Treatment of mtres1 related diseases and disorders

Abstract

Disclosed herein are compositions comprising an oligonucleotide that targets MTRES1. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating conditions associated with MTRES1 gene mutations that include providing an oligonucleotide that targets MTRES1 in a subject.

Description

TREATMENT OF MTRES1 RELATED DISEASES AND DISORDERSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Nos. 63 / 656,548, filed June 5, 2024 and 63 / 694,139, filed Sept 12, 2024, all of which applications are incorporated herein by reference in their entirety.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format.The Sequence Listing is provided as a file entitled 54462-775-60 l_SL.xml, created June 3, 2025, which is 11,689,601 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.BACKGROUND

[0003] Neurological disorders are a common problem, particularly in the older population.Improved therapeutics are needed for treating these disorders.SUMMARY

[0004] Provided herein are composition comprising an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases central nervous system (CNS) MTRES1, wherein the oligonucleotide comprises any one of SEQ ID NOS: 2571, 2633, 2674, 2681, 2683, 2684, 3337, 2790, 2801, 2842, 2856, 2861, 2863, 2865, 2866, 2972, 2983, 3022, 3024, 3143, 3341, 3342, 3343, 3344, 3345, 3346, 3347, 3348, 3349, 3350, 3351, 3352, 3353, 3354, 3355, 3356, 3373, 3374, 3375, 3376, 3377, or 3378. Further provided herein are compositions wherein the oligonucleotide comprises a modified intemucleoside linkage. Further provided herein are compositions wherein the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. Further provided herein are compositions wherein the modified intemucleoside linkage comprises one or more phosphorothioate linkages. Further provided herein are compositions wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages. Further provided herein are compositions wherein the oligonucleotide comprises a modified nucleoside. Further provided herein are compositions wherein the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2’, 4’ constrained ethyl nucleic acid, 2'-O-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-C-allyl, 2'-fluoro, 2'-deoxy, or 2’-O-methyl inosine, or a combination thereof. Further provided herein are compositions wherein the modified nucleoside comprises an LNA or a 2’, 4’ constrained ethyl nucleic acid. Further provided herein are compositions wherein the modified nucleoside comprises a 2'-O-methoxyethyl. Further provided herein are compositions wherein the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-0-DMAE0E) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof. Further provided herein are compositions wherein the modified nucleoside comprises one or more 2’-fluoro modified nucleosides. Further provided herein are compositions wherein the modified nucleoside comprises a 2'-O-alkyl modified nucleoside. Further provided herein are compositions wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. Further provided herein are compositions wherein the oligonucleotide comprises a lipophilic moiety attached at a 3’ or 5’ terminus of the oligonucleotide. Further provided herein are compositions wherein the lipophilic moiety comprises cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1 -pyrene butyric acid, dihydrotestosterone, l,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. Further provided herein are compositions wherein the lipophilic moiety comprises a C4-C30 hydrocarbon chain. Further provided herein are compositions wherein the lipophilic moiety comprises a lipid. Further provided herein are compositions wherein the lipid comprises myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, a-tocopherol, or a combination thereof. Further provided herein are compositions wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. Further provided herein are compositions wherein the sense strand is 12-30 nucleosides in length. Further provided herein are compositions wherein the antisense strand is 12-30 nucleosides in length.

[0005] Provided herein are compositions comprising an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NOS: 2571, 2633, 2674, 2681, 2683, 2684, 3337, 2790, 2801, 2842, 2856, 2861, 2863, 2865, 2866, 2972, 2983, 3022, 3024, 3143, 3341, 3342, 3343, 3344, 3345, 3346, 3347, 3348, 3349, 3350, 3351, 3352, 3353, 3354, 3355, 3356, 3373, 3374, 3375, 3376, 3377, or 3378. Further provided herein are compositions wherein any one of the following is true with regard to the sense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’- methyl modified pyrimidines; all purines comprise 2’-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-methyl modified pyrimidines; all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’ -methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-methyl modified purines; all pyrimidines comprise 2’-methyl modified pyrimidines, and 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. Further provided herein are compositions wherein any one of the following is true with regard to the sense strand: (a) all purines comprise 2’-fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethylmodified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-0-methyl, and 2’-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O- methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2’-fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O- methoxyethyl modified pyrimidines; (iii) a mixture of 2’ -fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2’-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O- methyl, and 2’-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2 ’-fluoro modified pyrimidines; (ii) 2’-O-methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O- methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; and with the proviso that in any of the foregoing, the sense strand may include a 2’-deoxy nucleoside. Further provided herein are compositions wherein any one of the following is true with regard to the antisense strand: all purines comprise 2’ -fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-methyl modified pyrimidines; all purines comprise 2’-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-methyl modified pyrimidines; all purines comprise 2’-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’-methyl modified purines; all pyrimidines comprise 2’-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-methyl modified purines; or all pyrimidines comprise 2’-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines. Further provided herein are compositions wherein the oligonucleotide comprises a phosphate at the 5’ end of the antisense strand. Further provided herein are compositions wherein the oligonucleotide comprises a phosphate mimic at the 5’ end of the antisense strand. Further provided herein are compositions wherein the phosphate mimic comprises a 5'-vinyl phosphonate (VP). Further provided herein are compositionswherein the oligonucleotide comprises an antisense oligonucleotide (ASO). Further provided herein are compositions wherein the ASO is 12-30 nucleosides in length.

[0006] Provided herein are compositions comprising: a small interfering RNA (siRNA) comprising a sense strand, an antisense strand complementary to a section of an MTRES 1 mRNA, and a ligand connected to an end of the sense or antisense strand. Further provided herein are compositions wherein the ligand comprises a peptide or protein. Further provided herein are compositions wherein the ligand is selected from a hydrophobic ligand, av[33 ligand, a deltorphin peptide (8 opioid agonist), a dermorphin peptide (p opioid agonist), a Neurotensin peptide, GHRP-6 peptide, a native protein for mediating degradation via Chaperone-Mediated Autophagy, a Nerve Growth Factor-derived peptide binding to tyrosine kinase receptors and to p75 neurotrophin receptors, a 4F peptide that binds LDL, and a ligand for mannose 6-phosphate receptors. In some embodiments, the ligand is selected from cycloRGDfK(N3-PEG4), YaFDW-N3K, YaFGYPK, KPPPAGSSPGLYENKPRRPYIL, -PEG2- CH2CO-GHwAWfK-NH2, PEG2-CH2CO-GKFERQQKILDQRFFE, PEG2-CH2CO- GTFVKALTMDGKQAAWR, PEG2-CH2CO-GDWFKAFYDKVAEKFKEAF-NH2, and alpha-Mannose 6-phosphate PEG3. Further provided herein are compositions wherein the ligand is connected to an end of the sense or antisense strand via linker. Further provided herein are compositions wherein the linker is formed through a conjugation a reaction. Further provided herein are compositions wherein the conjugation a reaction comprises a cycloaddition reaction. Further provided herein are compositions wherein the conjugation a reaction comprises reaction of an azide and an alkyne. Further provided herein are compositions wherein the composition comprises the structure: and. Further provided herein are compositions wherein the ligand comprises a lipid moiety connected to an end of the sense or antisense strand. Further provided herein are compositions wherein the lipid moiety comprises (a) a phenyl or cyclohexanyl linker, and (b) a lipid, wherein the linker is connected to the lipid and to the end of the sense or antisense strand. Further provided herein are compositions wherein the lipid and the end of the sense or antisense strand are connected to the phenyl or cyclohexanyl linker in the 1,4; 1,3; or 1,2 substitution pattern. Further provided herein are compositions wherein the lipid and the end of the sense or antisense strand are connected to the phenyl or cyclohexanyl linker in the 1,4 -substitution pattern. Further provided herein are compositions wherein the lipid moiety comprises the following structure:wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, with the proviso thatR is not an octane. Further provided herein are compositions wherein the lipid moiety comprises the following structure:; wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, n is 1-3, and R is an alkyl group containing 4-18 carbons. Further provided herein are compositions wherein the lipid moiety comprises the following structure:; wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, n is 0-3, and R is an alkyl group containing 4-18 carbons. Further provided herein are compositions wherein the lipid moiety comprises the followingstructure: ; wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand. Further provided herein are compositions wherein the lipid moiety comprises a lipid moiety depicted in Table 1. Further provided herein are compositions wherein the ligand comprises a ligand depicted in Table 115. A composition comprising an siRNA that targets MTRES1 and when administered to a cell modulates the expression of MTRES1, wherein the siRNA comprises a sense strand and an antisense strand; and wherein the sense strand or the antisense strand comprises any of modification patterns 64S to 83 S or 4 IAS to 45 AS. Further provided herein are compositions wherein the oligonucleotide comprises any one of SEQ ID NOS: 2571, 2633, 2674, 2681, 2683, 2684, 2790, 2801, 2842, 2856, 2861, 2863, 2865, 2866, 2972, 2983, 3024, 3143, 3341, 3342, 3343, 3344, 3345, 3346, 3347, 3348, 3349, 3350, 3351, 3352, 3353, 3354, 3355, 3356, 3373, 3374, 3375, 3376, 3377, or 3378. A composition comprising an siRNA that targets MTRES1 and when administered to a cell modulates the expression of MTRES1, wherein the siRNA comprises a sense strand and an antisense strand; and wherein the sense strand or the antisense strand comprises any one of SEQ ID NOs: 2571, 2633, 2674, 2681, 2683, 2684, 2790, 2801, 2842, 2856, 2866, 2861, 2863, 2865, 2972, 2983, 3022, 3024, 3143, 3341, 3342, 3343, 3344, 3345, 3346, 3347, 3348, 3349, 3350, 3351, 3352, 3353, 3354, 3355, 3356, 3373, 3374, 3375, 3376, 3377, or 3378. Further provided herein are compositions, wherein the sense strand or the antisense strand comprises any one of SEQ ID NOs: 2399, 2484, 2501, 2866, 3022, 3051,3095, 3106, 3119, 3177, 3183, 3194, 3207, 3239, 3241, 3242, 3243, 3244, 3248, 3296, 3306, 3326, 3337, 3357,3358, 3359, 3360, 3361, 3362, 3363, 3364, 3365, 3366, 3367, 3368, 3369, 3370, 3371, 3372, 3379, 3380, 3381, 3382, 3383, 3384, 3385, 3386, 3387, 3388, 3389, 3390, 3391, 3392, 3393, 3394, 3395-3414. Further provided herein are compositions further comprising a pharmaceutically acceptable carrier. Further provided herein are compositions wherein the composition is formulated for administration to a central nervous system. Further provided herein are compositions wherein the composition is formulated for delivery to a neural cell. In some embodiments, a composition comprises an oligonucleotide provided herein targets MTRES1 and when administered to a subject in an effective amount increases cognitive function or slows cognitive decline. Further provided herein are compositions wherein the cognitive function is increased by about 10% or more, as compared to prior to administration. Further provided herein are compositions wherein the cognitive decline is slowed by about 10% or more, as compared to prior to administration.

