Q is selected from a C5-6 carbocycle optionally substituted with one or more substituents independently selected from: 2 , and -NH 2In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is selected from halogen, -CN, -OH, -SH, -NO 2 , and -NH 2 In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R 1 -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 -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 In some embodiments, R 1-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 In some embodiments, R 1 -OP(O)(OR 7 )O- and -OP(OR 7 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 ) 2 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 from 1-3 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 )2 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 ) 2 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, and -NO, respectively. 2 , -NH 2 , =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , -NH(C 1-6 Alkyl), C3-10 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, and -NO 2 , -NH 2 , =O, =S, -OC 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 1-6 In some embodiments, R 7 each of which is 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, and Y is C and Q is phenyl or cyclohexyl, each of which is selected from halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , and C 1-3 optionally substituted with one or more substituents independently selected from alkyl, R 1 -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-, R 2 is -OH or -OC(O)CH 3 is a C1 alkyl substituted with R 3 is -OH or -OC(O)CH 3 and R 4 is -OH or -OC(O)CH 3 and R 5 -NH(O)CH 3In some embodiments, the compound is

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] [ka]

[0130] [ka] In some embodiments, the oligonucleotide (J) is attached 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 phosphonates, phosphorothioates, methyl phosphonates, phosphorodithioates, alkyl phosphonothioates, phosphoramidates, carbamates, carbonates, phosphotriesters, acetamidates, or carboxymethyl esters, or combinations thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets hepatocytes.

[0131] Some embodiments include the following, where J is an oligonucleotide.

[0132] [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.

[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 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.

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

[0138] [ka] The structure in this compound attached to an oligonucleotide (J) may be referred to as "ETL17" and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates attached to the oligonucleotide. J may include one or more phosphates attached to the oligonucleotide. J may include one or more phosphates attached to the oligonucleotide. J may include one or more phosphorothioates attached to the oligonucleotide. J may include phosphorothioates attached to the oligonucleotide.

[0139] Some embodiments include the following, where the phosphate or "5'" indicates the connection to the oligonucleotide:

[0140] [ka]

[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 J is an oligonucleotide:

[0144] [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.

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

[0146] [ka] The structure in this compound attached to an oligonucleotide (J) may be referred to as "ETL1" and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates attached to the oligonucleotide. J may include one or more phosphates attached to the oligonucleotide. J may include a phosphate attached to the oligonucleotide. J may include one or more phosphorothioates attached to the oligonucleotide. J may include a phosphorothioate attached to the oligonucleotide.

[0147] 3. siRNA modification patternIn some embodiments, a composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, the sense strand comprises the modification pattern 1S:5'NfsnsNfnNfnNfNfNfNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO:2444), 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:2445), 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' (sequence number 2446), 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:2447), 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 the following modification pattern 5S:5'-nsnsnnNfnNfNfNfNfnnnnnnnnnnsnsnN-moiety-3' (SEQ ID NO:2448), 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 moiety in the modification pattern 4S or 5S is a lipophilic moiety. In some embodiments, the moiety in modification pattern 4S or 5S is a lipid moiety.In some embodiments, the sense strand comprises the modification pattern 6S:5'NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO:2449), 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'nssnnNfNfNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO:2450), 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'nssnnnNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO:2451), 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'nssnnnnNfNfNfNfnnnnnnnnnsnsn-3' (SEQ ID NO:2452), 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'NfsnsnnNfnNfnNfnNfnNfnNfnNfnnsnsn-3' (SEQ ID NO:2525), 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 11S:5'nssNfnNfnNfnNfnNfnNfnNfnnnNfnNfsnsn-3' (SEQ ID NO:2526), ​​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 12S:5'NfsnsNfnNfnNfnNfnNfnnnNfnNfnNfsnsn-3' (SEQ ID NO:2527), 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 13S:5'nsnsnnnnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3' (SEQ ID NO:2528), 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 14S:5'snnnnnnNfNfNfNfnnnnnnnnnsnsn-3' (SEQ ID NO:2529), 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 15S:5'snnnnNfNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO:2530), 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'snnnnNfnNfNfdNnnnnnnnnnnsnsn-3' (SEQ ID NO:2531), where "Nf" is a 2' fluoro modified nucleoside, "dN" is a 2' deoxy 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'snnnnnNfNfnNfnnnnnnnnnnsnsn-3' (SEQ ID NO:2532), 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'snnnnnnNfnNfNfnnnnnnnnnsnsn-3' (SEQ ID NO:2533), 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'snnnnNfnNfnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO:2534), 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'snnnnNfnNfnNfnnnnnnnnnnsnsn-3' (SEQ ID NO:2535), 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'snnnnNfNfnnNfNfnnnnnnnnnsnsn-3' (SEQ ID NO:2536), 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'snnnnNfnnNfNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO:2537), 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'snnnnnNfnNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO:2538), 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 24S:5'snnnnnnnNfNfNfNfnnnnnnnnsnsn-3' (SEQ ID NO:2539), 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'snnnnnNfNfNfNfNfnnnnnnnnnsnsn-3' (SEQ ID NO:2540), 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'snnnnnNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO:2541), 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:2542), 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'snnnnNfNfnNfNfnNfnnnnnnnnsnsn-3' (SEQ ID NO:2543), 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'snnnnnnnnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO:2544), 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 30S:5'snnnnNfNfnnNfnNfnnnnnnnnsnsn-3' (SEQ ID NO:2545), 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 31S:5'snnnnNfNfNfNfnnnnnnnnnnsnsn-3' (SEQ ID NO:2546), 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 32S:5'snnnnnnNfNfdNNfnnnnnnnnnsnsn-3' (sequence number 2547), where "Nf" is a 2' fluoro modified nucleoside, "dN" is a 2' deoxy modified nucleoside, "n" is a 2' O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.

[0148] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, the antisense strand comprises the modification pattern 1AS: 5'nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3' (SEQ ID NO: 2453), 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 2AS: 5'nsNfsnnnNfnNfNfNfnnnnNfnNfnnnsnsn-3' (SEQ ID NO: 2454), 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:2455), 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:2456), 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'nsNfsnnnnnnnnnnNfnNfnnnsnsn 3' (SEQ ID NO:2457), 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:2458), 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:2459), 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:2460), 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'nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn 3' (SEQ ID NO:2548), 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'nsNfsnNfsnNfnNfnNfnNfnNfnNfnNfnsnsn 3' (SEQ ID NO:2549), where "Nf" is a 2'fluoro modified nucleoside, "n" is a 2'O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.

[0149] In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, the sense strand comprises pattern 1S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 5S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 6S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 7S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 9S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 10S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS.In some embodiments, the sense strand comprises a pattern 11S and the antisense strand comprises a pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises a pattern 12S and the antisense strand comprises a pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises a pattern 13S and the antisense strand comprises a pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises a pattern 14S and the antisense strand comprises a pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises a pattern 15S, and the antisense strand comprises a pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises a pattern 16S, and the antisense strand comprises a pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises a pattern 17S, and the antisense strand comprises a pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises a pattern 18S, and the antisense strand comprises a pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 19S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 20S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 21S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS.In some embodiments, the sense strand comprises pattern 22S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 23S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 24S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 25S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 26S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 27S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 28S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 29S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 30S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 31S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the sense strand comprises pattern 32S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS.

[0150] In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S, and the antisense strand comprises pattern 1AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S, and the antisense strand comprises pattern 2AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S, and the antisense strand comprises pattern 3AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S, and the antisense strand comprises pattern 4AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S, and the antisense strand comprises pattern 5AS.In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S, and the antisense strand comprises pattern 6AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S, and the antisense strand comprises pattern 7AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S, and the antisense strand comprises pattern 8AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S, and the antisense strand comprises pattern 9AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S, and the antisense strand comprises pattern 10AS.

[0151] In some embodiments, the sense strand comprises any one of the modification patterns 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, or 9S. In some embodiments, the sense strand comprises any one of the modification patterns 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S. In some embodiments, the sense strand comprises any one of the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, or 8AS. In some embodiments, the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS. In some embodiments, the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, or 8AS. In some embodiments, the antisense strand comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, or 32S. In some embodiments, the sense strand or the antisense strand comprises modification pattern ASO1.

[0152] 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.

[0153] 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 of the sense strand comprise 2'fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines.

[0154] In some embodiments, the purines of the sense strand include 2'fluoro modified purines and the pyrimidines of the sense strand include a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the sense strand include 2'-O-methyl modified purines and the pyrimidines of the sense strand include a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the sense strand include 2'fluoro modified purines and the pyrimidines of the sense strand include 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the sense strand include 2'-O-methyl modified purines and the pyrimidines of the sense strand include 2'fluoro modified pyrimidines. In some embodiments, the pyrimidines of the sense strand include 2'fluoro modified pyrimidines and the purines of the sense strand include a mixture of 2'fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the sense strand include 2'-O-methyl modified pyrimidines and the purines of the sense strand include 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] In some embodiments, the purines of the antisense strand include 2'fluoro modified purines and the pyrimidines of the antisense strand include a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the antisense strand include 2'-O-methyl modified purines and the pyrimidines of the antisense strand include a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the antisense strand include 2'fluoro modified purines and the pyrimidines of the antisense strand include 2'-O-methyl modified pyrimidines. In some embodiments, the purines of the antisense strand include 2'-O-methyl modified purines and the pyrimidines of the antisense strand include 2'fluoro modified pyrimidines. In some embodiments, the pyrimidines of the antisense strand include 2'fluoro modified pyrimidines and the purines of the antisense strand include a mixture of 2'fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the antisense strand include 2'-O-methyl modified pyrimidines and the purines of the antisense strand include a mixture of 2'fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the antisense strand include 2'fluoro modified pyrimidines and the purines of the antisense strand include 2'-O-methyl modified purines. In some embodiments, the pyrimidines of the antisense strand include 2'-O-methyl modified pyrimidines and the purines of the antisense strand include 2'fluoro modified purines.

[0159] 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.

[0160] 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 further contain vinyl phosphonates and hydrophobic groups.These modifications can aid in delivery to cells or tissues in a subject.Modified oligonucleotides can be used in methods such as treatment methods or methods for reducing gene expression.

[0161] In some embodiments, the oligonucleotide comprises a duplex consisting of a 21 nucleotide single strand with base pairing between 19 base pairs. 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 MTRES1 mRNA. Each end of the antisense strand has one to two phosphorothioate linkages. The 5' end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down MTRES1 mRNA or a target protein. In some embodiments, the sense strand has the same sequence as MTRES1 mRNA. In some embodiments, there are one to two phosphorothioates at the 3' end. In some embodiments, there is one phosphorothioate or no phosphorothioates at the 5' end. In some embodiments, there is a hydrophobic conjugate of 12 to 25 carbons attached to the 5' end via a phosphodiester bond.

[0162] In some cases, any sense strand of the siRNA comprises 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 only 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 only two other bases between positions 5 and 11 of the sense strand are pyrimidines, and these two other pyrimidines are adjacent positions, so there are not three 2'F modifications in a row, any combination of 2'F modifications can be made that gives 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 either siRNA contains a modification pattern that fits any or all of these sense strand rules.

[0163] In some embodiments, if position 9 of the sense strand is a purine, then 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 only 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 only purines, and these two other purines are in adjacent positions, and therefore there are not three 2'F modifications in a row, then any combination of 2'F modifications that gives 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 with 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 fits any or all of these sense strand rules.

[0164] 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 fits these sense strand rules.

[0165] In some cases, either sense strand of the siRNA contains a modification pattern that fits these sense strand rules.