[0007] Provided herein are composition comprising an oligonucleotide that targets MTRES 1 and when administered to a subject in an effective amount improves a marker of neurodegeneration. Further provided herein are compositions wherein the wherein the marker of neurodegeneration comprises a central nervous system (CNS), cerebrospinal fluid (CSF), or plasma marker of neurodegeneration.Further provided herein are compositions wherein the wherein the marker of neurodegeneration comprises a measurement of amyloid plaques, tau accumulation, beta-amyloid 42, beta-amyloid 40, the ratio of betaamyloid 42 to beta-amyloid 40, tau, phospho-tau, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), alpha-synuclein, or Lewy bodies. Further provided herein are compositions wherein the marker of neurodegeneration is improved by about 10% or more, as compared to prior to administration.

[0008] Provided herein are composition comprising an oligonucleotide that targets MTRES 1 and when administered to a subject in an effective amount improves a marker of mitochondrial function or mitochondrial energy metabolism. Further provided herein are compositions wherein the marker of mitochondrial function or mitochondrial energy metabolism comprises a central nervous system (CNS), cerebrospinal fluid (CSF), or plasma marker of mitochondrial function or mitochondrial energy metabolism. In some embodiments, the marker of mitochondrial function or mitochondrial energy metabolism comprises a measurement of metabolic dysfunction, mitochondrial dysfunction, mitochondrial respiration, oxidative phosphorylation, glycolysis, a ATP or ATP production, ketones or ketone metabolism, lipids or lipid metabolism, the astrocyte -neuron lactate shuttle (ANLS), neuron metabolism, astrocyte metabolism, glial cell metabolism, oligodendrocyte metabolism, CNS glucose or CNS glucose consumption, CNS oxygen or CNS oxygen consumption, the TCA or Krebs cycle, the electron transport chain, mitophagy or autophagy, mitochondrial fission or fusion, mitochondrial transcription or translation, mitochondrial biogenesis, gliotransmitter release or function, neurotransmitter release or function, connexin 43, lactate or lactate metabolism, pyruvate or pyruvate metabolism, amino acids or amino acid metabolism, or lipoprotein particle composition or concentration. Further provided herein are compositions wherein the mitochondrial function or mitochondrial energy metabolism is improved by about 10% or more, as compared to prior to administration.

[0009] Provided herein are methods of treating a subject having a neurological disorder, the method comprising administering an effective amount of a composition provided herein to the subject. Further provided herein are methods wherein the neurological disorder comprises dementia, Alzheimer’s disease, delirium, cognitive decline, cognitive impairment, vascular dementia, or Parkinson’s disease. Further provided herein are methods wherein the composition is administered intrathecally.

[0010] Provided herein are methods of treating a subject having a neurological disorder or who is at risk for developing the neurological disorder, the method comprising evaluating a subject’s risk for developing a neurological disorder and administering an effective amount of a composition provided herein to the subject. Further provided herein are methods wherein the subject has a genotype at risk for developing Alzheimer’s disease or dementia. Further provided herein are methods wherein the subject is a heterozygous or homozygous carrier of APOE4. Further provided herein are methods wherein the subject is a heterozygous or homozygous carrier of MTRES1 rsl 17058816-G (c.3+lG). Further provided herein are methods wherein evaluating a subject’s risk for developing a neurological disorder comprises calculating a polygenic risk score for developing Alzheimer’s disease or dementia. Further provided herein are methods wherein the subject has a polygenic risk score in the 40thpercentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia. Further provided herein are methods wherein the subject has a polygenic risk score in the 20thpercentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia. Further provided herein are methods wherein calculating a polygenic risk score comprises providing genomic data comprising one or more genotypes of the subject, wherein the one or more genotypes is associated with a high risk for developing Alzheimer’s disease or dementia.

[0011] Provided herein are compositions comprising an oligonucleotide that targets MTRES 1 and when administered to a subject in an effective amount decreases central nervous system (CNS) MTRES1, wherein the oligonucleotide comprises any one of SEQ ID NOS: 3595-3599.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 is a plot of MTRES 1 mRNA qPCR data in the CRISPR-engineered wildtype (left,“wt”) and MTRES1 c.3+lG>A knock-in cells (right, “KI”). The y-axis indicates fold change from 0.0 to 1.5 at 0.5 unit intervals.

[0013] FIG. 2A is an image of a western blot of MTRES 1 protein in the CRISPR-engineered wildtype (left 4 lanes, “WT HEK293”) and MTRES1 c.3+lG>A knock-in cells (right 4 lanes, “MTRES1 c.3+lG>A KI”), showing bands for MTRES1 (top row) and ACTB (bottom row).

[0014] FIG. 2B is a plot quantifying MTRES 1 western blot data in the wildtype (left, “WT”) and MTRES1 c.3+lG>A knock-in cells (right, “KI”). The y-axis indicates normalized fold change to ACTB from 0.0 to 1.5 at 0.5 unit intervals.

[0015] FIG. 3A is a plot of qRT-PCR analysis of MTRES 1 RNA levels in primary rat neuron cultures transfected with a non-targeting siRNA control (left) vs. siRNA construct ETD03205 (right). The y-axis is labeled relative fold change from 0.0 to 2.0 at 0.5 unit intervals (normalized to HPRT1).

[0016] FIG. 3B is an image of a western blot analyses of MTRES1 RNA and protein levels in primary rat neuron cultures transfected with siRNA construct ETD03205 (right) or a non-targeting siRNA control (left, “NTC”).

[0017] FIG. 4 is a plot of qRT-PCR analysis of Gjal RNA levels in primary rat neuron cultures transfected with a non-targeting siRNA control (left) vs. siRNA construct ETD03205 (right). The y-axis is labeled relative fold change from 0.0 to 1.5 at 0.5 unit intervals (normalized to HPRT1).

[0018] FIG. 5A is a plot of ATP quantification analyses in primary rat neuron cultures transfected with ETD03205 (right) or a non -targeting siRNA control (left). The y-axis is labeled relative fold change from 0.0 to 1.5 at 0.5 unit intervals (normalized to HPRT1).

[0019] FIG. 5B is a plot of nuclei counting analyses in primary rat neuron cultures transfected with ETD03205 (right) or a non-targeting siRNA control (left). The y-axis is labeled cell counts from 0 to 100,000 at 20,000 unit intervals.

[0020] FIG. 6 depicts a range of metabolite associations with MTRES 1 c.3+lG>A represented as p values. From left to right: acetoacetate (4.1E-05); 3 -hydroxybutyrate (0.008); acetone (0.024); cholesterol to total lipids in HDL (0.012); cholesterol to total lipids in VLDL (0.020); glycine (0.034); triglycerides to total lipids in VLDL (0.023); alanine (0.042); triglycerides to total lipids in HDL (0.017); and lactate (0.008). The effect size scale (bottom) is from -0.06 to 0.04 at 0.02 unit intervals.DETAILED DESCRIPTION

[0021] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GWAS) may detect associations between genetic variants and traits in a population sample. A GWAS may enable better understanding of the biology of disease and provide applicable treatments. A GWAS can utilize genotyping and / or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is said to be associated with disease. Association statistics that may be used in a GWAS are p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size. Researchers often assume an additive genetic model and calculate an allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.”

[0022] Functional annotation of variants and / or wet lab experimentation can identify the causal genetic variant identified via GWAS, and in many cases may lead to the identification of disease -causing genes. In particular, understanding the functional effect of a causal genetic variant (for example, loss of protein function, gain of protein function, increase in gene expression, or decrease in gene expression)may allow that variant to be used as a proxy for therapeutic modulation of the target gene, or to gain insight into potential therapeutic efficacy and safety of a therapeutic that modulates that target.

[0023] Identification of such gene-disease associations has provided insights into disease biology and may be used to identify novel therapeutic targets for the pharmaceutical industry. In order to translate the therapeutic insights derived from human genetics, disease biology in patients may be exogenously ‘programmed’ into replicating the observation from human genetics. There are several potential options for therapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines. These may include well established therapeutic modalities such as small molecules and monoclonal antibodies, maturing modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality can depend on several factors including the location of a target (for example, intracellular, extracellular, or secreted), a relevant tissue (for example, brain) and a relevant indication.

[0024] 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 include 240 amino acids. MTRES1 may include 245 amino acids. MTRES1 may be expressed in neural cells. MTRES1 may be expressed in neuronal cells. MTRES1 may be expressed in glial cells. MTRES1 may be cytoplasmic or intracellular. MTRES1 may be localized in mitochondria within the cell. MTRES1 may be involved in mitochondrial transcription regulation. MTRES1 may be involved in mitochondrial translation regulation. MTRES1 may be involved in mitochondrial energy metabolism. An example of a MTRES1 amino acid sequence, and further description of MTRES1 is included at uniprot.org under accession no. Q9P0P8 (last modified October 1, 2000).

[0025] MTRES1 RNA expression is often higher in mitochondria-rich tissues such as skeletal muscle, heart, liver, kidney, adrenal cortex, and brain. MTRES1 RNA may be expressed throughout the brain, with an average expression of 24 nTPM across all regions. Expression is generally higher within the cerebral cortex (nTPM=35.7), with highest expression within int prefrontal cortex. Within the prefrontal cortex, highest expression may be in the dorsomedial and dorsolateral regions. MTRES1 protein may also be detectable in the cortex, cerebellum, hippocampus and caudate, particularly within neuronal cells and astrocytes. Within neural cells, MTRES1 mRNA was found to have the highest levels of expression in astrocytes, neurons, and oligodendrocytes, with lower but measurable expression in microglia, endothelial cells, and fetal astrocytes.

[0026] Here it is shown that loss-of-function MTRES1 variants may protect against neurological diseases. For example, a loss-of-function MTRES1 variant was associated with protective associations against Alzheimer’s disease, family history of Alzheimer’s disease, dementia, cognitive symptoms, vascular dementia, anticholinesterase medication use, and delirium. Therefore, inhibition of MTRES1 may serve as a therapeutic for treatment of a neurological disorder such as dementia, Alzheimer’s disease, delirium, cognitive impairment or decline, vascular dementia, or Parkinson’s disease.

[0027] Disclosed herein are compositions comprising an oligonucleotide that targets MTRES 1.Where inhibition or targeting of MTRES 1 is disclosed, it is contemplated that some embodiments may include inhibiting or targeting a MTRES 1 protein or MTRES 1 RNA. For example, by inhibiting or targeting an RNA (e.g., mRNA) encoded by the MTRES1 gene using an oligonucleotide described herein, the MTRES 1 protein may be inhibited or targeted as a result of there being less production of the MTRES 1 protein by translation of the MTRES 1 RNA; or a MTRES 1 protein may be targeted or inhibited by an oligonucleotide that binds or interacts with a MTRES 1 RNA and reduces production of the MTRES 1 protein from the MTRES 1 RNA. Thus, targeting MTRES 1 may refer to binding a MTRES 1 RNA and reducing MTRES1 RNA or protein levels. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating a neurological disorder by providing an oligonucleotide that targets MTRES 1 to a subject in need thereof.

[0028] In some embodiments, the siRNAs described herein comprise a sense strand and an antisense strand. In some embodiments, the sense strand comprises any one of SEQ ID NOs: 3038-3124, 3239, 3241-3242, 3259-3260, 3267-3273, 3296-3299, or 3305-3318 or the antisense strand comprises any one of SEQ ID NOs: 3125-3212, 3243-3250, 3261-3262, 3274-3280, 3300-3304, or 3319-3337. In some embodiments, the sense strand or the antisense strand comprise any one of SEQ ID NOS : 2675, 2677- 2686, 2689, 2720, 2729, 2739, 2745, 2748, 2749, 2754, 2758-2762, 2766, 2767, 2769, 2770, 2786, 2787- 2812, 2814-2816, 2819-2822, 2824, 2828-2833, 2836, 2838, 2839, 2857, 2859-2868, 2871, 2873, 2874, 2877-2879, 2940-2944, 2948-2952, 2968-2994, 2996-2998, 3001-3004, 3006, 3010, 3011, 3013-3015, 3018, or 3020. In some embodiments, the sense strand or the antisense strand comprises any of modification patterns IS to 63S or IAS to 41AS. In some embodiments, the sense strand or the antisense strand comprises any of modification patterns 33S to 63S or 1 IAS to 41AS.

[0029] In certain aspects, disclosed herein is a method of treating a subject having a neurological disorder, comprising administering an effective amount of the siRNAs disclosed herein to the subject. In some embodiments, disclosed herein is a method of treating a subject having a neurological disorder or who is at risk for developing the neurological disorder, the method comprising evaluating a subject’s risk for developing a neurological disorder and administering an effective amount of the siRNAs disclosed herein to the subject. In some embodiments, the subject has a genotype at risk for developing Alzheimer’s disease or dementia. In some embodiments, the subject is a heterozygous or homozygous carrier of APOE4. In some embodiments, the subject is a heterozygous or homozygous carrier of MTRES1 rsl 17058816-G (c.3+lG). In some embodiments, evaluating a subject’s risk for developing a neurological disorder comprises calculating a polygenic risk score for developing Alzheimer’s disease or dementia. In some embodiments, the subject has a polygenic risk score in the 40thpercentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia. In some embodiments, the subject has a polygenic risk score in the 20thpercentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia. In some embodiments, calculating a polygenic risk score comprises providing genomic data comprising one or more genotypes of the subject, wherein the one or more genotypes is associated with a high risk for developing Alzheimer’s disease or dementia.I. COMPOSITIONS

[0030] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets MTRES1. In some embodiments, the composition consists of an oligonucleotide that targets MTRES1. In some embodiments, the oligonucleotide reduces MTRES1 mRNA expression in the subject. In some embodiments, the oligonucleotide reduces MTRES1 protein expression in the subject. The oligonucleotide may include a small interfering RNA (siRNA) described herein. The oligonucleotide may include an antisense oligonucleotide (ASO) described herein. In some embodiments, a composition described herein is used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder as described herein. Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder as described herein. In some embodiments, an oligonucleotide modulates MTRES1 mRNA or protein levels.

[0031] Some embodiments include a composition comprising an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount decreases MTRES1 mRNA or protein levels in a cell, fluid or tissue. In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases MTRES1 mRNA levels in a cell or tissue. 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 CNS or brain tissue. In some embodiments, the MTRES1 mRNA levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0032] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount decreases MTRES1 protein levels in a cell, fluid or tissue. 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 CNS or brain tissue. In some embodiments, the MTRES1 protein levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the MTRES 1 protein levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the MTRES 1 protein levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0033] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES 1 and when administered to a subject in an effective amount alters MTRES 1 function, activity or binding in a cell, fluid or tissue. In some embodiments, the composition comprises an oligonucleotide that targets MTRES 1 and when administered to a subject in an effective amount decreases MTRES 1 function, activity or binding in a cell, fluid or tissue. 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 CNS or brain tissue. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the MTRES1 protein function, activity or binding are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0034] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount diminishes a neurological disorder phenotype. The neurological disorder may include dementia, Alzheimer’s disease, delirium, cognitive decline, cognitive impairment (such as mild cognitive impairment), vascular dementia, or Parkinson’s disease. In some embodiments, the neurological disorder phenotype is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%. 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0035] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount enhances a protective phenotype against a neurological disorder in the subject. The neurological disorder may include dementia, Alzheimer’s disease, delirium, cognitive decline, cognitive impairment (such as mild cognitive impairment), 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, as compared to prior to administration. In some embodiments, the protective phenotype is increased by about 10% or more, as compared to prior to 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, as compared to prior to 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, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 10%, as compared to prior toadministration. In some embodiments, the protective phenotype is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the 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 by a range defined by any of the two aforementioned percentages.

[0036] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves a marker of neurodegeneration in the subject. Some example markers of neurodegeneration may include amyloid plaques, tau accumulation, beta-amyloid 42, beta-amyloid 40, the ratio of beta-amyloid 42 to betaamyloid 40, tau, phospho-tau (such as p-tau217), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Lewy bodies, or alpha-synuclein. In some embodiments, the marker of neurodegeneration is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is improved by about 10% or more, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0037] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount decreases central nervous system (CNS) amyloid plaques in the subject. In some embodiments, the CNS amyloid plaques are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by about 10% or more, as compared to priorto administration. In some embodiments, the CNS amyloid plaques are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0038] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount decreases central nervous system (CNS) tau accumulation in the subject. In some embodiments, the CNS tau accumulation is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0039] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves cerebrospinal fluid (CSF) or plasma beta-amyloid 42 in the subject. In some embodiments, the CSF or plasma beta-amyloid 42 is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF or plasma beta-amyloid 42 is improved by about 10% or more, as compared to prior to administration. In some embodiments, the CSF or plasma beta-amyloid 42 is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF or plasma beta-amyloid 42 is improved by nomore than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF or plasma beta-amyloid 42 is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF or plasma betaamyloid 42 is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF or plasma beta-amyloid 42 is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0040] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves cerebrospinal fluid (CSF) or plasma beta-amyloid 40 in the subject. In some embodiments, the CSF or plasma beta-amyloid 40 is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF or plasma beta-amyloid 40 is improved by about 10% or more, as compared to prior to administration. In some embodiments, the CSF or plasma beta-amyloid 40 is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF or plasma beta-amyloid 40 is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF or plasma beta-amyloid 40 is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF or plasma betaamyloid 40 is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF or plasma beta-amyloid 40 is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0041] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves cerebrospinal fluid (CSF) or plasma ratio of beta-amyloid 42 to beta-amyloid 40. In some embodiments, the CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 is improved by about 10% or more, as compared to prior to administration. In some embodiments, the CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF or plasma ratio of betaamyloid 42 to beta-amyloid 40 is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0042] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) or plasma tau in the subject. In some embodiments, the CSF or plasma tau is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF or plasma tau is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF or plasma tau is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF or plasma tau is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF or plasma tau is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF or plasma tau is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF or plasma tau is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0043] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) or plasma phospho-tau in the subject. In some embodiments, the CSF or plasma phospho-tau is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF or plasma phospho-tau is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF or plasma phospho-tau is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF or plasma phospho-tau is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. Insome embodiments, the CSF or plasma phospho-tau is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF or plasma phospho-tau is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF or plasma phospho-tau is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%.75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0044] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) or plasma neurofilament light chain (NfL) in the subject. In some embodiments, the CSF or plasma NfL is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF or plasma NfL is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF or plasma NfL is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF or plasma NfL is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF or plasma NfL is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF or plasma NfL is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF or plasma NfL is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0045] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) or plasma glial fibrillary acidic protein (GFAP) in the subject. In some embodiments, the CSF or plasma GFAP is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF or plasma GFAP is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF or plasma GFAP is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF or plasma GFAP is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF or plasma GFAP is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF or plasma GFAP is decreased by no more thanabout 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF or plasma GFAP is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0046] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) alpha-synuclein in the subject. In some embodiments, the CSF alpha-synuclein is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0047] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount decreases Lewy bodies in the subject. In some embodiments, the Lewy bodies are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by 2.5%, 5%,7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0048] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount increases cognitive function. In some embodiments, the cognitive function is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the cognitive function is increased by about 10% or more, as compared to prior to 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, as compared to prior to 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, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the 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 by a range defined by any of the two aforementioned percentages