[0166] Terminal modifications useful for regulating activity include modification of the 5'-end of the antisense strand with phosphate or phosphate analog. In certain embodiments, the 5'-end of the antisense strand is phosphorylated or comprises a phosphoryl analog. Exemplary 5'-phosphate modifications include those that are compatible with RNA-induced silencing complex (RISC)-mediated gene silencing. In some embodiments, the 3'-end of the antisense strand is phosphorylated or comprises a phosphoryl analog. In some embodiments, the 5'-end of the sense strand is phosphorylated or comprises a phosphoryl analog. In some embodiments, the 3'-end of the sense strand is phosphorylated or comprises a phosphoryl analog.

[0167] In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimetic at the 5'-end of the antisense strand. In some embodiments, the phosphate mimetic comprises 5'-vinylphosphonate (VP). In some embodiments, the phosphate mimetic is 5'-VP. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimetic at the 3'-end of the antisense strand. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimetic at the 5'-end of the sense strand. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimetic at the 3'-end of the sense strand.

[0168] In some embodiments, disclosed herein is a composition comprising an oligonucleotide that targets MTRES1 and reduces expression of MTRES1 when administered to a cell, the oligonucleotide comprising a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, the sense strand comprising 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 an oligonucleotide sequence with at least one internucleoside linkage modified and at least one nucleoside modified, and the antisense strand comprising 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 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.

[0169] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of the siRNA of Table 8, 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 strand and / or antisense strand of the siRNA of Table 8, 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 strand and / or antisense strand of the siRNA of Table 8. The siRNA may comprise the same internucleoside linkage modifications or nucleoside modifications as those of Table 8. The siRNA may comprise any different internucleoside linkage modifications or nucleoside modifications that are different from those of Table 8. The siRNA may comprise some unmodified internucleoside linkages or nucleosides.

[0170] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of the siRNA in Table 9, 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 strand and / or antisense strand of the siRNA in Table 9, 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 strand and / or antisense strand of the siRNA in Table 9. The siRNA may comprise the same internucleoside linkage modifications or nucleoside modifications as those in Table 9. The siRNA may comprise any different internucleoside linkage modifications or nucleoside modifications that are different from those in Table 9. The siRNA may comprise some unmodified internucleoside linkages or nucleosides.

[0171] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of the siRNA of Table 11A, or the nucleic acid sequence thereof with 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 the siRNA of Table 11A, or the nucleic acid sequence thereof with 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 the siRNA of Table 11A. The siRNA may comprise the same internucleoside bond modification or nucleoside modification as that of Table 11A. The siRNA may comprise any different internucleoside bond modification or nucleoside modification that is different from that of Table 11A. The siRNA may comprise some unmodified internucleoside bond or nucleoside.

[0172] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of the siRNA of Table 13A, or the nucleic acid sequence thereof with 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 the siRNA of Table 13A, or the nucleic acid sequence thereof with 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 the siRNA of Table 13A. The siRNA may comprise the same internucleoside bond modification or nucleoside modification as those of Table 13A. The siRNA may comprise any different internucleoside bond modification or nucleoside modification that is different from those of Table 13A. The siRNA may comprise some unmodified internucleoside bond or nucleoside.

[0173] In some embodiments, the siRNA comprises the sequence of the sense strand and / or antisense strand of the siRNA of Table 15A, or the nucleic acid sequence thereof with 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 the siRNA of Table 15A, or the nucleic acid sequence thereof with 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 the siRNA of Table 15A. The siRNA may comprise the same internucleoside bond modification or nucleoside modification as those of Table 15A. The siRNA may comprise any different internucleoside bond modification or nucleoside modification that is different from those of Table 15A. The siRNA may comprise some unmodified internucleoside bond or nucleoside.

[0174] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in SEQ ID NO:2472. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2472, at least 80% identical to SEQ ID NO:2472, at least 85% identical to SEQ ID NO:2472, at least 90% identical to SEQ ID NO:2472, or at least 95% identical to SEQ ID NO:2472. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO:2472, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO:2472, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2472. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence set forth in SEQ ID NO: 2489. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 2489, at least 80% identical to SEQ ID NO: 2489, at least 85% identical to SEQ ID NO: 2489, at least 90% identical to SEQ ID NO: 2489, or at least 95% identical to SEQ ID NO: 2489. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2489, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2489, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2489. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0175] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in SEQ ID NO:2478. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2478, at least 80% identical to SEQ ID NO:2478, at least 85% identical to SEQ ID NO:2478, at least 90% identical to SEQ ID NO:2478, or at least 95% identical to SEQ ID NO:2478. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO:2478, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO:2478, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2478. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence set forth in SEQ ID NO: 2495. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 2495, at least 80% identical to SEQ ID NO: 2495, at least 85% identical to SEQ ID NO: 2495, at least 90% identical to SEQ ID NO: 2495, or at least 95% identical to SEQ ID NO: 2495. In some embodiments, the antisense strand sequence comprises or consists of a sequence of SEQ ID NO: 2495, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence of SEQ ID NO: 2495, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2495. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0176] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 2479. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 2479, at least 80% identical to SEQ ID NO: 2479, at least 85% identical to SEQ ID NO: 2479, at least 90% identical to SEQ ID NO: 2479, or at least 95% identical to SEQ ID NO: 2479. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 2479, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 2479, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2479. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence set forth in SEQ ID NO:2496. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2496, at least 80% identical to SEQ ID NO:2496, at least 85% identical to SEQ ID NO:2496, at least 90% identical to SEQ ID NO:2496, or at least 95% identical to SEQ ID NO:2496. In some embodiments, the antisense strand sequence comprises or consists of a sequence of SEQ ID NO:2496, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence of SEQ ID NO:2496, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2496. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0177] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in SEQ ID NO: 2480. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO: 2480, at least 80% identical to SEQ ID NO: 2480, at least 85% identical to SEQ ID NO: 2480, at least 90% identical to SEQ ID NO: 2480, or at least 95% identical to SEQ ID NO: 2480. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 2480, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO: 2480, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2480. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence set forth in SEQ ID NO:2497. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2497, at least 80% identical to SEQ ID NO:2497, at least 85% identical to SEQ ID NO:2497, at least 90% identical to SEQ ID NO:2497, or at least 95% identical to SEQ ID NO:2497. In some embodiments, the antisense strand sequence comprises or consists of a sequence of SEQ ID NO:2497, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence of SEQ ID NO:2497, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2497. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0178] In some embodiments, the siRNA comprises a sense strand having a sequence set forth in SEQ ID NO:2507. In some embodiments, the sense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2507, at least 80% identical to SEQ ID NO:2507, at least 85% identical to SEQ ID NO:2507, at least 90% identical to SEQ ID NO:2507, or at least 95% identical to SEQ ID NO:2507. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO:2507, or a sense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence of SEQ ID NO:2507, or a sense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2507. The sense strand may include a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence set forth in SEQ ID NO:2517. In some embodiments, the antisense strand sequence comprises or consists of a sequence at least 75% identical to SEQ ID NO:2517, at least 80% identical to SEQ ID NO:2517, at least 85% identical to SEQ ID NO:2517, at least 90% identical to SEQ ID NO:2517, or at least 95% identical to SEQ ID NO:2517. In some embodiments, the antisense strand sequence comprises or consists of a sequence of SEQ ID NO:2517, or an antisense strand sequence thereof having one, two, three, or four nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence of SEQ ID NO:2517, or an antisense strand sequence thereof having one or two nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO:2517. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0179] 4. ASO modification pattern In some embodiments, the composition comprises an oligonucleotide that inhibits expression of MTRES1, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO comprises the modification pattern ASO1:5'nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3' (SEQ ID NO: 2461), 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 1S1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, or 10AS.

[0180] D. Preparation In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharma- ceutically acceptable carrier.

[0181] In some embodiments, the pharma- ceutically acceptable carrier comprises water. In some embodiments, the pharma- ceutically acceptable carrier comprises a buffer. In some embodiments, the pharma- ceutically acceptable diluent is saline. In some embodiments, the pharma- ceutically acceptable carrier comprises water, a buffer, or saline. In some embodiments, the composition comprises a liposome. In some embodiments, the pharma- ceutically acceptable carrier comprises a liposome, a lipid, a nanoparticle, a protein, a protein-antibody complex, a peptide, cellulose, a nanogel, or a combination thereof.

[0182] In some embodiments, the composition is formulated to cross the blood-brain barrier. In some embodiments, the composition is formulated for central nervous system (CNS) delivery. In some embodiments, the composition comprises a lipophilic compound. The lipophilic compound can be useful for crossing the blood-brain barrier or for CNS delivery.

[0183] 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.

[0184] Some embodiments relate to a method of treating a disorder in a subject in need of treatment. Some embodiments relate to the use of a composition described herein in a treatment method. Some embodiments include 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.

[0185] In some embodiments, treatment includes preventing, inhibiting, or reversing a disorder in a subject. Some embodiments relate to the use of a composition described herein in a method of preventing, inhibiting, or reversing a disorder. Some embodiments relate to a method of preventing, inhibiting, or reversing a disorder in a subject. Some embodiments include administering a composition described herein to a subject suffering from a disorder. In some embodiments, the administration prevents, inhibits, or reverses a disorder in the subject. In some embodiments, the composition prevents, inhibits, or reverses a disorder in the subject.

[0186] Some embodiments relate to a method of preventing a disorder in a subject. Some embodiments relate to the use of a composition described herein in a method of preventing a disorder. Some embodiments include administering a composition described herein to a subject suffering from the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject.

[0187] Some embodiments relate to a method of inhibiting a disorder in a subject. Some embodiments relate to the use of a composition described herein in a method of inhibiting a disorder. Some embodiments include administering a composition described herein to a subject suffering from the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject.

[0188] Some embodiments relate to a method of reversing a disorder in a subject. 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 suffering from a disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.

[0189] In some embodiments, administration is systemic, in some embodiments, administration is intravenous, in some embodiments, administration is by injection.

[0190] A. Disability Some embodiments of the methods described herein include treating a disorder in a subject in need of treatment. In some embodiments, the disorder is a neurological disorder. Non-limiting examples of neurological disorders may include dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. In some embodiments, the neurological disorder includes cognitive decline. In some embodiments, the neurological disorder includes delirium. In some embodiments, the neurological disorder includes dementia. In some embodiments, the neurological disorder includes vascular dementia. In some embodiments, the neurological disorder includes Alzheimer's disease. In some embodiments, the neurological disorder includes Parkinson's disease. The neurological disorder may include a neurodegenerative disease. The neurological disorder may be characterized by protein aggregation.

[0191] B. Target Some embodiments of the methods described herein include treatment of 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.

[0192] In some embodiments, the subject is male. In some embodiments, the subject is female.

[0193] In some embodiments, the subject is an adult (e.g., at least 18 years of age). In some embodiments, the subject is 90 years of age or older. In some embodiments, the subject is 85 years of age or older. In some embodiments, the subject is 80 years of age or older. In some embodiments, the subject is 70 years of age or older. In some embodiments, the subject is 60 years of age or older. In some embodiments, the subject is 50 years of age or older. In some embodiments, the subject is 40 years of age or older. In some embodiments, the subject is 30 years of age or older. In some embodiments, the subject is 20 years of age or older. In some embodiments, the subject is 10 years of age or older. In some embodiments, the subject is 1 year of age or older. In some embodiments, the subject is zero years of age or older.

[0194] In some embodiments, the subject is 100 years old or younger. In some embodiments, the subject is 90 years old or younger. In some embodiments, the subject is 85 years old or younger. In some embodiments, the subject is 80 years old or younger. In some embodiments, the subject is 70 years old or younger. In some embodiments, the subject is 60 years old or younger. In some embodiments, the subject is 50 years old or younger. In some embodiments, the subject is 40 years old or younger. In some embodiments, the subject is 30 years old or younger. In some embodiments, the subject is 20 years old or younger. In some embodiments, the subject is 10 years old or younger. In some embodiments, the subject is 1 year old or younger.