[0049] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount reduces or slows cognitive decline in the subject. In some embodiments, the cognitive decline is reduced or slowed by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the cognitive decline is reduced or slowed by about 10% or more, as compared to prior to administration. In some embodiments, the cognitive decline is reduced or slowed by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the cognitive decline is reduced or slowed by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the cognitive decline is reduced or slowed by no more than about 10%, as compared to prior to administration. In some embodiments, the cognitive decline is reduced or slowed by no more than about 20%, no more than about30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the cognitive decline is reduced or slowed by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0050] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) metabolic dysfunction in the subject. In some embodiments, the metabolic dysfunction is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the metabolic dysfunction is improved by about 10% or more, as compared to prior to administration. In some embodiments, the metabolic dysfunction is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the metabolic dysfunction is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the metabolic dysfunction is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the metabolic dysfunction is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the metabolic dysfunction is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the metabolic dysfunction is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the metabolic dysfunction is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0051] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) mitochondrial dysfunction in the subject. In some embodiments, the mitochondrial dysfunction is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the mitochondrial dysfunction is improved by about 10% or more, as compared to prior to administration. In some embodiments, the mitochondrial dysfunction is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to priorto administration. In some embodiments, the mitochondrial dysfunction is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the mitochondrial dysfunction is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the mitochondrial dysfunction is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the mitochondrial dysfunction is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the mitochondrial dysfunction is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the mitochondrial dysfunction is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0052] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) mitochondrial respiration in the subject. In some embodiments, the mitochondrial respiration is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the mitochondrial respiration is improved by about 10% or more, as compared to prior to administration. In some embodiments, the mitochondrial respiration is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the mitochondrial respiration is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the mitochondrial respiration is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the mitochondrial respiration is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the mitochondrial respiration is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the mitochondrial respiration is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior toadministration. In some embodiments, the mitochondrial respiration is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0053] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) oxidative phosphorylation in the subject. In some embodiments, the oxidative phosphorylation is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the oxidative phosphorylation is improved by about 10% or more, as compared to prior to administration. In some embodiments, the oxidative phosphorylation is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the oxidative phosphorylation is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the oxidative phosphorylation is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the oxidative phosphorylation is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the oxidative phosphorylation is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the oxidative phosphorylation is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the oxidative phosphorylation is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0054] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) glycolysis in the subject. In some embodiments, the glycolysis is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the glycolysis is improved by about 10% or more, as compared to prior to administration. In some embodiments, the glycolysis is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the glycolysis is improved by about 200% or more, about 300% or more, about 400% or more, about 500% ormore, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the glycolysis is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the glycolysis is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the glycolysis is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the glycolysis is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the glycolysis is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0055] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) ATP or ATP production in the subject. In some embodiments, the ATP or ATP production is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the ATP or ATP production is improved by about 10% or more, as compared to prior to administration. In some embodiments, the ATP or ATP production is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the ATP or ATP production is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the ATP or ATP production is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the ATP or ATP production is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the ATP or ATP production is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the ATP or ATP production is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the ATP or ATP production is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%,300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0056] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) ketone production or utilization in the subject. In some embodiments, the ketone production or utilization is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the ketone production or utilization is improved by about 10% or more, as compared to prior to administration. In some embodiments, the ketone production or utilization is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the ketone production or utilization is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the ketone production or utilization is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the ketone production or utilization is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the ketone production or utilization is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the ketone production or utilization is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the ketone production or utilization is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0057] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) lipids or lipid metabolism in the subject. In some embodiments, the lipid or lipid metabolism is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the lipid or lipid metabolism is improved by about 10% or more, as compared to prior to administration. In some embodiments, the lipid or lipid metabolism is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the lipid or lipid metabolism is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700%or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the lipid or lipid metabolism is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the lipid or lipid metabolism is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the lipid or lipid metabolism is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the lipid or lipid metabolism is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the lipid or lipid metabolism is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0058] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) the astrocyte -neuron lactate shuttle (ANLS) in the subject. In some embodiments, the astrocyte -neuron lactate shuttle (ANLS) is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the astrocyte -neuron lactate shuttle (ANLS) is improved by about 10% or more, as compared to prior to administration. In some embodiments, the astrocyte-neuron lactate shuttle (ANLS) is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the astrocyte-neuron lactate shuttle (ANLS) is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the astrocyte -neuron lactate shuttle (ANLS) is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the astrocyte -neuron lactate shuttle (ANLS) is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the astrocyte -neuron lactate shuttle (ANLS) is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the astrocyte -neuron lactate shuttle (ANLS) is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the astrocyte -neuronlactate shuttle (ANLS) is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%,500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0059] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) neuron metabolism production in the subject. In some embodiments, the neuron metabolism is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the neuron metabolism is improved by about 10% or more, as compared to prior to administration. In some embodiments, the neuron metabolism is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the neuron metabolism is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the neuron metabolism is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the neuron metabolism is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the neuron metabolism is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the neuron metabolism is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the neuron metabolism is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0060] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) astrocyte metabolism in the subject. In some embodiments, the astrocyte metabolism is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the astrocyte metabolism is improved by about 10% or more, as compared to prior to administration. In some embodiments, the astrocyte metabolism is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the astrocyte metabolism is improved by about 200% or more,about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the astrocyte metabolism is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the astrocyte metabolism is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the astrocyte metabolism is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the astrocyte metabolism is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the astrocyte metabolism is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0061] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) glial cell metabolism in the subject. In some embodiments, the glial cell metabolism is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the glial cell metabolism is improved by about 10% or more, as compared to prior to administration. In some embodiments, the glial cell metabolism is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the glial cell metabolism is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the glial cell metabolism is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the glial cell metabolism is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the glial cell metabolism is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the glial cell metabolism is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the glial cell metabolism is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0062] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) oligodendrocyte metabolism in the subject. In some embodiments, the oligodendrocyte metabolism is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the oligodendrocyte metabolism is improved by about 10% or more, as compared to prior to administration. In some embodiments, the oligodendrocyte metabolism is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the oligodendrocyte metabolism is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the oligodendrocyte metabolism is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the oligodendrocyte metabolism is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the oligodendrocyte metabolism is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the oligodendrocyte metabolism is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the oligodendrocyte metabolism is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0063] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) Central Nervous System (CNS) glucose or CNS glucose consumption in the subject. In some embodiments, the CNS glucose or CNS glucose consumption is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CNS glucose or CNS glucose consumption is improved by about 10% or more, as compared to prior to administration. In some embodiments, the CNS glucose or CNS glucose consumption is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the CNS glucose or CNS glucose consumption is improved byabout 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the CNS glucose or CNS glucose consumption is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CNS glucose or CNS glucose consumption is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the CNS glucose or CNS glucose consumption is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the CNS glucose or CNS glucose consumption is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the CNS glucose or CNS glucose consumption is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0064] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) Central Nervous System (CNS) oxygen or CNS oxygen consumption in the subject. In some embodiments, the CNS oxygen or CNS oxygen consumption is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CNS oxygen or CNS oxygen consumption is improved by about 10% or more, as compared to prior to administration. In some embodiments, the CNS oxygen or CNS oxygen consumption is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the CNS oxygen or CNS oxygen consumption is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the CNS oxygen or CNS oxygen consumption is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CNS oxygen or CNS oxygen consumption is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the CNS oxygen or CNS oxygen consumption is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the CNS oxygen or CNS oxygen consumption is improved by no more than about 200%, no more than about 300%, no more than about 400%, no morethan about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the CNS oxygen or CNS oxygen consumption is improved by 2.5%, 5%, 7.5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%,150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0065] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) the TCA or Krebs cycle in the subject. In some embodiments, the TCA or Krebs cycle is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the TCA or Krebs cycle is improved by about 10% or more, as compared to prior to administration. In some embodiments, the TCA or Krebs cycle is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the TCA or Krebs cycle is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the TCA or Krebs cycle is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the TCA or Krebs cycle is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the TCA or Krebs cycle is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the TCA or Krebs cycle is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the TCA or Krebs cycle is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0066] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) the electron transport chain in the subject. In some embodiments, the electron transport chain is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the electron transport chain is improved by about 10% or more, as compared to prior to administration. In some embodiments, the electron transport chain is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more,about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the electron transport chain is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the electron transport chain is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the oxidative phosphorylation is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the electron transport chain is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the electron transport chain is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the electron transport chain is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0067] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) mitophagy or autophagy in the subject. In some embodiments, the mitophagy or autophagy is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the mitophagy or autophagy is improved by about 10% or more, as compared to prior to administration. In some embodiments, the mitophagy or autophagy is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the mitophagy or autophagy is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the mitophagy or autophagy is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the mitophagy or autophagy is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the mitophagy or autophagy is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the mitophagy or autophagy is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, nomore than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the mitophagy or autophagy is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0068] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) mitochondrial fission or fusion in the subject. In some embodiments, the mitochondrial fission or fusion is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the mitochondrial fission or fusion is improved by about 10% or more, as compared to prior to administration. In some embodiments, the mitochondrial fission or fusion is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the mitochondrial fission or fusion is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the mitochondrial fission or fusion is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the mitochondrial fission or fusion is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the mitochondrial fission or fusion is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the mitochondrial fission or fusion is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the mitochondrial fission or fusion is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0069] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) mitochondrial biogenesis in the subject. In some embodiments, the mitochondrial biogenesis is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the mitochondrial biogenesis is improved by about 10% or more, as compared to prior to administration. In some embodiments, the mitochondrial biogenesis is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to priorto administration. In some embodiments, the mitochondrial biogenesis is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the mitochondrial biogenesis is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the mitochondrial biogenesis is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the mitochondrial biogenesis is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the mitochondrial biogenesis is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the mitochondrial biogenesis is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0070] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) mitochondrial transcription or translation in the subject. In some embodiments, the mitochondrial transcription or translation is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the mitochondrial transcription or translation is improved by about 10% or more, as compared to prior to administration. In some embodiments, the mitochondrial transcription or translation is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the mitochondrial transcription or translation is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the mitochondrial transcription or translation is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the mitochondrial transcription or translation is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the mitochondrial transcription and / or translation is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the mitochondrial transcription or translation is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%,no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the mitochondrial transcription or translation is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0071] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) gliotransmitter release or function in the subject. In some embodiments, the gliotransmitter release or function is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the gliotransmitter release or function is improved by about 10% or more, as compared to prior to administration. In some embodiments, the gliotransmitter release or function is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the gliotransmitter release or function is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the gliotransmitter release or function is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the gliotransmitter release or function is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the gliotransmitter release or function is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the gliotransmitter release or function is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the gliotransmitter release or function is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0072] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) neurotransmitter release or function in the subject. In some embodiments, the neurotransmitter release or function is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the neurotransmitter release or function is improved by about 10% or more, as compared to prior to administration. In some embodiments, theneurotransmitter release or function is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the neurotransmitter release or function is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the neurotransmitter release or function is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the neurotransmitter release or function is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the neurotransmitter release or function is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the neurotransmitter release or function is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the neurotransmitter release or function is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0073] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) connexin 43 expression or function in the subject. In some embodiments, the connexin 43 expression or function is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the connexin 43 expression or function is improved by about 10% or more, as compared to prior to administration. In some embodiments, the connexin 43 expression is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the connexin 43 expression or function is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the connexin 43 expression or function is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the connexin 43 expression or function is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the connexin 43 expression or function is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, ascompared to prior to administration. In some embodiments, the connexin 43 expression or function is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the connexin 43 expression or function is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0074] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) lactate or lactate metabolism in the subject. In some embodiments, the lactate or lactate metabolism is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the lactate or lactate metabolism is improved by about 10% or more, as compared to prior to administration. In some embodiments, the lactate or lactate metabolism is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the lactate or lactate metabolism is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the lactate or lactate metabolism is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the lactate or lactate metabolism is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the lactate or lactate metabolism is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the lactate or lactate metabolism is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the lactate or lactate metabolism is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0075] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) pyruvate or pyruvate metabolism in the subject. In some embodiments, the pyruvate or pyruvate metabolism is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the pyruvate or pyruvate metabolism isimproved by about 10% or more, as compared to prior to administration. In some embodiments, the pyruvate or pyruvate metabolism is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the pyruvate or pyruvate metabolism is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the pyruvate or pyruvate metabolism is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the pyruvate or pyruvate metabolism is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the pyruvate or pyruvate metabolism is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the pyruvate or pyruvate metabolism is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the pyruvate or pyruvate metabolism is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0076] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) amino acids or amino acid metabolism in the subject. In some embodiments, the amino acid or amino acid metabolism is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the amino acid or amino acid metabolism is improved by about 10% or more, as compared to prior to administration. In some embodiments, the amino acid or amino acid metabolism is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the amino acid or amino acid metabolism is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the amino acid or amino acid metabolism is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the amino acid or amino acid metabolism is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the amino acid or amino acid metabolism is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no morethan about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the amino acid or amino acid metabolism is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the amino acid or amino acid metabolism is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0077] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount improves (e.g., increases or decreases) lipoprotein particle composition or concentration in the subject. In some embodiments, the lipoprotein particle composition or concentration is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the lipoprotein particle composition or concentration is improved by about 10% or more, as compared to prior to administration. In some embodiments, the lipoprotein particle composition or concentration is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the lipoprotein particle composition or concentration is improved by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the lipoprotein particle composition or concentration is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the lipoprotein particle composition or concentration is improved by no more than about 10%, as compared to prior to administration. In some embodiments, the lipoprotein particle composition or concentration is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the lipoprotein particle composition or concentration is improved by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the lipoprotein particle composition or concentration is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.A. siRNAs

[0078] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide that targets MTRES1, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

[0079] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises a sense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The sense strand may be 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The antisense strand may be 14-30 nucleosides in length.

[0080] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human MTRES1 mRNA sequence such as SEQ ID NO: 2443. In some embodiments, at least one of the sense strand and the antisense strand comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 2443.

[0081] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human MTRES1 mRNA sequence such as SEQ ID NO: 2462. In some embodiments, at least one of the sense strand and the antisense strand comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 2462.

[0082] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand of the composition-3’ and an antisense strand of composition-3’. Where (N) 0-7 are independently nucleic acid stretches of 0 to 7 nucleotides,andcontain at least 15 contiguous nucleotides from Tables 3-5 and contain no cyclic ribose nucleotides with 2’ hydroxyl groups. The sense and antisense strand have 1-5 phosphorothioate inter-nucleotide linkages and either thesense or antisense strand has a targeting ligand attached to the 5’ or 3’ end. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand composition. The targeting ligand may be a lipid moiety, a GalNAc moiety, an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or L-9, Sirius GalNAc, GLS-5, GLS-15, Olix GalNAc, lgT3, 5gn2c6, [Gal-6]s[Gal-6]s[Gal-6], Janssen, Arbutus THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety are ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial -specific integrin, integrin alpha-v-beta-6 (av[36) or integrin alpha-v- beta-3 or arginine -glycine -aspartic acid (RGD) peptide.

[0083] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double -stranded RNA duplex. In some embodiments, the first base pair of the double -stranded RNA duplex is an AU base pair.

[0084] In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0085] In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.

[0086] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human MTRES1 mRNA. In someembodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human MTRES 1 mRNA.

[0087] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES 1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 17mer in a non -human primate MTRES1 mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a non -human primate MTRES1 mRNA.

[0088] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a human MTRES1 mRNA and less than or equal to 20 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 10 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 30 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 40 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 50 human off- targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 10 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 20 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES 1 mRNA and less than or equal to 30 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES 1 mRNA and less than or equal to 40 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES 1 mRNA and less than or equal to 50 human off-targets, with no more than 3 mismatches in the antisense strand.

[0089] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES 1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a human MTRES 1 mRNA target site that does not harbor an SNP, with a minor allele frequency (MAF) greater or equal to 1% (pos. 2-18). In some embodiments, the MAF is greater or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0090] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES 1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting ofthe sequence of any one of SEQ ID NOs: 1-1140, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1140, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1140, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1 , wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1- 1140. In any of SEQ ID NOs: 1-1140, thymine (T) may be replaced with uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5 ’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 1-1140 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1140 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1140 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1- 1140 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1- 1140 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1140 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1140 is modified to an C.

[0091] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 1-1140. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 1-1140, at least 80% identical to any one of SEQ ID NOs: 1-1140, at least 85% identical to of any one of SEQ ID NOs: 1-1140, at least 90% identical to any one of SEQ ID NOs: 1-1140, or at least 95% identical to any one of SEQ ID NOs: 1- 1140. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-1140, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1-1140, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 1-1140. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of one of SEQ ID NO: 1-1140. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18,ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial -specific integrin, integrin alpha-v-beta-6 (av[36) or integrin alpha-v-beta-3 or arginine -glycine -aspartic acid (RGD) peptide.

[0092] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1141-2280, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1141-2280, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1141-2280, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES 1 , wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1141-2280. In any of SEQ ID NOs: 1141-2280, thymine (T) may be replaced with uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1141-2280 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 1141-2280 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1141-2280 is modified to an A. Insome embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 1141-2280 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1141-2280 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1141-2280 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 1141-2280 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1141-2280 is modified to an C.

[0093] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 1141-2280. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 1141-2280, at least 80% identical to any one of SEQ ID NOs: 1141-2280, at least 85% identical to of any one of SEQ ID NOs: 1141-2280, at least 90% identical to any one of SEQ ID NOs: 1141-2280, or at least 95% identical to any one of SEQ ID NOs: 1141-2280. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1141-2280, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 1141-2280, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 1141-2280. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any ofthe aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to antisense strand sequence of one of SEQ ID NO: 1141-2280. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (av[36) or integrin alpha-v-beta-3 or arginineglycine -aspartic acid (RGD) peptide.

[0094] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3341-3348 or 3373-3375, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3341-3348 or 3373-3375, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3341-3348 or 3373-3375, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3341-3348 or 3373-3375. In any of SEQ ID NOs: 3341-3348 or 3373-3375, thymine (T) may be replaced with uracil (U). Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5 ’ nucleoside has been modified to a U or T. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373- 3375 is modified to an A, T, C, U, or G. In some embodiments, position 6 (from the 5’ end) of any one ofSEQ ID NOs: 3341-3348 or 3373-3375 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373- 3375 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to an A. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to a T or U. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3341- 3348 or 3373-3375 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3341-3348 or 3373-3375 is modified to an C. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3341-3348 or 3373- 3375 is modified to an C.

[0095] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 3341-3348 or 3373-3375. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 3341-3348 or 3373-3375, at least 80% identical to any one of SEQ ID NOs: 3341-3348 or 3373-3375, at least 85% identical to of any one of SEQ ID NOs: 3341-3348 or 3373-3375, at least 90% identical to any one of SEQ ID NOs: 3341-3348 or 3373-3375, or at least 95% identical to any one of SEQ ID NOs: 3341-3348 or 3373-3375. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3341-3348 or 3373-3375, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3341-3348 or 3373-3375, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhangcomprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 3341-3348 or 3373-3375. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise a modification pattern described herein. The sense strand may comprise an overhang. The sense strand may comprise a lipid moiety. The sense strand may comprise a GalNAc moiety. The sense strand may comprise an integrin or an integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’ A of a sense strand sequence of one of SEQ ID NO: 3341-3348 or 3373-3375. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (avP6) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.

[0096] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3349-3356 or 3376-3378, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3349-3356 or 3376-3378, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3349-3356 or 3376-3378, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1 , wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3349-3356 or 3376-3378. In any of SEQ ID NOs: 3349-3356 or 3376-3378, thymine (T) may be replaced with uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3349- 3356 or 3376-3378 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 3349- 3356 or 3376-3378 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one ofSEQ ID NOs: 3349-3356 or 3376-3378 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3349-3356 or 3376-3378 is modified to an C.

[0097] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 3349-3356 or 3376-3378. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 3349-3356 or 3376-3378, at least 80% identical to any one of SEQ ID NOs: 3349-3356 or 3376-3378, at least 85% identical to of any one of SEQ ID NOs: 3349-3356 or 3376-3378, at least 90% identical to any one of SEQ ID NOs: 3349-3356 or 3376-3378, or at least 95% identical to any one of SEQ ID NOs: 3349- 3356 or 3376-3378. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3349-3356 or 3376-3378, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 3349-3356 or 3376- 3378, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 3349-3356 or 3376-3378. The antisense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to antisense strand sequence of one of SEQ ID NO: 3349-3356 or 3376-3378. Representative example of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial-specific integrin, integrin alpha-v-beta-6 (av[36) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.

[0098] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any one of Tables 3A, 7, 10, 13, 21, 22, 25, 28, 31, 34, 37, 39, 47, 50, 53, 56, 59, 62, 64B, 67B, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 117, 120, 123, 125, and 129, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any one of Table 3A, 7, 10, 13, 21, 22, 25, 28, 31, 34, 37, 39, 47, 50, 53, 56, 59, 62, 64B, 67B, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 117, 120, 123, 125, and 129, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any one of Table 3A, 7, 10, 13, 21, 22, 25, 28, 31, 34, 37, 39, 47, 50, 53, 56, 59, 62, 64B, 67B, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 117, 120, 123, 125, and 129. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. In some embodiments, a sense strand sequence of an siRNA in any one of Table 3A, 7, 10, 13, 21, 22, 25, 28, 31, 34, 37, 39, 47, 50, 53, 56, 59, 62, 64B, 67B, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 117, 120, 123, 125, and 129 is modified by substitution of the 3’ nucleoside to an A. In some embodiments, a sense strand sequence of an siRNA in any one of Tables 3-8 is modified by substitution of the nucleoside to an A at position 19 (from the 5’ end). In some embodiments, an antisense strand sequence of an siRNA in any one of Table 3A, 7, 10, 13, 21, 22, 25, 28, 31, 34, 37, 39, 47, 50, 53, 56, 59, 62, 64B, 67B, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99,102. 105. 108. 117. 120. 123. 125, and 129 is modified by substitution of the 3’ nucleoside to an U. Any of the aforementioned siRNAs may include a sense strand where the 3 ’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand comprise a oligonucleotide sequences as disclosed in Tables 3A, 7, 10, 13, 21, 22, 25, 28, 31, 34, 37, 39, 47, 50, 53, 56, 59, 62, 64B, 67B, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 117, 120, 123, 125, and 129, each strand is independently about 19-21 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising at least about 15 contiguous nucleosides of oligonucleotide sequences as disclosed in Tables 3A, 7, 10, 13, 21, 22, 25, 28, 31, 34, 37, 39, 47, 50, 53, 56, 59, 62, 64B, 67B, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 117, 120,123. 125, and 129.