[0195] In some embodiments, the subject is 0-100 years old. In some embodiments, the subject is 20-90 years old. In some embodiments, the subject is 30-80 years old. In some embodiments, the subject is 40-75 years old. In some embodiments, the subject is 50-70 years old. In some embodiments, the subject is 40-85 years old.

[0196] C. Baseline Measurements Some embodiments of the method described herein include obtaining a baseline measurement from the subject.For example, in some embodiments, the baseline measurement is obtained from the subject before treating the subject.Non-limiting examples of baseline measurements include baseline cognitive function measurements, baseline central nervous system (CNS) amyloid plaque measurements, baseline CNS tau accumulation measurements, baseline cerebrospinal fluid (CSF) beta-amyloid 42 measurements, baseline CSF tau measurements, baseline CSF phospho-tau measurements, baseline neurofilament light (NfL) measurements, baseline CSF alpha-synuclein measurements, baseline Lewy body measurements, baseline MTRES1 protein measurements, or baseline MTRES1 mRNA measurements.

[0197] In some embodiments, the baseline measurements are obtained directly from the subject. In some embodiments, the baseline measurements are obtained by observation, e.g., by observation of the subject or tissues of the subject. In some embodiments, the baseline measurements are obtained non-invasively using an imaging device.

[0198] In some embodiments, the baseline measurements are obtained on a sample from the subject. In some embodiments, the baseline measurements are obtained on one or more histological tissue sections. In some embodiments, the baseline measurements are 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 measurements are obtained by an immunoassay, a colorimetric assay, a fluorescent assay, or a chromatographic (e.g., HPLC) assay. In some embodiments, the baseline measurements are obtained by PCR.

[0199] 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 evaluation 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 impairment.

[0200] The baseline measurement may include baseline. In some embodiments, markers of neurodegeneration measurements. Examples of markers of neurodegeneration may include central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) beta-amyloid 42, CSF tau, CSF phospho-tau, CSF or plasma neurofilament light chain (NfL), Lewy bodies, or CSF alpha-synuclein. Any of these measurements may be decreased relative to the baseline measurement. Some examples of methods for measuring these may include assays such as immunoassays, colorimetric assays, or microscopy.

[0201] 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 with a 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. The baseline beta amyloid plaque measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease.

[0202] In some embodiments, the baseline measurement is a baseline beta-amyloid 42 measurement. The baseline beta-amyloid 42 measurement may include a cerebrospinal fluid (CSF) beta-amyloid 42 measurement. In some embodiments, the baseline beta-amyloid 42 measurement includes a baseline concentration or amount. The baseline beta-amyloid 42 measurement may be performed with a biopsy. The baseline beta-amyloid 42 measurement may be performed using a spinal tap (e.g., where the baseline beta-amyloid 42 measurement includes a baseline CSF beta-amyloid 42 measurement). In some embodiments, the baseline beta-amyloid 42 measurement is obtained by an assay such as an immunoassay. The baseline beta-amyloid 42 measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease.

[0203] 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 can 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 can be indicative of a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

[0204] 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.

[0205] The baseline tau measurement may include a cerebrospinal fluid (CSF) tau measurement. The baseline CSF tau measurement may be performed after the use of a spinal tap. The baseline CSF tau measurement may indicate a neurodegenerative disease, such as Alzheimer's disease or Parkinson's disease.

[0206] The baseline CSF tau measurement may include a baseline CSF phospho-tau measurement. The baseline CSF phospho-tau measurement may include the amount of phospho-tau relative to total tau or non-phosphorylated tau. For example, the baseline CSF phospho-tau measurement may include the phospho-tau / tau ratio. The baseline CSF phospho-tau measurement may indicate a neurodegenerative disease, such as Alzheimer's disease or Parkinson's disease.

[0207] In some embodiments, the baseline neurofilament light chain (NfL) measurement comprises a baseline CSF or plasma NfL measurement. The baseline NfL measurement can be a baseline CSF NfL measurement. The baseline NfL measurement can be a baseline plasma NfL measurement. The NfL measurement can include a concentration or amount. The baseline NfL measurement can be indicative of a neurodegenerative disease, such as Alzheimer's disease or Parkinson's disease.

[0208] 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 includes a baseline concentration or amount. The baseline alpha-synuclein measurement may be performed on a 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.

[0209] 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. The baseline beta Lewy body measurement may be indicative of dementia.

[0210] In some embodiments, the baseline measurement is a baseline MTRES1 protein measurement. In some embodiments, the baseline MTRES1 protein measurement comprises a baseline MTRES1 protein level. In some embodiments, the baseline MTRES1 protein level is expressed as a mass or percentage of MTRES1 protein per sample weight. In some embodiments, the baseline MTRES1 protein level is expressed as a mass or percentage of MTRES1 protein per sample volume. In some embodiments, the baseline MTRES1 protein level is expressed as a mass or percentage of MTRES1 protein per total protein in the sample. In some embodiments, the baseline MTRES1 protein measurement is a baseline CNS or CSF MTRES1 protein measurement. In some embodiments, the baseline MTRES1 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescent assay.

[0211] In some embodiments, the baseline measurement is a baseline MTRES1 mRNA measurement. In some embodiments, the baseline MTRES1 mRNA measurement is a baseline MTRES1 mRNA level. In some embodiments, the baseline MTRES1 mRNA level is presented as the amount or percentage of MTRES1 mRNA per sample weight. In some embodiments, the baseline MTRES1 mRNA level is presented as the amount or percentage of MTRES1 mRNA per sample volume. In some embodiments, the baseline MTRES1 mRNA level is presented as the amount or percentage of MTRES1 mRNA per total mRNA in the sample. In some embodiments, the baseline MTRES1 mRNA level is presented as the amount or percentage of MTRES1 mRNA per total nucleic acid in the sample. In some embodiments, the baseline MTRES1 mRNA level is presented relative to another mRNA level, such as the mRNA level of a housekeeping gene in the sample. In some embodiments, the baseline MTRES1 mRNA measurement is a baseline CNS or CSF MTRES1 mRNA measurement. In some embodiments, the baseline MTRES1 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 involves reverse transcription of MTRES1 mRNA.

[0212] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, a baseline measurement is obtained from 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 the composition to the subject.

[0213] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the fluid sample is a CSF sample. In some embodiments, the fluid sample comprises a central nervous system (CNS) fluid sample. The CNS fluid may comprise cerebrospinal fluid (CSF). In some embodiments, the fluid sample comprises a CSF 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. The blood sample may be a plasma sample. In some embodiments, the sample comprises serum. In some embodiments, the sample is a serum sample. The blood sample may be a serum sample.

[0214] In some embodiments, the sample comprises tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the tissue comprises central nervous system (CNS) tissue. For example, a baseline MTRES1 mRNA measurement or a baseline MTRES1 protein measurement may be obtained in a CNS tissue sample obtained from a patient. The CNS tissue may comprise brain tissue. The CNS tissue may comprise neural tissue. The CNS tissue may comprise neurons, glia, microglia, astrocytes, or oligodendrocytes, or a combination thereof. The CNS tissue may comprise neurons. The CNS tissue may comprise glia. The CNS tissue may comprise microglia. The CNS tissue may comprise astrocytes. The CNS tissue may comprise oligodendrocytes.

[0215] In some embodiments, the sample comprises cells. In some embodiments, the sample comprises cells. In some embodiments, the cells comprise CNS cells. The CNS cells may comprise brain cells. The CNS cells may comprise neuronal cells. The CNS cells may be neurons, glial cells, microglial cells, astrocytes, or oligodendrocytes. The CNS cells may be neurons. The CNS cells may be glial cells. The CNS cells may be microglial cells. The CNS cells may be astrocytes. The CNS cells may be oligodendrocytes.

[0216] D. Effects In some embodiments, the composition or administration of the composition affects a measurement such as a cognitive function measurement, a central nervous system (CNS) amyloid plaque measurement, a CNS tau accumulation measurement, a cerebrospinal fluid (CSF) beta-amyloid 42 measurement, a CSF tau measurement, a CSF phospho-tau measurement, an NfL measurement, a CSF alpha-synuclein measurement, a Lewy body measurement, an MTRES1 protein measurement, or an MTRES1 mRNA measurement, as compared to a baseline measurement.

[0217] Some embodiments of the method described herein include obtaining a measurement from a subject. For example, the measurement may be obtained from the subject after the subject is treated. In some embodiments, the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after the composition is administered to the subject. In some embodiments, the measurement is indicative of the disorder being treated.

[0218] 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 the assays 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 histological examination. In some embodiments, the measurements are obtained by observation. In some embodiments, further measurements are provided in a third sample, a fourth sample, a fifth sample, etc.

[0219] In some embodiments, the 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, the 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, the 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, the 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, the 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.

[0220] In some embodiments, the composition reduces the measurement compared to a baseline measurement. For example, a deleterious phenotype of a neurological disorder may be reduced upon administration of the composition. The neurological disorder may include dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. In some embodiments, the reduction is measured in a second sample obtained from the subject after administration of the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administration of 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 a baseline measurement. In some embodiments, the measurement is reduced by about 10% or more compared to a 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, about 90% or more compared to a 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 a baseline measurement. In some embodiments, the measurement is decreased 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. In some embodiments, the measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any of the two aforementioned percentages.

[0221] In some embodiments, the composition increases the measurement compared to a baseline measurement. For example, a protective phenotype of a neurological disorder may be increased upon administration of the composition. The neurological disorder may include dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. In some embodiments, the increase is measured in a second sample obtained from the subject after administration of the composition to the subject. In some embodiments, the increase is measured directly in the subject after administration of the composition to the subject. In some embodiments, the measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more compared to a baseline measurement. In some embodiments, the measurement is increased by about 10% or more compared to a baseline measurement. In some embodiments, the measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more compared to a baseline measurement. In some embodiments, the measurement is increased 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 is increased 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 increased by about 10% or less compared to the baseline measurement. In some embodiments, the measurement is increased 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. In some embodiments, the measurement is increased 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 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 of the two aforementioned percentages.

[0222] 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 evaluation 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 neurological impairment.

[0223] 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, 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 is increased 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 is increased by about 10% or less compared to the baseline cognitive function measure. In some embodiments, the cognitive function measure is increased 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 is increased 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 of the two aforementioned percentages.

[0224] In some embodiments, the measurements are amyloid plaque measurements. The amyloid plaque measurements may include central nervous system (CNS) amyloid plaque measurements. In some embodiments, the amyloid plaque measurements include concentration or amount. The amyloid plaque measurements may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The amyloid plaque measurements may be performed in a biopsy. The amyloid plaque measurements may be performed using a spinal tap (e.g., where the amyloid plaque measurements include cerebrospinal fluid (CSF) amyloid plaque measurements). In some embodiments, the amyloid plaque measurements are obtained by an assay such as an immunoassay. The beta amyloid plaque measurements may indicate the therapeutic effect of an oligonucleotide on a neurodegenerative disease such as Alzheimer's disease.

[0225] 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, 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 decreased by about 10% or less compared to baseline amyloid plaque measurements. In some embodiments, amyloid plaque measurements are 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 baseline amyloid plaque measurements. In some embodiments, amyloid plaque measurements are decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any of the two aforementioned percentages.

[0226] In some embodiments, the measurement is a beta-amyloid 42 measurement. The beta-amyloid 42 measurement may include a cerebrospinal fluid (CSF) beta-amyloid 42 measurement. In some embodiments, the beta-amyloid 42 measurement includes a concentration or amount. The beta-amyloid 42 measurement may be performed on a biopsy. The beta-amyloid 42 measurement may be performed using a spinal tap (e.g., where the beta-amyloid 42 measurement includes a CSF beta-amyloid 42 measurement). In some embodiments, the beta-amyloid 42 measurement is obtained by an assay such as an immunoassay. The beta-amyloid 42 measurement may indicate the therapeutic effect of an oligonucleotide on a neurodegenerative disease such as Alzheimer's disease.