[0099] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting ofthe sequence of any one of SEQ ID NOs: 2674-2855, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2674-2855, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2674-2855, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1 , wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2674-2855. In any of SEQ ID NOs: 2674-2855, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3 ’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 2674-2855 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 2674-2855 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2674-2855 is modified to an A,T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 2674-2855 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5 ’ end) of any one of SEQ ID NOs: 2674-2855 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 2674-2855 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2674-2855 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 2674-2855 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 2674-2855 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 2674-2855 is modified to a T orU. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 32674-2855 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 2674- 2855 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ IDNOs: 2674-2855 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 2674-2855 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2674-2855 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 2674-2855 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 2674-2855 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 2674-2855 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2674-2855 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 2674-2855 is modified to an C.

[0100] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with any of SEQ ID NOs: 2674-2855. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 2674-2855, at least 80% identical to any one of SEQ ID NOs: 2674-2855, at least 85% identical to of any one of SEQ ID NOs: 2674-2855, at least 90% identical to any one of SEQ ID NOs: 2674-2855, or at least 95% identical to any one of SEQ ID NOs: 2674-2855. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 2674-2855, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 2674-2855, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 2674-2855. The sense strand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The sense strand may comprise an overhang. The sense strand may comprise a modification pattern described herein. The sense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to antisense strand sequence of one of SEQ ID NO: 2674-2855. Representative examples of the GalNAc moiety is ETL1, ETL17, NAG37, ST23, GluGalNAc,K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial- specific integrin, integrin alpha-v-beta-6 (av[36) or integrin alpha-v-beta-3 or arginine-glycine-aspartic acid (RGD) peptide.

[0101] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2856-3037, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2856-3037, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2856-3037, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES 1 , wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2856-3037. In any of SEQ ID NOs: 2856-3037, thymine (T) may be replaced with Uracil (U). Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A. Any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to an A, T, C, U, or G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to an A, T, C, U, or G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to an A, T, C, U, or G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 2856-3037 is modified to an A, T, C, U, or G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to an A. In some embodiments, position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 2856-3037 is modified to an A. In someembodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to an A. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 2856-3037 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 2856-3037 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to a T or U. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 2856-3037 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to an G. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 2856-3037 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs: 2856-3037 is modified to an C. In some embodiments, position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 2856-3037 is modified to an C.

[0102] In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with any of SEQ ID NOs: 2856-3037. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of SEQ ID NOs: 2856-3037, at least 80% identical to any one of SEQ ID NOs: 2856-3037, at least 85% identical to of any one of SEQ ID NOs: 2856-3037, at least 90% identical to any one of SEQ ID NOs: 2856-3037, or at least 95% identical to any one of SEQ ID NOs: 2856-3037. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 2856-3037, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of any one of SEQ ID NOs: 2856-3037, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang. In some embodiments, the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NOs: 2856-3037. The antisensestrand sequence may include the first 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand sequence may include the last 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 nucleotides (in the 5’ to 3’ direction) of any of the aforementioned sequences. The antisense strand may comprise an overhang. The antisense strand may comprise a modification pattern described herein. The antisense strand may comprise a lipid moiety or a GalNAc moiety or integrin or integrin targeting ligand or angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand attached to antisense strand sequence of one of SEQ ID NO: 2856-3037. Representative example of the GalNAc moiety includes, but is not limited to, ETL1, ETL17, NAG37, ST23, GluGalNAc, K2GalNAc, PyrGalNAc, PipGalNAc, TEG-GalNAc, GalNAc23 or THA. Preferably, the GalNAc moiety is ETL17. Representative examples of lipid moiety is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22, ETL28, ETL29, ETL31 or ETL32. Preferably, the lipid moiety is ETL20. Representative examples of integrin or integrin targeting ligand is epithelial -specific integrin, integrin alpha-v-beta-6 (avP6) or integrin alpha-v- beta-3 or arginine -glycine -aspartic acid (RGD) peptide

[0103] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset A. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset A. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset A. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’ A of a sense strand sequence of subset A. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset A. Any of the aforementioned siRNAs may include a sense strand of subset A, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset A, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset A. In some embodiments, the sense strand or antisense strand comprises a sequence ofa sense or antisense strand of subset A, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset A, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset A.

[0104] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. In some embodiments, the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA of subset B. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset B. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset B. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’ A of a sense strand sequence of subset B. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset B. Any of the aforementioned siRNAs may include a sense strand of subset B, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset B, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset B. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset B. The sense strand or antisense strand may comprise any modifications described herein.

[0105] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 3 or 4 nucleosidesubstitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset C. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset C. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’ A of a sense strand sequence of subset C. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset C. Any of the aforementioned siRNAs may include a sense strand of subset C, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset C, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset C. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset C, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset C.

[0106] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset D. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. Any of the aforementioned siRNAs may include asense strand that lacks a 3’ A of a sense strand sequence of subset D. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset D. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset D. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset D. Any of the aforementioned siRNAs may include a sense strand of subset D, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset D, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset D. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset D, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset D.

[0107] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset E. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset E. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5 ’ U of an antisense strand sequence of subset E. Any of the aforementioned siRNAs may include a sense strand that lacks a 3 ’ A of a sense strand sequence of subset E. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset E. Any of the aforementioned siRNAs may include a sense strand of subset E, wherein the nucleotide at the 3’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset E, wherein the nucleotide at the 5’ end of the sense strand sequence has been modified to a T.

[0108] In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95%identical, to a sense strand or antisense strand sequence of subset E. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset E, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset E.

[0109] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset F, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset F, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset F. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more intemucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. Any of the aforementioned siRNAs may include a sense strand that lacks a 3’ A of a sense strand sequence of subset F. Any of the aforementioned siRNAs may include an antisense sense strand that lacks a 5’ U of an antisense strand sequence of subset F. Any of the aforementioned siRNAs may include a sense strand of subset F, wherein the nucleotide at the 3 ’ end of the sense strand sequence has been modified to an A. Any of the aforementioned siRNAs may include an antisense strand of one of subset F, wherein the nucleotide at the 5 ’ end of the sense strand sequence has been modified to a T. In some embodiments, the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence of subset F. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense strand comprises a sequence of a sense or antisense strand of subset F, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence of subset F.

[0110] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2576. In some embodiments, the sense strand sequence comprises or consists of 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 orconsists of the sequence of SEQ ID NO: 2576, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2576, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2576. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2638. In some embodiments, the antisense strand sequence comprises or consists of 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 the sequence of SEQ ID NO: 2638, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2638, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2638. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0111] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2582. In some embodiments, the sense strand sequence comprises or consists of 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 the sequence of SEQ ID NO: 2582, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2582, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2582. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2644. In some embodiments, the antisense strand sequence comprises or consists of 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 an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2644, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In someembodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2644. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0112] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2583. In some embodiments, the sense strand sequence comprises or consists of 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 the sequence of SEQ ID NO: 2583, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2583, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2583. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2645. In some embodiments, the antisense strand sequence comprises or consists of 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 an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2645, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2645. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0113] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2584. In some embodiments, the sense strand sequence comprises or consists of 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 the sequence of SEQ ID NO: 2584, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2584, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2584. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strandhaving a sequence in accordance with SEQ ID NO: 2646. In some embodiments, the antisense strand sequence comprises or consists of 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 an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2646, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2646. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0114] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2604. In some embodiments, the sense strand sequence comprises or consists of 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 the sequence of SEQ ID NO: 2604, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2604, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2604. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2666. In some embodiments, the antisense strand sequence comprises or consists of 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 an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2666, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2666. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0115] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2551. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2551, at least 80% identical to SEQ ID NO: 2551, at least 85% identical to SEQ ID NO: 2551, at least 90% identical to SEQ ID NO: 2551, or at least95% identical to SEQ ID NO: 2551. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2551, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2551, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2551. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2613. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2613, at least 80% identical to SEQ ID NO: 2613, at least 85% identical to SEQ ID NO: 2613, at least 90% identical to SEQ ID NO: 2613, or at least 95% identical to SEQ ID NO: 2613. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2613, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2613, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2613. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0116] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2681. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2681, at least 80% identical to SEQ ID NO: 2681, at least 85% identical to SEQ ID NO: 2681, at least 90% identical to SEQ ID NO: 2681, or at least 95% identical to SEQ ID NO: 2681. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2681, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2681, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2681. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2863. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2863, at least 80% identical to SEQ ID NO: 2863, at least 85% identical to SEQ ID NO: 2863, at least 90% identical to SEQ ID NO: 2863, or at least 95% identical to SEQ ID NO: 2863. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2863, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2863, or an antisensestrand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2863. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0117] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2683. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2683, at least 80% identical to SEQ ID NO: 2683, at least 85% identical to SEQ ID NO: 2683, at least 90% identical to SEQ ID NO: 2683, or at least 95% identical to SEQ ID NO: 2683. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2683, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2683, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2683. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2865. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2865, at least 80% identical to SEQ ID NO: 2865, at least 85% identical to SEQ ID NO: 2865, at least 90% identical to SEQ ID NO: 2865, or at least 95% identical to SEQ ID NO: 2865. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2865, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2865, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2865. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

[0118] In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 3284. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3284, at least 80% identical to SEQ ID NO: 3284, at least 85% identical to SEQ ID NO: 3284, at least 90% identical to SEQ ID NO: 3284, or at least 95% identical to SEQ ID NO: 3284. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3284, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3284, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3284. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety suchas a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3295. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3295, at least 80% identical to SEQ ID NO: 3295, at least 85% identical to SEQ ID NO: 3295, at least 90% identical to SEQ ID NO: 3295, or at least 95% identical to SEQ ID NO: 3295. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3295, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3295, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3295. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.B. ASOs

[0119] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression ofMTRESl, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17,18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

[0120] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression ofMTRESl, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full- length human MTRES1 mRNA sequence such as SEQ ID NO: 2443; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified intemucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17,18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 2443.

[0121] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression ofMTRESl, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full- length human MTRES1 mRNA sequence such as SEQ ID NO: 2462; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified intemucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17,18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 2462.C. Modification patterns

[0122] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression ofMTRESl, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified intemucleoside linkage, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification comprising a modified nucleoside and / or a modified intemucleoside linkage. In some embodiments, the oligonucleotide comprises a modified intemucleoside linkage. In some embodiments, the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified intemucleoside linkage comprises one or more phosphorothioate linkages. A phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur. Modified intemucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified intemucleoside linkage may include decreased toxicity or improved pharmacokinetics.