[0227] In some embodiments, the composition reduces the CSF beta-amyloid 42 measurement compared to a baseline beta-amyloid 42 measurement. In some embodiments, the reduction is measured in a second sample (e.g., a CSF sample) obtained from the subject after administering the composition to the subject. In some embodiments, the CSF beta-amyloid 42 measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is reduced by about 10% or more compared to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 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, about 90% or more compared to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by about 10% or less compared to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 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 CSF beta-amyloid 42 measurement. In some embodiments, CSF beta-amyloid 42 measurements are reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0228] In some embodiments, the measurement is a tau measurement. In some embodiments, the tau measurement comprises a concentration or amount. The tau measurement can be performed on a biopsy. In some embodiments, the tau measurement is obtained by an assay such as an immunoassay. The beta tau measurement can indicate the therapeutic effect of an oligonucleotide on a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

[0229] 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 oligonucleotides on neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.

[0230] In some embodiments, the composition reduces a CNS tau accumulation measure compared to a baseline CNS tau accumulation measure. 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 measure is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline CNS tau accumulation measure. In some embodiments, the CNS tau accumulation measure is reduced by about 10% or more compared to the baseline CNS tau accumulation measure. In some embodiments, the CNS tau accumulation measure 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 compared to the baseline CNS tau accumulation measure. In some embodiments, the CNS tau accumulation measure is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline CNS tau accumulation measure. In some embodiments, the CNS tau accumulation measure is decreased by about 10% or less as compared to a baseline CNS tau accumulation measure. In some embodiments, the CNS tau accumulation measure 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 as compared to a baseline CNS tau accumulation measure. In some embodiments, the CNS tau accumulation measure 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 of the two aforementioned percentages.

[0231] Tau measurements can include cerebrospinal fluid (CSF) tau measurements.CSF tau measurements can be performed after the use of spinal tap.CSF tau measurements can indicate the therapeutic effect of oligonucleotides on neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.

[0232] In some embodiments, the composition reduces the CSF tau measurement compared to a baseline CSF tau measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured in a second CSF sample obtained from the subject after administering the composition to the subject. In some embodiments, the CSF tau measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is reduced by about 10% or more compared to the baseline CSF tau measurement. In some embodiments, the CSF tau 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, about 90% or more compared to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by about 10% or less as compared to the baseline CSF tau measurement. In some embodiments, the CSF tau 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 as compared to the baseline CSF tau measurement. In some embodiments, the CSF tau 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 of the two aforementioned percentages.

[0233] CSF tau measurement can include CSF phospho-tau measurement.CSF phospho-tau measurement can include the amount of phospho-tau relative to total tau or non-phosphorylated tau.For example, CSF phospho-tau measurement can include phospho-tau / tau ratio.CSF phospho-tau measurement can indicate the therapeutic effect of oligonucleotide on neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.

[0234] In some embodiments, the composition reduces the CSF phospho-tau measurement compared to a baseline CSF phospho-tau measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured in a second CSF sample obtained from the subject after administering the composition to the subject. In some embodiments, the CSF phospho-tau measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is reduced by about 10% or more compared to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau 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, about 90% or more compared to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by about 2.5% or less, about 5% or less, or about 7.5% or less compared to a baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by about 10% or less compared to a baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau 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 a baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau 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 of the two aforementioned percentages.

[0235] In some embodiments, the neurofilament light chain (NfL) measurement comprises a CSF or plasma NfL measurement. The NfL measurement can be a CSF NfL measurement. The NfL measurement can be a plasma NfL measurement. The NfL measurement can include a concentration or amount. The NfL measurement can be indicative of a neurodegenerative disease, such as Alzheimer's disease or Parkinson's disease.

[0236] In some embodiments, the composition reduces the NfL measurement compared to a baseline NfL measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the NfL measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline NfL measurement. In some embodiments, the NfL measurement is reduced by about 10% or more compared to the baseline NfL measurement. In some embodiments, the NfL 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, about 90% or more compared to the baseline NfL measurement. In some embodiments, the NfL measurement is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline NfL measurement. In some embodiments, the NfL measurement is reduced by about 10% or less compared to the baseline NfL measurement. In some embodiments, the NfL 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 NfL measurement. In some embodiments, the NfL 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 of the two aforementioned percentages.

[0237] In some embodiments, the measurement is an α-synuclein measurement. The α-synuclein measurement may include a cerebrospinal fluid (CSF) α-synuclein measurement. In some embodiments, the α-synuclein measurement includes a concentration or amount. The α-synuclein measurement may be performed on a biopsy. The α-synuclein measurement may be performed using a spinal tap (e.g., where the α-synuclein measurement includes a CSF α-synuclein measurement). In some embodiments, the α-synuclein measurement is obtained by an assay such as an immunoassay. The α-synuclein measurement may indicate the therapeutic effect of an oligonucleotide on a neurodegenerative disease such as Parkinson's disease. The α-synuclein measurement may indicate the therapeutic effect of an oligonucleotide on dementia.

[0238] In some embodiments, the composition reduces an α-synuclein measurement compared to a baseline α-synuclein measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the α-synuclein measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline α-synuclein measurement. In some embodiments, the α-synuclein measurement is reduced by about 10% or more compared to the baseline α-synuclein measurement. In some embodiments, the α-synuclein 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, about 90% or more compared to the baseline α-synuclein measurement. In some embodiments, the α-synuclein measurement is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to the baseline α-synuclein measurement. In some embodiments, the α-synuclein measurement is decreased by about 10% or less compared to a baseline α-synuclein measurement. In some embodiments, the α-synuclein 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 a baseline α-synuclein measurement. In some embodiments, the α-synuclein 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 of the two aforementioned percentages.

[0239] In some embodiments, the measurement is a Lewy body measurement. The Lewy body measurement may include a central nervous system (CNS) Lewy body measurement. In some embodiments, the Lewy body measurement includes a concentration or amount. The Lewy body measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The beta Lewy body measurement may indicate the therapeutic effect of an oligonucleotide on dementia.

[0240] In some embodiments, the composition reduces Lewy body measurements compared to baseline Lewy body 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 Lewy body measurements are reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to baseline Lewy body measurements. In some embodiments, the Lewy body measurements are reduced by about 10% or more compared to baseline Lewy body measurements. In some embodiments, the Lewy body 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, about 90% or more compared to baseline Lewy body measurements. In some embodiments, the Lewy body measurements are reduced by about 2.5% or less, about 5% or less, or about 7.5% or less compared to baseline Lewy body measurements. In some embodiments, Lewy body measurements are decreased by about 10% or less compared to baseline Lewy body measurements. In some embodiments, Lewy body measurements are 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 baseline Lewy body measurements. In some embodiments, Lewy body measurements are decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any of the two aforementioned percentages.

[0241] In some embodiments, the measurements are MTRES1 protein measurements. In some embodiments, the MTRES1 protein measurements include MTRES1 protein levels. In some embodiments, the MTRES1 protein levels are presented as mass or percentage of MTRES1 protein per sample weight. In some embodiments, the MTRES1 protein levels are presented as mass or percentage of MTRES1 protein per sample volume. In some embodiments, the MTRES1 protein levels are presented as mass or percentage of MTRES1 protein per total protein in the sample. In some embodiments, the MTRES1 protein measurements are CNS tissue or fluid MTRES1 protein measurements. In some embodiments, the MTRES1 protein measurements are obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescent assay.

[0242] In some embodiments, the composition reduces the MTRES1 protein measurement relative to a baseline MTRES1 protein measurement. In some embodiments, the composition reduces CNS tissue or fluid MTRES1 protein levels relative to a baseline MTRES1 protein measurement. In some embodiments, the reduced MTRES1 protein level is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the MTRES1 protein measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is reduced by about 10% or more compared to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein 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, about 90% or more, or about 100% or more compared to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by about 2.5% or less, about 5% or less, or about 7.5% or less, as compared to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by about 10% or less, as compared to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein 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, as compared to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any of the two aforementioned percentages.

[0243] In some embodiments, the measurements are MTRES1 mRNA measurements. In some embodiments, the MTRES1 mRNA measurements include MTRES1 mRNA levels. In some embodiments, the MTRES1 mRNA levels are presented as the amount or percentage of MTRES1 mRNA per sample weight. In some embodiments, the MTRES1 mRNA levels are presented as the amount or percentage of MTRES1 mRNA per sample volume. In some embodiments, the MTRES1 mRNA levels are presented as the amount or percentage of MTRES1 mRNA per total mRNA in the sample. In some embodiments, the MTRES1 mRNA levels are presented as the amount or percentage of MTRES1 mRNA per total nucleic acid in the sample. In some embodiments, the MTRES1 mRNA levels are presented relative to another mRNA level, such as the mRNA level of a housekeeping gene in the sample. In some embodiments, the MTRES1 mRNA protein measurements are CNS tissue or fluid MTRES1 mRNA protein measurements. In some embodiments, the MTRES1 mRNA measurements are obtained by an assay, such as a PCR assay. In some embodiments, the PCR comprises qPCR. In some embodiments, the PCR comprises reverse transcription of MTRES1 mRNA.

[0244] In some embodiments, the composition reduces the MTRES1 mRNA measurement compared to a baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is obtained in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the composition reduces the MTRES1 mRNA level relative to a baseline MTRES1 mRNA level. In some embodiments, the reduced MTRES1 mRNA level is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the second sample is a CNS sample. In some embodiments, the MTRES1 mRNA measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to a baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is reduced by about 10% or more compared to a baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA 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, about 90% or more, or about 100% or more compared to a baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by about 2.5% or less, about 5% or less, or about 7.5% or less compared to a baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by about 10% or less compared to a baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA 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 a baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA 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 of the two aforementioned percentages.

[0245] III. Definition Unless otherwise defined, all terminology, notations, and other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or ready reference, and the inclusion of such definitions herein should not necessarily be construed as indicating that they are substantially different from those commonly understood in the art.

[0246] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Thus, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, the description of a range such as 1-6 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and individual numerical values ​​within the range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0247] As used in this specification and claims, "a," "an," and "the" include plural references unless the content clearly dictates otherwise. For example, the term "a sample" includes multiple samples, including mixtures thereof.

[0248] "Determining," "measuring," "evaluating," "assessing," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement. The terms include determining whether an element is present (e.g., detecting). Such terms can include quantitative, qualitative, or quantitative and qualitative determinations. Assessing can be relative or absolute. "Detecting the presence of" can include determining the amount of something present in addition to determining whether something is present or absent depending on the context.

[0249] The terms "subject" and "patient" may be used interchangeably. A "subject" may be a biological entity that contains expressed genetic material. The biological entity may be, for example, a plant, an animal, or a microorganism, including bacteria, viruses, fungi, and protozoa. The subject may be a mammal. The mammal may be a human. The subject may be diagnosed or suspected to be at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected to be at high risk for a disease.

[0250] As used herein, a number followed by the term "about" refers to a number that is plus or minus 10% of that number. A range followed by the term "about" refers to a range of minus 10% of the minimum value and plus 10% of the maximum value.

[0251] As used herein, the term "treatment" or "treating" is used in reference to a pharmaceutical or other intervention regimen to obtain a beneficial or desired outcome in a recipient. A beneficial or desired outcome includes, but is not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may also refer to the eradication or amelioration of the condition or underlying disease being treated. Similarly, a therapeutic benefit may be achieved by the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease, such that an improvement in the subject is observed, even though the subject may still be affected by the underlying disease. A prophylactic benefit includes delaying, preventing, or eliminating the appearance of a disease or illness, delaying or eliminating the onset of symptoms of a disease or illness, slowing, stopping, or reversing the progression of a disease or illness, or any combination thereof. With respect to a prophylactic benefit, a subject at risk of developing a particular disease or reporting one or more physiological symptoms of a disease may receive treatment, even if a diagnosis of the disease has not been made.

[0252] The terms "Cx-y" or "Cx-Cy", when used with a chemical moiety such as alkyl, alkynyl, or alkenyl, are meant to include groups that contain from x to y carbons in the chain. For example, "C 1-6 The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain and branched-chain alkyl groups containing from 1 to 6 carbons.

[0253] The terms "C x -y alkenyl" and "C x -y alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively.

[0254] The term "carbocycle" as used herein refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles include 3-10 membered monocyclic rings, 5-12 membered bicyclic rings, 5-12 membered spiro bicyclic rings, and 5-12 membered bridged rings. Each ring of a bicyclic carbocycle may be selected from a saturated ring, an unsaturated ring, and an aromatic ring. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Bicyclic carbocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, as valences permit. Bicyclic carbocycles further include spiro bicyclic rings, e.g., spiropentane. Bicyclic carbocycles include any combination of ring sizes such as a 3-3 spiro ring system, a 4-4 spiro ring system, a 4-5 fused ring system, a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, a 5-7 fused ring system, a 6-7 fused ring system, a 5-8 fused ring system, and a 6-8 fused ring system. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo[1.1.1]pentanyl.

[0255] The term "aryl" refers to an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains hydrogen and carbon from 5 to 18 carbon atoms, and at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to the Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.

[0256] The term "cycloalkyl" as used herein refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyls can include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 5-12 membered bicyclic rings, 5-12 membered spiro bicyclic rings, and 5-12 membered bridged rings. In certain embodiments, cycloalkyls contain 3-10 carbon atoms. In other embodiments, cycloalkyls contain 5-7 carbon atoms. Cycloalkyls can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, and the like.

[0257] The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyls can include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 5-12 membered bridged rings. In other embodiments, cycloalkenyls contain 5-7 carbon atoms. Cycloalkenyls can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0258] The term "halo" or alternatively "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0259] The term "haloalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more halo radicals, such as, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl radical is optionally further substituted as described herein.

[0260] The term "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, 5-12 membered spiro bicyclic rings, and 5-12 membered bridged rings. Bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, as valences permit. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene. Bicyclic heterocycles include any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles further include spiro bicyclic rings, for example 5-12 membered spiro bicycles, for example 2-oxa-6-azaspiro[3.3]heptane.

[0261] "Heteroaryl" refers to a radical derived from a 5-18 membered aromatic ring radical containing 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to the Huckel theory. Heteroaryl includes fused or bridged ring systems. The heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, olyl), benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro5H-cyclopenta[4,5]thieno[2,3 d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxazolyl, Xoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl quinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloquinazin ... Hepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl).

[0262] The term "heterocycloalkyl" refers to a saturated ring having carbon atoms and at least one heteroatom. Typical heteroatoms include atoms of N, O, Si, P, B, and S. Heterocycloalkyls can include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, 5-12 membered spiro bicyclic rings, and 5-12 membered bridged rings. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl is attached to the remainder of the molecule through any atom of the heterocycloalkyl, such as any carbon or nitrogen atom of the heterocycloalkyl, where valence allows. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and 1,1-dioxo-thiomorpholinyl.

[0263] The term "heterocycloalkenyl" refers to an unsaturated ring having carbon atoms and at least one heteroatom, and at least one double bond exists between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Typical heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl can include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 5-12 membered bridged rings. In other embodiments, heterocycloalkenyl contains 5-7 ring atoms. Heterocycloalkenyl can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazolin (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxin, dihydrodioxin, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[0264] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbon or substitutable heteroatoms, e.g., NH or NH2 of a compound. "Substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valences of the substituted atoms and substituents, and results in a stable compound, i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to a moiety having a substituent replacing two hydrogen atoms on the same carbon atom (e.g., replacing two hydrogen atoms on one carbon with an oxo, imino, or thioxo group). As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0265] In some embodiments, a substituent may be any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oximo (=N-OH), hydrazino (=N-NH 2), -Rb ORa, -Rb OC(O) Ra, -Rb OC(O) ORa, -Rb OC(O) N(Ra)2, -Rb N(Ra)2, -Rb C(O)Ra, -Rb C(O)ORa, -Rb C(O)N(Ra)2, -Rb O Rc C(O)N(Ra)2, -Rb N(Ra)C(O)ORa, -Rb N(Ra)C(O)Ra, -Rb N(Ra)S(O)tRa (t is 1 or 2), -Rb S(O)tRa (t is 1 or 2), -Rb S(O)tORa (t is 1 or 2), and -Rb S(O)tN(Ra)2 (where t is 1 or 2), as well as alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl (any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oximo (=N-OH), hydrazine (=N-NH 2), -Rb ORa, -Rb OC(O) Ra, -Rb OC(O) ORa, -Rb OC(O) N(Ra)2, -Rb N(Ra)2, -Rb C(O)Ra, -Rb C(O)ORa, -Rb C(O)N(Ra)2, -Rb O Rc C(O)N(Ra)2, -Rb N(Ra)C(O)ORa, -Rb N(Ra)C(O)Ra, -Rb N(Ra)S(O)tRa (t is 1 or 2), -Rb S(O)tRa (t is 1 or 2), -Rb S(O)tORa (t is 1 or 2), and -Rb and optionally substituted by S(O)tN(Ra)2, where t is 1 or 2, where each Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, where each Ra, as valences permit, is alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), oximo (=N-OH), hydrazine (=N-NH 2 ), -Rb ORa, -Rb OC(O) Ra, -Rb OC(O) ORa, -Rb OC(O) N(Ra)2, -Rb N(Ra)2, -Rb C(O)Ra, -Rb C(O)ORa, -Rb C(O)N(Ra)2, -Rb O Rc C(O)N(Ra)2, -Rb N(Ra)C(O)ORa, -Rb N(Ra)C(O)Ra, -Rb N(Ra)S(O)tRa (t is 1 or 2), -Rb S(O)tRa (t is 1 or 2), -Rb S(O)tORa (t is 1 or 2), and -Rb S(O)tN(Ra)2 (t is 1 or 2), and each Rb is independently selected from a direct bond or a straight or branched alkylene chain, alkenylene chain, or alkynylene chain, and each Rc is a straight or branched alkylene chain, alkenylene chain, or alkynylene chain.

[0266] A double bond to an oxygen atom, such as an oxo group, is represented herein as both "=O" and "(O)". A double bond to a nitrogen atom is represented herein as both "=NR" and "(NR)". A double bond to a sulfur atom is represented herein as both "=S" and "(S)".

[0267] In some embodiments, a "derivative" polypeptide or peptide is one that has been modified, for example, by glycosylation, pegylation, phosphorylation, sulfation, reduction / alkylation, acylation, chemical conjugation, or mild formalin treatment. Derivatives may be further modified to contain, directly or indirectly, a detectable label, including, but not limited to, a radioisotope label, a fluorescent label, and an enzyme label.

[0268] Some embodiments refer to nucleic acid sequence information. It is contemplated that in some embodiments, thymine (T) may be replaced with uracil (U) or vice versa. For example, some sequences in the sequence listing may list T, but in some embodiments, these may be replaced with U. In some oligonucleotides having nucleic acid sequences that include uracil, uracil may be replaced with thymine. Similarly, in some oligonucleotides having nucleic acid sequences that include thymine, thymine may be replaced with uracil. In some embodiments, oligonucleotides such as siRNAs include or consist of RNA. In some embodiments, oligonucleotides may include or consist of DNA. For example, ASOs may include DNA.

[0269] Some embodiments include sequences with nucleotide modifications or modified internucleoside linkages. Generally, unless otherwise specified, Nf (e.g., Af, Cf, Gf, Tf, or Uf) refers to 2'fluoro-modified nucleosides, dN (e.g., dA, dC, dG, dT, or dU) refers to 2'deoxynucleosides, n (e.g., a, c, g, t, or u) refers to 2'O-methyl-modified nucleosides, and "s" refers to phosphorothioate linkages.

[0270] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0271] VI. Working Examples Example 1: Loss-of-function variants in MTRES1 demonstrate protective association with dementia and Alzheimer's-related traits. Variants in MTRES1 were evaluated for association with dementia, Alzheimer's disease, and related traits in approximately 452,000 individuals using genotype data from the UK Biobank cohort. rs117058816 is a rare (AAF=0.006) splice donor variant (c.3+1G>A) in MTRES1. This variant is believed to be a loss-of-function variant that results in reduced abundance or activity of the MTRES1 gene product.

[0272] The analysis led to the identification of dementia- and Alzheimer's disease-related associations for MTRES1 loss-of-function variants. For example, rs117058816 was associated with a reduced risk of Alzheimer's disease, dementia, delirium, and vascular dementia. rs117058816 was further associated with a reduced risk of family history of Alzheimer's disease and a reduced risk of dementia medication use (Tables 1A and 1B).

[0273] [Table 2A]

[0274] [Table 2B]

[0275] These results indicate that loss of function of MTRES1 confers protection against dementia and Alzheimer's disease and related disorders, and further indicate that therapeutic inhibition of MTRES1 may confer similar disease-preventing effects.

[0276] Protective mutations in MTRES1 result in reduced MTRES1 mRNA and MTRES1 protein. Minigene expression constructs were generated encoding wild-type and rs117058816 (c.3+1G>A) MTRES1 proteins. Minigene constructs (<10 kb) are easier to synthesize than constructs over 10 kb in length and have higher transfection efficiency in downstream experiments. Minigene constructs have some of the internal intron sequences removed but retain all exons and UTRs. Thus, the exons, reduced introns, and pre-mRNA of the 5' and 3' UTRs of the protein-coding transcript of MTRES1 (ENST00000625458) were cloned into the pcDNA3.1(+) vector driven by the CMV promoter. An empty vector was used as a control. For the rs117058816 expression construct, the A allele replaced the G allele at DNA sequence position chr6:107030108 (human genome build 38). This results in the loss of a splice donor site (c.3+1G>A).

[0277] Transfection of HEK-293 cells was optimized. HEK-293 cells were seeded in 6-well plates in complete growth medium and grown for 48 hours, after which the medium was changed. Cells were then transfected with 2 μg of plasmid DNA and 7 μl of TransIT-2020. Cells were incubated for 48 hours and then harvested.

[0278] Cell lysates from transfected cells were assayed to assess intracellular MTRES1 protein by Western blot (Figure 1). In HEK-293 cells transfected with empty vector, a faint band representing endogenous MTRES1 expression was detected by Western blot as a 24 kDa band. In cells transfected with the wild-type construct, significant expression of MTRES1 was detected by Western blot as a 24 kDa band. In cells transfected with the rs117058816 construct, reduced MTRES1 protein compared to wild type was detected by Western blot as a 24 kDa band. When normalized to total protein, cells transfected with the rs117058816 construct express approximately 75% less MTRES1 protein compared to cells transfected with the wild-type construct (Figure 2).

[0279] Cell lysates from transfected cells were also assayed to assess MIRES1 mRNA by qPCR. Cells transfected with the rs117058816 construct express approximately 60% less MTRES1 mRNA compared to cells transfected with the wild-type construct (Figure 3).

[0280] These data provide experimental validation that MTRES1 gene variants associated with dementia and Alzheimer's disease prevention result in loss of MTRES1 protein and MTRES1 mRNA abundance or function. Thus, in some cases, therapeutic inhibition or modulation of MTRES1 may be an effective genetically informed method of treating these diseases.