[0123] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression ofMTRESl, wherein the oligonucleotide comprises a modified intemucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages, or a range of modified intemucleoside linkages defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified intemucleoside linkages, 3 or more modified intemucleoside linkages, 4 or more modified intemucleoside linkages, 5 or more modified intemucleoside linkages, 6 or more modified intemucleoside linkages, 7 or more modified intemucleoside linkages, 8 or more modified intemucleoside linkages, 9 or more modified intemucleoside linkages, 10 or more modified intemucleoside linkages, 11 or more modified intemucleoside linkages, 12 or more modified intemucleoside linkages, 13 or more modified intemucleoside linkages, 14 or more modified intemucleoside linkages, 15 or more modified intemucleoside linkages, 16 or more modified intemucleoside linkages, 17 or more modified intemucleoside linkages, 18 or more modified intemucleoside linkages, 19 or more modified intemucleoside linkages, or 20 or more modified intemucleoside linkages.

[0124] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression ofMTRESl, wherein the oligonucleotide comprises the modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2’-C-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2’, 4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises HLA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2’-O-methoxyethyl group(“MOE”). In some embodiments, the modified nucleoside comprises a 2'-C-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, 2'- deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-0-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-0-DMAE0E) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-0-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-0-DMAE0E nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2’- fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2’-O-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics.

[0125] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure:3’ nucleotide5’ nucleotide wherein the base can be any pyrimidine or purine.

[0126] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:are independently an H or a 3 ’ or 5 ’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.

[0127] In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises methylphosphonate. An example of a nucleotide that comprises a methylphosphonate is shown below:’ methylphosphonate 2’-O-Methyl Uridine).

[0128] In some embodiments, the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5 ’or 3’ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothioates at the 5’ and 3’ ends.

[0129] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range of nucleosides defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0130] In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprise a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprise a 2’-fluoro modified nucleoside, a 2’-O- methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the groupconsisting of a 2 ’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O- methoxyethyl. In some embodiments, the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.

[0131] In some embodiments, the antisense strand is combination of 2’-fluoro and 2’-O-methyl modifications. In some embodiments, each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2 ’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside. In some embodiments, the sense strand comprises at least a 2 ’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.

[0132] The oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), or guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0133] In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2 ’-fluoro and 2’-O- methoxyethyl. In some embodiments, all purine nucleosides comprise 2’-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O- methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2 ’-fluoro and 2’-O-methyl. In some embodiments, the sense strand may include a 2 ’-deoxy nucleoside.

[0134] In some embodiments, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2 ’-fluoromodified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.

[0135] In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of2’-fluoro and 2’-0-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; or all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. In some embodiments, all purine nucleosides comprise 2 ’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro.

[0136] Some embodiments include an oligonucleotide comprising: a sense strand having a 5' end, a 3' end and a region of complementarity with an antisense strand; an antisense strand having a 5 'end, a 3 'end and a region of complementarity with the sense strand and a region of complementarity to an mRNA target; an overhang region at the 3' end of the sense strand having at least 3 contiguous phosphorothioated nucleotides; and an overhang region at the 3' end of the antisense strand having at least 3 contiguous phosphorothioated nucleotides.

[0137] Some embodiments include an oligonucleotide comprising: a sense strand having a 5' end, a 3' end and a region of complementarity with an antisense strand; an antisense strand having a 5 'end, a 3 'end and a region of complementarity with the sense strand and a region of complementarity to an mRNA target; and an overhang region at the 3' end of the sense strand having at least 3 contiguous phosphorothioated nucleotides.

[0138] In some embodiments, the oligonucleotide includes two to eight oligonucleotides attached through 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 have full chemical stabilization (i.e., all of the constituent bases are chemically -modified). In some embodiments, the oligonucleotide includes one or more single-stranded phosphorothioated tails, each independently having two to twenty nucleotides. In some embodiments, each single -stranded tail has eight to ten nucleotides.

[0139] In certain embodiments, a compound (e.g., moiety attached to the oligonucleotide) includes three properties: (1) a branched structure, (2) full metabolic stabilization, and (3) the presence of a single -stranded tail comprising phosphorothioate linkers. In a particular embodiment, a compound has 2 or 3 branches. The increased overall size of the branched structures promote increased uptake. Also, without being bound by a particular theory of activity, multiple adjacent branches (e.g., 2 or 3) allow eachbranch to act cooperatively and thus dramatically enhance rates of internalization, trafficking and release. The compound may include an oligonucleotide described herein, as part of the compound.

[0140] In certain embodiments, a compound includes the following properties: (1) two or more branched oligonucleotides linked via a non-natural linker (2) substantially chemically stabilized, e.g., wherein more than 40%, optimally 100%, of oligonucleotides are chemically modified (e.g., no RNA and optionally no DNA); and (3) phosphorothioated single oligonucleotides containing at least 3, optimally 5- 20 phosphorothioated bonds.

[0141] In some embodiments, the oligonucleotide comprises a phosphate at a 5' end. In some embodiments, the oligonucleotide comprises a phosphate at a 3' end. In some embodiments, the oligonucleotide comprises a phosphate mimic at a 5' end. In some embodiments, the oligonucleotide comprises a phosphate mimic at a 3' end.

[0142] The oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), or guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

[0143] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2 ’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. 2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’-methyl modification may be included, and vice versa.

[0144] In some embodiments, pyrimidines of the oligonucleotide comprise 2 ’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified pyrimidines.

[0145] In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise amixture of 2’-fluoro and 2’-0-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’- O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O- methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’-fluoro modified purines.

[0146] 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.

[0147] In some cases, the oligonucleotide comprises a particular modification pattern. In some embodiments, position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification. In some embodiments, when position 9 of a strand of the oligonucleotide is a pyrimidine, then all purines in a strand of the oligonucleotide have a 2’0Me modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modificationsin a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0148] In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’0Me modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

[0149] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’0Me modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.

[0150] In some embodiments, the oligonucleotide is delivered to a cell or tissue by linking the oligonucleotide to a targeting group. In some embodiments, the targeting group includes a cell receptor ligand, such as an integrin targeting ligand. Integrins may include a family of transmembrane receptors that facilitate cell -extracellular matrix (ECM) adhesion. In some embodiments, the moiety includes an epithelial-specific integrin. Integrin alpha-v-beta-6 (av[36) bay be an example of an epithelial -specific integrin av[36 may be a receptor for an ECM protein or TGF-beta latency-associated peptide (LAP). Integrin av[36 may be expressed in a cell or tissue. Integrin av[36 may be expressed or upregulated in injured pulmonary epithelium.

[0151] In some embodiments, the oligonucleotide is linked to an integrin targeting ligand that has affinity for integrin av[36. An integrin targeting ligand may include a compound that has affinity for integrin av[36 or integrin alpha-v-beta-3 (av[33), may be useful as a ligand to facilitate targeting or delivery of the oligonucleotide to which it is attached to a particular cell type or tissue (e.g., to cells expressing integrin av[33 or av[36). In some embodiments, multiple integrin targeting ligands are linked to the oligonucleotide. In some embodiments, the oligonucleotide -integrin targeting ligand conjugates are selectively internalized by chondrocytes, either through receptor-mediated endocytosis or by other means.

[0152] In some embodiments, an oligonucleotide that targets MTRES 1 further comprises a targeting ligand that targets a receptor which mediates delivery to a specific CNS tissue. In someembodiments, the targeting ligand is conjugated to the oligonucleotide. In one embodiment, the targeting ligand is selected from the group consisting of Angiopep-2, lipoprotein receptor related protein (LRP) ligand, bEnd.3 cell binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter protein, and LDL receptor ligand. In one embodiment, the targeting ligand is selected from the group consisting of trans-retinol, RGD peptide, LDL receptor ligand, and carbohydrate -based ligands. In one embodiment, the targeting ligand is a RGD peptide, such as H-Gly-Arg-Gly-Asp-Ser-Pro-Lys-Cys- OH or Cyclo(-Arg-Gly-Asp-D-Phe-Cys).

[0153] Examples of targeting groups useful for delivering the oligonucleotide that include integrin targeting ligands may be based upon peptides or peptide mimics containing an arginine -glycine - aspartic acid (RGD) peptide. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an RGD peptide. In some embodiments, the composition comprises an RGD peptide. In some embodiments, the composition comprises an RGD peptide derivative. In some embodiments, the RGD peptide is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the RGD peptide is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the RGD peptide is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the RGD peptide is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises an RGD peptide attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the oligonucleotide comprises an RGD peptide, and a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. The RGD peptide may be linear. The RGD peptide may be cyclic. An RGD peptide may include a D-amino acid. In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Cys). In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Lys). In some embodiments, the RGD peptide comprises Cyclo(- Arg-Gly-Asp-D-Phe-azido). In some embodiments, the RGD peptide comprises an amino benzoic acid derived RGD. In some embodiments, the RGD peptide comprises Cyclo(-Arg-Gly-Asp-D-Phe-Cys), Cyclo(-Arg-Gly-Asp-D-Phe-Lys), Cyclo(-Arg-Gly-Asp-D-Phe-azido), an amino benzoic acid derived RGD, or a combination thereof. In some embodiments, the RGD peptide comprises multiple of such RGD peptides. Lor example, the RGD peptide may include 2, 3, or 4 RGD peptides. Some embodiments include an arginine-glycine-glutamic acid peptide.

[0154] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2 ’fluoromodified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides, 2’-O-methyl modifiednucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine; all purines of the sense strand comprises 2’-O-methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’fluoro-modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even -numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0155] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’fluoro-modified purine, provided there are not three 2’-fluoro-modified purine in a row. In some embodiments, the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even -numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’- fluoro -modified purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines;1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2’-fluoro-modified purines in a row. In some embodiments, there are not three 2’- fluoro -modified pyrimidines in a row.

[0156] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2’-fIuoro-modified purines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’ -fluoro -modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O-methyl modified purines or 2’-fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and theeven-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0157] In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’ -fluoro -modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’fluoro-modified nucleotides and unmodified deoxyribonucleotide.

[0158] In some embodiments, the moiety includes a negatively charged group attached at a 5’ end of the oligonucleotide. This may be referred to as a 5 ’-end group. In some embodiments, the negatively charged group is attached at a 5’ end of an antisense strand of an siRNA disclosed herein. The 5 ’-end group may be or include a 5 ’-end phosphorothioate, 5 ’-end phosphorodithioate, 5 ’-end vinylphosphonate (5 ’-VP), 5 ’-end methylphosphonate, 5 ’-end cyclopropyl phosphonate, or a 5’-deoxy-5’- C-malonyl. The 5’-end group may comprise 5’-VP. In some embodiments, the 5’-VP comprises a trans- vinylphosphonate or cis-vinylphosphonate. The 5 ’-end group may include an extra 5’ phosphate. A combination of 5 ’-end groups may be used.