[0281] Example 2: Bioinformatics selection of sequences to identify therapeutic siRNAs to downregulate MTRES1 mRNA expression Screening sets were defined based on bioinformatics analysis. Therapeutic siRNAs were designed to target human MTRES1 and at least one toxicologically relevant species, in this case the MTRES1 sequences of non-human primates (NHPs) rhesus and cynomolgus macaques. The driving force behind the design of the screening sets was the predicted specificity of the siRNAs for the transcriptomes of the relevant species and the cross-reactivity between species. The predicted specificity in human, rhesus, cynomolgus, mouse, and rat was determined for the sense (S) and antisense (AS) strands. These were assigned a "specificity score", which takes into account the number and position of mismatches as well as the possibility of unintended downregulation of any other transcripts due to full or partial complementarity of the siRNA strands (up to four mismatches within positions 2-18). In this way, off-targets of the antisense and sense strands of each siRNA were identified. In addition, the number of possible off-targets was used as an additional specificity factor in the specificity score. If identified, siRNAs with high specificity and low predicted number of off-targets offer the advantage of increased targeting specificity.

[0282] In addition to selecting siRNA sequences with high sequence specificity for MTRES1 mRNA, siRNA sequences within the seed region were analyzed for similarity to the seed regions of known miRNAs. siRNAs can function like miRNAs through base pairing with complementary sequences within the 3'-UTR of mRNA molecules. The complementarity usually encompasses the 2-7th 5'-base (seed region) of the miRNA. To avoid siRNAs that act through functional miRNA binding sites, siRNA strands containing natural miRNA seed regions were avoided. Seed regions identified in miRNAs from human, mouse, rat, rhesus monkey, dog, rabbit, and pig are referred to as "conserved". Combining the "specificity score" with the miRNA seed analysis results in a "specificity category", which is divided into categories 1-4, with 1 being the most specific and 4 being the least specific. Each strand of the siRNA is assigned to a specificity category.

[0283] Specificity and species cross-reactivity were evaluated for MTRES1 in human, cynomolgus monkey, rhesus monkey, mouse, and rat. Analyses were based on canonical siRNA designs using 19 and 17 bases (without considering positions 1 and 19) and assessed for cross-reactivity. Analysis of perfect matches and single mismatches was also included.

[0284] An analysis of the Human Single Nucleotide Polymorphism (SNP) Database (NCBI-DB-SNP) to identify siRNA targeting regions with known SNPs was also performed to identify siRNAs that are likely non-functional in individuals containing the SNP. This analysis provided information on the location of the SNP within the target sequence as well as the minor allele frequency (MAF) in the case data.

[0285] Initial analysis of related MTRES1 mRNA sequences revealed that few sequences met the specificity parameters and simultaneously targeted MTRES1 mRNA in all related species analyzed, therefore it was decided to design an independent screening subset for therapeutic siRNAs.

[0286] The siRNAs in these subsets recognize human, cynomolgus, and rhesus MTRES1 sequences and therefore can be used to target human MTRES1 in a therapeutic setting.

[0287] The number of siRNA sequences that could be derived from human MTRES1 mRNA (ENST00000311381.8, SEQ ID NO: 2443) without considering specificity or species cross-reactivity was 1,140 (sense and antisense strand sequences included in SEQ ID NOs: 1 to 2280).

[0288] Prioritizing the sequences for target specificity, species cross-reactivity, miRNA seed region sequences, and SNPs as described above results in Subset A. Subset A contains 82 siRNAs whose sequences are shown in Table 2.

[0289] [Table 3-1]

[0290] [Table 3-2]

[0291] The siRNAs in subset A have the following characteristics: Cross-reactivity: with the 19-mer in human MTRES1 mRNA and with the 17-mer / 19-mer in NHP MTRES1 Specificity category: For humans and NHPs: AS2 or better, SS3 or better miRNA seed: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in more than four species Off-target frequency: 20 or fewer human off-targets matched with two mismatches in the antisense strand SNP: The siRNA target site does not harbor any SNP with a MAF of 1% or more (positions 2-18).

[0292] The siRNA sequences of subset A were selected for more stringent specificity to obtain subset B. Subset B contains 73 siRNAs whose sequences are shown in Table 3.

[0293] [Table 4-1]

[0294] [Table 4-2]

[0295] The siRNAs in subset B have the following characteristics: Cross-reactivity: with the 19-mer in human MTRES1 mRNA and with the 17-mer / 19-mer in NHP MTRES1 Specificity category: For humans and NHPs: AS2 or better, SS3 or better miRNA seed: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in more than four species Off-target frequency: ≤15 human off-targets matched with 2 mismatches in the antisense strand SNP: The siRNA target site does not harbor any SNP with a MAF of 1% or more (positions 2-18).

[0296] The siRNA sequences of subset B were further selected for those that did not have a seed region in the AS strand that was identical to the seed region of a known human miRNA to obtain subset C. Subset C contains 54 siRNAs whose sequences are shown in Table 4.

[0297] [Table 5-1]

[0298] [Table 5-2]

[0299] The siRNAs in subset C have the following characteristics: Cross-reactivity: with the 19-mer in human MTRES1 mRNA and with the 17-mer / 19-mer in NHP MTRES1 Specificity category: For humans and NHPs: AS2 or better, SS3 or better miRNA seed: AS+SS strand: a seed region that is not conserved in human, mouse, and rat and does not exist in more than four species. AS strand: a seed region that is not identical to the seed region of any known human miRNA. Off-target frequency: ≤15 human off-targets matched by two mismatches by the antisense strand SNP: The siRNA target site does not harbor any SNP with a MAF of 1% or more (positions 2-18).

[0300] The siRNA sequences of subset C were further selected for those that did not have AS or S strand seed regions identical to those of known human miRNAs to obtain subset D. Subset D contains 35 siRNAs whose sequences are shown in Table 5.

[0301] [Table 6]

[0302] The siRNAs in subset D have the following characteristics: Cross-reactivity: with the 19-mer in human MTRES1 mRNA and with the 17-mer / 19-mer in NHP MTRES1 Specificity category: For humans and NHPs: AS2 or better, SS3 or better miRNA seed: AS+SS strand: a seed region that is not conserved in human, mouse, and rat and is absent in more than four species. AS+SS strand: a seed region that is not identical to the seed region of any known human miRNA. Off-target frequency: 20 or fewer human off-targets matched by the antisense strand with two mismatches SNP: The siRNA target site does not harbor any SNP with a MAF of 1% or more (positions 2-18).

[0303] The siRNA sequences of subset D were further selected for more stringent specificity to obtain subset E. Subset E contains 30 siRNAs whose sequences are shown in Table 6.

[0304] [Table 7]

[0305] The siRNAs in subset E have the following characteristics: Cross-reactivity: with the 19-mer in human MTRES1 mRNA and with the 17-mer / 19-mer in NHP MTRES1 Specificity category: For humans and NHPs: AS2 or better, SS3 or better miRNA seed: AS+SS strand: a seed region that is not conserved in human, mouse, and rat and is absent in more than four species. AS+SS strand: a seed region that is not identical to the seed region of any known human miRNA. Off-target frequency: ≤15 human off-targets matched by two mismatches by the antisense strand SNP: The siRNA target site does not harbor any SNP with a MAF of 1% or more (positions 2-18).

[0306] Subset F includes 54 siRNAs. The siRNAs of subset F include the siRNAs of subset A and are included in Table 7. In some cases, the sense strand of any of the siRNAs of subset F includes modification pattern 6S (Table 8). In some cases, the antisense strand of any of the siRNAs of subset F includes modification pattern 7AS (Table 8, "Subset G"). In some cases, the sense strand of any of the siRNAs of subset F includes an alternative modification pattern (Table 9, "Subset H"). In some cases, the antisense strand of any of the siRNAs of subset F includes modification pattern 7AS (Table 9). The siRNAs of subset F may include any other modification pattern. In Tables 8 and 9, Nf (e.g., Af, Cf, Gf, Tf, or Uf) is a 2'fluoro-modified nucleoside, n (e.g., a, c, g, t, or u) is a 2'O-methyl-modified nucleoside, and "s" is a phosphorothioate linkage.

[0307] [Table 8-1]

[0308] [Table 8-2]

[0309] [Table 9-1]

[0310] [Table 9-2]

[0311] [Table 10-1]

[0312] [Table 10-2]

[0313] Any siRNA in any of subsets A-H may contain any of the modification patterns described herein. If the sequence is a different number of nucleotides long than the modification pattern, the modification pattern can still be used with the appropriate number of nucleotides added to the 5' or 3' to match the number of nucleotides in the modification pattern. For example, if the sense or antisense strand of any of subsets A-F of the siRNA contains 19 nucleotides and the modification pattern contains 21 nucleotides, UU can be added to the 5' end of the sense or antisense strand.

[0314] Example 3: Screening MTRES1 siRNAs for activity in human cells in culture The chemically modified MTRES1 siRNAs in Table 9 were analyzed for MTRES1 mRNA knockdown activity in cells in culture. SK-LMS-1 cells (ATCC® HTB-88) were seeded in 96-well tissue culture plates at a density of 7,500 cells per well in EMEM (ATCC Catalog No. 30-2003) supplemented with 10% fetal bovine serum and incubated overnight at 37°C in a water-jacketed humidified incubator in an atmosphere consisting of air + 5% carbon dioxide. These siRNAs were derived from sequences of siRNA subset F and were cross-reactive to humans and non-human primates. MTRES1 siRNAs were transfected individually into SK-LMS-1 cells in duplicate wells at final concentrations of 10 nM and 1 nM using 0.3 μL per well of Lipofectamine RNAiMax (Fisher). As a control, Silencer Select Negative Control #1 (ThermoFisher, Catalog No. 4390843) was transfected at a final concentration of 10 nM and 1 nM. Silencer Select human MTRES1 (ThermoFisher, Catalog No. 4427037, ID: s27762) was transfected at a final concentration of 10 nM and 1 nM and used as a positive control. After 48 hours of incubation at 37°C, total RNA was harvested from each well and cDNA was prepared using TaqMan® Fast Advanced Cells-to-CT™ Kit (ThermoFisher, Catalog No. A35374) according to the manufacturer's instructions. Levels of MTRES1 mRNA from each well were measured in triplicate by real-time qPCR on a QuantStudio™ 6 Pro Real-Time PCR System using the TaqMan Gene Expression Assay for human MTRES1 (ThermoFisher, assay number Hs00360684_m1).PPIA mRNA levels were measured using TaqMan Gene Expression Assay (ThermoFisher, assay number Hs99999904_m1) and used to determine relative MTRES1 mRNA levels in each well using the delta-delta Ct method. All data was normalized to relative MTRES1 mRNA levels in untreated SK-LMS-1 cells. Results are shown in Table 10. siRNAs ETD01228, ETD01270, ETD01251, ETD01235, ETD01249, ETD01258, ETD01268, ETD01273, ETD01263, ETD01240, ETD01223, ETD01262, ETD01239, ETD01242, ETD01272, ETD01220, ETD01261, ETD01243, ETD01269, ETD01256, ETD01241, ETD01238, ETD01247, and ETD01266 reduced MTRES1 levels by more than 50% when transfected at 10 nM.

[0315] [Table 11-1]

[0316] [Table 11-2]

[0317] Example 4: Determination of IC50 of MTRES1 siRNA The IC50 value for the knockdown of MTRES1 mRNA by selected MTRES1 siRNA is determined in SK-LMS-1 (ATCC® HTB-88) cells. siRNA is assayed individually at 30nM, 10nM, 3nM, 1nM, and 0.3nM, or 3nM, 1nM, 0.3nM, 0.1nM, and 0.03nM, or 30nM, 10nM, 3nM, 1nM, 0.3nM, 0.1nM, and 0.03nM. SK-LMS-1 cells are seeded in 96-well tissue culture plates at a density of 7,500 cells per well in EMEM (ATCC Catalog No. 30-2003) supplemented with 10% fetal bovine serum, and incubated overnight at 37°C in a water-jacketed humidified incubator in an atmosphere composed of air + 5% carbon dioxide. MTRES1 siRNA is transfected individually into SK-LMS-1 cells in triplicate wells using 0.3 μL per well of Lipofectamine RNAiMax (Fisher). After 48 hours of incubation at 37° C., total RNA is harvested from each well and cDNA is prepared using TaqMan® Fast Advanced Cells-to-CT™ Kit (ThermoFisher, Catalog No. A35374) according to the manufacturer's instructions. The level of MTRES1 mRNA from each well is measured in triplicate by real-time qPCR on a QuantStudio™ 6 Pro Real-Time PCR System using the TaqMan Gene Expression Assay for human MTRES1 (ThermoFisher, Assay No. Hs01568158_m1). PPIA mRNA levels were measured using a TaqMan Gene Expression Assay (ThermoFisher, assay number Hs99999904_m1) and used to determine relative MTRES1 mRNA levels in each well using the delta-delta Ct method. All data were normalized to relative MTRES1 mRNA levels in untreated SK-LMS-1 cells.Curve fitting is accomplished using the [inhibitor] vs. response (three parameters) function in GraphPad Prism software.

[0318] Example 5: siRNA-mediated knockdown of MTRES1 in HCN-2 cells MTRES1 mRNA-targeting siRNA, which downregulates the levels of MTRES1 mRNA, can reduce the mRNA abundance of mitochondrially expressed NADH-ubiquinone oxidoreductase chain 5 protein (ND5), NADH-ubiquinone oxidoreductase chain 6 protein (ND6), cytochrome b (CYTB), and mitochondrially encoded 12S ribosomal RNA (12S rRNA) when administered to the cultured human neuronal cell line HCN-2 under conditions of ethidium bromide-induced mitochondrial stress.

[0319] On day 0, HCN-2 cells are seeded at 150,000 cells / mL into Falcon 24-well tissue culture plates (ThermoFisher catalog number 353047) at 0.5 mL per well.

[0320] On day 1, cells are treated with ethidium bromide (100 ng / ml), a well-established mitochondrial DNA replication / transcription inhibitor and stressor. Also on day 1, MTRES1 siRNA and negative control siRNA master mixes are prepared. The MTRES1 siRNA master mix contains 350 μL of Opti-MEM (ThermoFisher Cat. No. 4427037-s1288 Lot No. AS02B02D) and 3.5 μL of a mixture of two MTRES1 siRNAs (10 μM stock). The negative control siRNA master mix contains 350 μL of Opti-MEM and 3.5 μL of negative control siRNA (ThermoFisher Cat. No. 4390843, 10 μM stock). Then, 3 μL of TransIT-X2 (Mirus Cat. No. MIR-6000) is added to each master mix. The mix is ​​incubated for 15 minutes to allow transfection complexes to form, after which 51 μL of the appropriate master mix+TransIT-X2 is added to duplicate wells of HCN-2 cells for a final siRNA concentration of 10 nM.

[0321] On day 3, 48 hours after transfection, duplicate wells are lysed using the Cells-to-Ct kit (ThermoFisher catalog number 4399002) according to the manufacturer's protocol, or protein lysis buffer containing protease and phosphatase inhibitors. For Cells-to-Ct, cells are washed with 50 μL of cold 1× PBS and lysed by adding 49.5 μL of lysis solution and 0.5 μL of DNase I per well, pipetting up and down 5 times, and incubating at room temperature for 5 minutes. Stop solution (5 μL / well) is added to each well, mixed by pipetting up and down 5 times, and incubating at room temperature for 2 minutes. Perform reverse transcriptase reaction with 22.5 μL of lysate according to the manufacturer's protocol. Samples are stored at -80°C until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (using Applied Biosystems FAM / MTRES1, FAM / ND5, FAM / ND6, FAM / CYTB, and FAM / 12srRNA, and BioRad CFX96 catalog number 1855195).

[0322] A decrease in MTRES1 mRNA expression in HCN-2 cells is expected following transfection with MTRES1 siRNA compared to MTRES1 mRNA levels in HCN-2 cells transfected with a nonspecific control siRNA 48 hours after transfection. A decrease in the abundance of the mitochondrially expressed genes ND5, ND6, CYTB, and 12s rRNA mRNA is expected. These results indicate that MTRES1 siRNA induces knockdown of MTRES1 mRNA in HCN-2 cells and that the decrease in MTRES1 expression correlates with a decrease in the abundance of the mitochondrially expressed genes ND5, ND6, CYTB, and 12s rRNA mRNA.

[0323] Example 6: ASO-mediated knockdown of MTRES1 in HCN-2 cells ASOs targeting MTRES1 mRNA that downregulate the levels of MTRES1 mRNA could result in a reduction in the mRNA abundance of mitochondrially expressed ND5, ND6, CYTB, and 12s rRNA when administered to the cultured neuronal cell line HCN-2 under ethidium bromide-induced mitochondrial stress conditions.

[0324] On day 0, HCN-2 cells are seeded at 150,000 cells / mL into Falcon 24-well tissue culture plates (ThermoFisher catalog number 353047) at 0.5 mL per well.

[0325] On day 1, treat the cells with ethidium bromide (100 ng / ml), a well-established mitochondrial DNA replication / transcription inhibitor and stressor. Also on day 1, prepare the MTRES1 ASO and negative control ASO master mixes. The MTRES1 ASO master mix contains 350 μL of Opti-MEM (ThermoFisher catalog number 4427037-s1288 lot number AS02B02D) and 3.5 μL of a mixture of the two MTRES1 ASOs (10 μM stock). The negative control ASO master mix contains 350 μL of Opti-MEM and 3.5 μL of the negative control ASO (ThermoFisher catalog number 4390843, 10 μM stock). Then, add 3 μL of TransIT-X2 (Mirus catalog number MIR-6000) to each master mix. The mix is ​​incubated for 15 min to allow transfection complexes to form, after which 51 μL of the appropriate master mix+TransIT-X2 is added to duplicate wells of HCN-2 cells for a final ASO concentration of 10 nM.

[0326] On day 3, 48 hours after transfection, duplicate wells are lysed using the Cells-to-Ct kit (ThermoFisher catalog number 4399002) according to the manufacturer's protocol, or protein lysis buffer containing protease and phosphatase inhibitors. For Cells-to-Ct, cells are washed with 50 μL of cold 1× PBS and lysed by adding 49.5 μL of lysis solution and 0.5 μL of DNase I per well, pipetting up and down 5 times, and incubating at room temperature for 5 minutes. Stop solution (5 μL / well) is added to each well, mixed by pipetting up and down 5 times, and incubating at room temperature for 2 minutes. Perform reverse transcriptase reaction with 22.5 μL of lysate according to the manufacturer's protocol. Samples are stored at -80°C until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (using Applied Biosystems FAM / MTRES1, FAM / ND5, FAM / ND6, FAM / CYTB, and FAM / 12srRNA, and BioRad CFX96 catalog number 1855195).

[0327] A decrease in MTRES1 mRNA expression in HCN-2 cells is expected following transfection with the MTRES1 ASO compared to MTRES1 mRNA levels in HCN-2 cells transfected with a nonspecific control ASO 48 hours after transfection. A decrease in the abundance of the mitochondrially expressed genes ND5, ND6, CYTB, and 12s rRNA mRNA is expected. These results indicate that the MTRES1 ASO induces knockdown of MTRES1 mRNA in HCN-2 cells and that the decrease in MTRES1 expression correlates with a decrease in the abundance of the mitochondrially expressed genes ND5, ND6, CYTB, and 12s rRNA mRNA.

[0328] Example 7: Inhibition of MTRES1 in mouse models of Alzheimer's disease using MTRES1 siRNA or ASO In this experiment, a mouse model of Alzheimer's disease (AD) is used to evaluate the effects of siRNA or ASO inhibition of MTRES1. The model includes Tg2576 mice expressing human amyloid-β precursor protein (APP) and a presenilin-1 (PSEN1) transgene with five AD-binding mutations. Cognitive function is measured using the forced swim test (FST).

[0329] Seven-month-old mice were divided into four groups: Group 1 - treated with non-targeting control siRNA, Group 2 - treated with non-targeting control ASO, Group 3 - treated with MTRES1 siRNA1, and Group 4 - treated with MTRES1 ASO1. Each group contained eight rats (4 males, 4 females), and Group 5 was treated with vehicle.

[0330] Administration of siRNA, ASO, or vehicle is accomplished by intracerebroventricular (ICV) injection of 10 μL of siRNA or ASO resuspended in PBS at a concentration of 10 μM. On study day 0, mice in group 1 receive non-targeting control siRNA by ICV, mice in group 2 receive non-targeting control ASO by ICV, mice in group 3 receive siRNA1 targeting mouse MTRES1 by ICV, mice in group 4 receive ASO1 targeting mouse MTRES1 by ICV, and mice in group 5 receive vehicle by ICV. Thereafter, animals in each group are administered a total of four injections every other week. Behavioral testing is performed 24 hours after the last injection.

[0331] Potential effects of siRNA or ASO treatment on locomotor activity are assessed to exclude non-specific motor effects that may affect the FST results. Mice are assessed using an open field paradigm (44 × 44 × 40 cm) in a soundproof room. The total distance (cm) traveled by each mouse is recorded for 5 min by a video monitoring system (SMART; Panlab SL, Barcelona, ​​Spain) and used to quantify activity levels. The floor of the open field apparatus is cleaned with 10% ethanol between trials.

[0332] The FST includes behavioral tests that are useful for screening potential drugs that affect cognition and for evaluating other treatments that are expected to affect cognition-related behaviors. On day 1, mice are individually placed in water and allowed to swim for 15 min. The next day, mice are placed in the water again and observed for 6 min duration of immobility using a camera. After a 1 min acclimation session to the apparatus, all behaviors are recorded for 5 min by a video monitoring system (SMART2.5.21, Panlab SL). Immobility is defined as the animal floating motionless in the water, allowing only movements necessary to keep the head above the water. The total immobility time in the FST is recorded as an index of cognitive performance.

[0333] 24 hours after behavioral assessment, mice are sacrificed by cervical dislocation after intraperitoneal injection of 0.3 ml Nembutal (5 mg / ml) (Sigma Cat. No. 1507002). Brain and spinal cord tissues are removed and placed in RNAlater for mRNA isolation.

[0334] Isolate mRNA from tissues placed in RNAlater solution using the PureLink kit (ThermoFisher Cat# 12183020) according to the manufacturer's protocol. Perform reverse transcriptase reactions according to the manufacturer's protocol. Store samples at -80°C until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems FAM / MTRES1 using BioRad CFX96 Cat# 1855195). A decrease in MTRES1 mRNA expression in cortical tissue from mice administered MTRES1 siRNA1 or ASO1 is expected compared to MTRES1 mRNA levels in cortical tissue from mice administered a non-specific control. A decrease in total immobility time in the FST in mice administered MTRES1 siRNA or ASO is expected compared to total immobility time in the FST in mice administered a non-specific control, with no change between treatment groups in the locomotor activity test. These results show that MTRES1 siRNA or ASO induces knockdown of MTRES1 mRNA in cortical tissue, and that reduced MTRES1 expression correlates with reduced total immobility time in the FST without changes in locomotor activity. These results indicate that administration of oligonucleotides targeting MTRES1 to mammalian subjects can be used to treat neurological disorders, including cognitive decline.

[0335] Example 8: Screening of siRNAs targeting human and mouse MTRES1 in mice Several siRNAs designed to cross-react with human and mouse MTRES1 mRNA were tested for activity in mice. siRNAs were linked to GalNAc ligand ETL1. siRNA sequences are shown in Table 11A, where Nf is 2'fluoro-modified nucleoside, n is 2'O-methyl-modified nucleoside, and "s" is phosphorothioate bond.

[0336] Six to eight week old female mice (ICR strain, n=3) were injected subcutaneously on day 0 with a single 200ug dose of GalNAc-conjugated siRNA or PBS as vehicle control.

[0337] Mice were euthanized 14 days after injection and liver samples were collected from each and placed in RNAlater (ThermoFisher Cat. No. AM7020) until processing. Total liver RNA was prepared by homogenizing liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10-second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) following the manufacturer's recommendations. cDNA preparation was performed using Quanta qScript cDNA SuperMix (VWR, Cat. No. 95048-500) following the manufacturer's instructions. Relative levels of hepatic MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay number Mm01229834_m1) and mouse housekeeping gene PPIA (ThermoFisher, assay number Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, catalog number 101419-222). Data were normalized to the mean MTRES1 mRNA levels of animals administered PBS. Results are shown in Table 12. Mice injected with ETD01506, ETD01507, ETD01508, and ETD01509 had substantially lower mean hepatic MTRES1 mRNA levels on day 14 compared to mice administered PBS.

[0338] [Table 12A]

[0339] [Table 12B]

[0340] [Table 13]

[0341] Example 9: Screening of siRNA targeting human MTRES1 mRNA in mice transfected with AAV8-TBG-h-MTRES1 Several siRNAs designed to cross-react with human and cynomolgus monkey MTRES1 mRNA were tested for activity in mice after transfection with adeno-associated virus vector. siRNAs were linked to GalNAc ligand ETL17. siRNA sequences are shown in Table 13A, where "Nf" is 2'fluoro-modified nucleoside, "n" is 2'O-methyl-modified nucleoside, "d" is deoxynucleoside, and "s" is phosphorothioate bond.

[0342] On day -13, 6-8 week old female mice (C57Bl / 6) were injected with 10μL of recombinant adeno-associated virus 8 (AAV8) vector (8.8x10E12 genome copies / mL) by retro-orbital route. The recombinant AAV8 contained the open reading frame and most of the 3'UTR of the human MTRES1 sequence (NM_016487.5) under the control of the human thyroxine-binding globulin promoter in an AAV2 backbone packaged into an AAV8 capsid (AAV8-TBG-h-MTRES1). On day 0, infected mice (n=4) were given a single 100ug dose of GalNAc-conjugated siRNA or PBS as a vehicle control, subcutaneously.

[0343] Mice were euthanized 10 days after subcutaneous injection and liver samples were collected from each and placed in RNAlater (ThermoFisher Cat. No. AM7020) until processing. Total liver RNA was prepared by homogenizing liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10-second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) following the manufacturer's recommendations. cDNA preparation was performed using Quanta qScript cDNA SuperMix (VWR, Cat. No. 95048-500) following the manufacturer's instructions. Relative levels of hepatic MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human MTRES1 (ThermoFisher, assay number Hs01568158_g1) and mouse housekeeping gene PPIA (ThermoFisher, assay number Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, catalog number 101419-222). Data were normalized to the mean MTRES1 mRNA levels of animals administered PBS. Results are shown in Table 14. Mice injected with ETD01880, 1886, 1887, 1888, 1893 had the greatest reduction in mean hepatic MTRES1 mRNA on day 10 compared to mice administered PBS.

[0344] [Table 14-1]

[0345] [Table 14-2]

[0346] [Table 14-3]

[0347] [Table 15]

[0348] Example 10: Screening of siRNAs targeting human and mouse MTRES1 in mice Several siRNAs designed to cross-react with human, mouse and cynomolgus monkey MTRES1 mRNA were tested for activity in mice. siRNAs were linked to GalNAc ligands ETL1 or ETL17. siRNA sequences are shown in Table 15A, where Nf is 2'fluoro-modified nucleoside, n is 2'O-methyl-modified nucleoside, "d" is deoxynucleoside, and "s" is phosphorothioate bond.

[0349] Six to eight week old female mice (ICR strain, n=3) were injected subcutaneously on day 0 with a single 200ug dose of GalNAc-conjugated siRNA or PBS as vehicle control.

[0350] Mice were euthanized 10 days after injection and liver samples were collected from each and placed in RNAlater (ThermoFisher Cat. No. AM7020) until processing. Total liver RNA was prepared by homogenizing liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10-second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) following the manufacturer's recommendations. cDNA preparation was performed using Quanta qScript cDNA SuperMix (VWR, Cat. No. 95048-500) following the manufacturer's instructions. Relative levels of hepatic MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay number Mm01229834_m1) and mouse housekeeping gene PPIA (ThermoFisher, assay number Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, catalog number 101419-222). Data were normalized to the average MTRES1 mRNA levels of animals administered PBS. Results are shown in Table 16. Mice injected with ETD01597, ETD01955, ETD01958 had substantially lower average hepatic MTRES1 mRNA levels on day 10 compared to mice administered PBS.

[0351] [Table 16A]

[0352] [Table 16B]

[0353] [Table 17]

[0354] Example 11: Oligonucleotide Synthesis Oligonucleotides such as siRNAs can be synthesized according to the phosphoramidite technique on a solid phase. For example, a K&A oligonucleotide synthesizer can be used. The synthesis can be carried out on a solid support made of controlled pore glass (CPG, 500 Å or 600 Å, obtained from AM Chemicals, Oceanside, CA, USA). All 2'-OMe and 2'-F phosphoramidites can be purchased from Hongene Biotech (Union City, CA, USA). All phosphoramidites can be dissolved in anhydrous acetonitrile (100 mM) and molecular sieves (3 Å) can be added. 5-benzylthio-1H-tetrazole (BTT, 250 mM in acetonitrile) or 5-ethylthio-1H-tetrazole (ETT, 250 mM in acetonitrile) can be used as activator solutions. Coupling times can be 9 to 18 min (e.g., with GalNAc such as ETL17), 6 min (e.g., with 2'OMe and 2'F). To introduce phosphorothioate linkages, a 100 mM solution of 3-phenyl-1,2,4-dithiazolin-5-one (POS, available from PolyOrg, Inc., Leominster, Mass., USA) in anhydrous acetonitrile can be used.

[0355] After solid phase synthesis, the dried solid support can be treated with a 1:1 volume solution of 40 wt% methylamine and 28% ammonium hydroxide solution (Aldrich) in water at 30° C. for 2 hours. The solution can be evaporated and the solid residue can be reconstituted in water and purified by anion exchange HPLC using a TKSgel SuperQ-5PW 13u column. Buffer A can be 20 mM Tris, 5 mM EDTA, pH 9.0, containing 20% ​​acetonitrile and buffer B can be the same as buffer A with the addition of 1 M...

Claims

1. An oligonucleotide-containing composition that targets MTRS1 and, when administered to a subject in an effective amount, (a) reduces CNS MTRS1, (b) improves cognitive function, (c) delays the decline of cognitive function, or (d) improves markers of neurodegeneration.

2. The composition according to claim 1, wherein the marker of neurodegeneration comprises a marker of the central nervous system (CNS), cerebrospinal fluid (CSF), or plasma of neurodegeneration.

3. The composition according to claim 1, wherein the marker of neurodegeneration comprises a measured value of amyloid plaques, tau accumulation, beta-amyloid 42, tau, phospho-tau, neurofilament light chain (NfL), Lewy bodies, or α-synuclein.

4. The composition according to claim 1, wherein the oligonucleotide comprises a modified internucleoside linkage, and the modified internucleoside linkage comprises one or more phosphorothioate linkages.

5. The composition according to claim 4, 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. **Claim 6**: The oligonucleotide contains modified nucleosides, 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 oligonucleosides, and the modified nucleoside contains locked nucleic acid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA), 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro, 2'-deoxy, 2'-O-methyl nucleoside, 2'-deoxyfluoronucleoside, 2'-O-N-methylacetamide (2'-O-NMA) nucleoside, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. The composition according to claim 1. **Claim 7**: The oligonucleotide contains a lipophilic moiety attached at the 3'-end or 5'-end of the oligonucleotide. The lipophilic moiety contains cholesterol, retinoic acid, cholic acid, adamantaneacetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl, palmitic acid, myristic acid, O3-(oleoyl) lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. The composition according to claim 1. **Claim 8**: The oligonucleotide contains a lipophilic moiety attached at the 3'-end or 5'-end of the oligonucleotide, the lipophilic moiety contains a lipid, and the lipid contains myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or α-tocopherol, or a combination thereof. The composition according to claim 1. **Claim 9**: The composition according to claim 1, wherein the oligonucleotide comprises small interfering RNA (siRNA) comprising a sense strand and an antisense strand, and each strand is independently 12 to 30 nucleosides in length. **Claim 10**: With respect to the sense strand, the following, 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, any one of the above applies, or, With respect to the antisense strand, the following, 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 include 2'-O-methyl modified pyrimidines, and all purines include a mixture of 2'-fluoro and 2'-O-methyl modified purines, or, All pyrimidines include 2'-O-methyl modified pyrimidines, and all purines include 2'-fluoro modified purines, The composition according to claim 9, to which any one of the above applies.

11. A composition comprising an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide is (a) siRNA comprising a sense strand and an antisense strand, each strand independently being about 12 to 30 nucleosides in length, and at least one of the sense strand and the antisense strand comprising a nucleoside sequence comprising about 12 to 30 adjacent nucleosides of SEQ ID NO: 2443, siRNA, (b) an antisense oligonucleotide (ASO) 12 to 30 nucleosides in length, and a nucleoside sequence complementary to 12 to 30 adjacent nucleosides of SEQ ID NO: 2443 A composition comprising.

12. Regarding the sense strand, as follows, 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, All pyrimidines include 2'-O-methyl modified pyrimidines, and all purines include 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. Any one of Regarding the antisense strand, hereinafter, 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'-O-methyl-modified purines, and all pyrimidines include 2'-fluoro-modified pyrimidines. All pyrimidines include 2'-fluoro-modified pyrimidines, and all purines include a mixture of 2'-fluoro- and 2'-O-methyl-modified purines. All pyrimidines include 2'-O-methyl-modified pyrimidines, and all purines include a mixture of 2'-fluoro- and 2'-O-methyl-modified purines, or All pyrimidines include 2'-O-methyl-modified pyrimidines, and all purines include 2'-fluoro-modified purines. The composition according to claim 11, wherein any one of

13. The composition according to claim 11, wherein the oligonucleotide contains a phosphate or a phosphate mimetic or 5'-vinyl phosphate (VP) at the 3' end or 5' end of the antisense strand.

14. The composition according to any one of claims 1 to 13, further comprising a pharmaceutically acceptable carrier.

15. A composition comprising an oligonucleotide that inhibits the expression of MTRES1 for use in a method of treating a subject having a neuropathy, the method comprising the step of administering an effective amount of the composition to the subject, The oligonucleotide is (a) An siRNA comprising a sense strand and an antisense strand, each strand independently being about 12 to 30 nucleosides in length, and at least one of the sense strand and the antisense strand comprising a nucleoside sequence comprising about 12 to 30 adjacent nucleosides of SEQ ID NO: 2443, or, (b) An antisense oligonucleotide (ASO) 12 to 30 nucleosides in length, and a nucleoside sequence complementary to the 12 to 30 adjacent nucleosides of SEQ ID NO: 2443 A composition comprising. **Claim 16**: The composition according to claim 15, wherein the neuropathy comprises dementia, Alzheimer's disease, delirium, decline in cognitive function, vascular dementia, or Parkinson's disease.

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