[0159] In some embodiments, the oligonucleotide includes a negatively charged group. The negatively charged group may aid in cell or tissue penetration. The negatively charged group may be attached at a 5’ or 3’ end (e.g., a 5’ end) of the oligonucleotide. This may be referred to as an end group. The end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy-C-malonyl. The end group may include an extra 5’ phosphate such as an extra 5’ phosphate. A combination of end groups may be used.

[0160] In some embodiments, the oligonucleotide includes a phosphate mimic. In some embodiments, the phosphate mimic comprises vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises atrans-vinylphosphonate. In some embodiments, the vinyl phosphonate comprises a cis- vinylphosphonate. An example of a nucleotide that includes a vinyl phosphonate is shown below.5’ vinylphosphonate 2’-0-methyl uridine

[0161] In some embodiments, the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.

[0162] In some embodiments, the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.1. Hydrophobic moieties

[0163] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a moiety attached at a 3’ or 5’ terminus of the oligonucleotide. Examples of moieties include a hydrophobic moiety or a sugar moiety, or a combination thereof. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 5’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3’ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5’ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3 ’ end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 5’ end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 3’ end of the ASO.

[0164] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbonmay be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[0165] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or a-tocopherol, or a combination thereof.

[0166] In some embodiments, the oligonucleotide comprises a lipophilic moiety attached at a 3 ’ or 5’ terminus 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, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3 -propanediol, a heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine, or a combination thereof. The lipophilic moiety may include a steroid such as cholesterol. The lipophilic moiety may include retinoic acid. The lipophilic moiety may include cholic acid. The lipophilic moiety may include adamantane acetic acid. The lipophilic moiety may include 1-pyrene butyric acid. The lipophilic moiety may include dihydrotestosterone. The lipophilic moiety may include l,3-bis-O(hexadecyl)glycerol. The lipophilic moiety may include geranyloxyhexyanol. The lipophilic moiety may include hexadecylglycerol. The lipophilic moiety may include borneol. The lipophilic moiety may include menthol. The lipophilic moiety may include 1,3- propanediol. The lipophilic moiety may include a heptadecyl group. The lipophilic moiety may include palmitic acid. The lipophilic moiety may include myristic acid. The lipophilic moiety may include 03- (oleoyl)lithocholic acid. The lipophilic moiety may include O3-(oleoyl)cholenic acid. The lipophilic moiety may include ibuprofen. The lipophilic moiety may include naproxen. The lipophilic moiety may include dimethoxytrityl. The lipophilic moiety may include phenoxazine.

[0167] In some embodiments, the lipophilic moiety comprises a hydrocarbon chain. The hydrocarbon chain may comprise or consist of a C4-C30 hydrocarbon chain. In some embodiments, the lipophilic moiety comprises a lipid.

[0168] In some embodiments, the oligonucleotide includes one or more lipophilic monomers, containing one or more lipophilic moieties, conjugated to one or more positions on at least one strand of the oligonucleotide, optionally via a linker or carrier. For instance, some embodiments provide an oligonucleotide comprising: an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; and one or more lipophilic monomers, containing one or more lipophilic moieties, conjugated to one or more positions on at least one strand, optionally via a linker or carrier. In some embodiments, the lipophilicity of the lipophilic moiety, measured by octanol-water partition coefficient, logP, exceeds 0.

[0169] 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 linear or branched aliphatic hydrocarbon, or an aromatic. Exemplary lipophilic moieties may include lipid, cholesterol, retinoic acid,cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis- O(hexadecyl)glycerol, geranyloxyhexyanol, 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 also 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 to attach the lipophilic moiety to the oligonucleotide. In some embodiments, the lipophilic moiety contains a saturated or unsaturated C6-C18 hydrocarbon chain (e.g., a linear C6-C18 alkyl or alkenyl). In some embodiments, the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain (e.g., a linear C16 alkyl or alkenyl). In some embodiments, the lipophilic moiety contains two or more carbon -carbon double bonds.

[0170] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

[0171] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof.

[0172] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a hydrophobic ligand or moiety. In some embodiments, the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety s attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide.

[0173] In some embodiments, a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and / or an antisense strand of a siRNA). In some embodiments, a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attachedat a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl.

[0174] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or a-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid includes a sterol such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12.

[0175] In some embodiments, the oligonucleotide comprises any aspect of the following structure:. In some embodiments, R is not octane. In some embodiments, R is not an octane. In some embodiments, R is an alkyl group containing 4-7 or 9-18 carbons. In some embodiments, the oligonucleotide comprises any aspect of the following structure:some embodiments, the oligonucleotidecomprises any aspect of the following structure:In some embodiments, the oligonucleotide comprises any aspect of the following structure: The aspectincluded in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown. In some embodiments, n is 1-3. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carbons. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the oligonucleotide does not comprise a phenyloctyl group. In some embodiments, the alkyl group contains 11 carbons. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 13 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, R is not an octane (Cs). In some embodiments, R includes a branched carbon chain. In some embodiments, R includes an unbranched carbon chain. In some embodiments, the lipid moiety comprises an alcohol or ether. In some embodiments, the lipid moiety has at least one degree of unsaturation. In some embodiments, the lipid moiety is an omega fatty acid, such as an omega-3, omega-5, omega-6, omega-7, or omega-9 fatty acid.

[0176] In some embodiments, the lipid includes a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 1. The example lipid moieties in Table 1 are shown attached at a 5’ end of an oligonucleotide, in which the 5 ’ terminal phosphate of the oligonucleotide is shown with the lipid moiety. In some embodiments, a lipid moiety in Table 1 may be attached at a different point of attachment than shown. For example, the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end. In some embodiments, the lipid is used for targeting the oligonucleotide to a non-hepatic cell or tissue.Table 1: Hydrophobic moiety examples

[0177] In some embodiments, the lipid or lipid moiety includes 16 to 18 carbons. In some embodiments, the lipid includes 16 carbons. In some embodiments, the lipid includes 17 carbons. In some embodiments, the lipid includes 18 carbons. In some embodiments, the lipid moiety includes 16 carbons. In some embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety includes 18 carbons. In some embodiments, the lipid moiety includes 19 carbons. In some embodiments, the lipid moiety includes 20 carbons.

[0178] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4-substitution pattern (e.g., the para phenyl configuration). The lipid may be attached to the carbocycle in the 1,4-substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,3 -substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,2-substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.

[0179] The lipid moiety may comprise or consist of the following structure:some embodiments, the lipid moiety comprises or consists of the following structure:. In some embodiments, the lipid moiety comprises the following structure:some embodiments, thelipid moiety comprises or consist of the following structure:some embodiments, the dotted line indicates a covalent connection. The covalent connection may between an end of the sense or antisense strand. For example, the connection may be to the 5’ end of the sense strand. In some embodiments, n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, R includes a branched carbon chain. In some embodiments, R includes an unbranched carbon chain. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 11 carbons. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 13 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. In some embodiments, the lipid moiety is not a phenyloctyl group. In some embodiments, R is not octane. In some embodiments, R is a carbon chain containing 4-7 or 9-18 carbons. In some embodiments, the lipid moiety is not a phenyloctyl group.

[0180] In some embodiments, the 5 ’ hydrophobic moiety comprises any one of the following structures:, wherein the dotted line indicates a covalent connection to the end of the 5’ end of the sense strand, n is 1-3, and R is an alkyl group containing 4-18 carbons. In some embodiments, R is not an octane. In some embodiments,the alkyl group contains 4-7 or 9-18 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, the 5’ hydrophobic moiety comprises a hydrophobic moiety in Table 1. In some embodiments, the 5’ hydrophobic moiety comprises phenyl para C12. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In some embodiments, n is0-3. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments n is 2. In some embodiments, the hydrophobic moiety comprises an alcohol or an ether. In some embodiments, R is an unsaturated alkyl group. In some embodiments, the unsaturated alkyl group may be monounsaturated. In some embodiments, the unsaturated alkyl group may be unsaturated at the omega-3, position, omega-4 position, omega-5 position, omega-6 position, omega-7 position, omega-8 position, omega-9 position, or a combination thereof. In some embodiments, the 5’ hydrophobic moiety is not a phenyloctyl group.

[0181] The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4-substitution pattern (e.g., the para phenyl configuration). The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,4 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,3 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,2 orientation relative to the oligonucleotide.

[0182] In some embodiments, when the lipid moiety comprises the structure:, R is not an octyl group. In some embodiments, R is an unsaturated hydrocarbon. In some embodiments, R is a monounsaturated acyl group. In some embodiments, the monounsaturated acyl group is unsaturated at the omega-3, omega-5, omega-6, omega-7, omega-8, or omega-9 position. In some embodiments, the unsaturated hydrocarbon is a polyunsaturated fatty acyl gro...

Claims

CLAIMSWhat is claimed is:

1. A composition comprising an oligonucleotide that targets MTRES 1 and when administered to a subject in an effective amount decreases central nervous system (CNS) MTRES1, wherein the oligonucleotide comprises any one of SEQ ID NOS: 2571, 2633, 2674, 2681, 2683, 2684, 3337, 2790, 2801, 2842, 2856, 2861, 2863, 2865, 2866, 2972, 2983, 3022, 3024, 3143, 3341, 3342, 3343, 3344, 3345, 3346, 3347, 3348, 3349, 3350, 3351, 3352, 3353, 3354, 3355, 3356, 3373, 3374, 3375, 3376, 3377, or 3378.

2. The composition of claim 1, wherein the oligonucleotide comprises a modified intemucleoside linkage.

3. The composition of claim 2, wherein the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.

4. The composition of claim 2, wherein the modified intemucleoside linkage comprises one or more phosphorothioate linkages.

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

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

7. The composition of claim 6, wherein the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2’, 4’ constrained ethyl nucleic acid, 2'-O-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-C-allyl, 2'-fluoro, 2'-deoxy, or 2’-O-methyl inosine, or a combination thereof.

8. The composition of claim 7, wherein the modified nucleoside comprises an LNA or a 2’, 4’ constrained ethyl nucleic acid.

9. The composition of claim 7, wherein the modified nucleoside comprises a 2'-O- methoxy ethyl.

10. The composition of claim 7, wherein the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-0-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof.

11. The composition of claim 7, wherein the modified nucleoside comprises one or more 2’- fluoro modified nucleosides.

12. The composition of claim 7, wherein the modified nucleoside comprises a 2'-O-alkyl modified nucleoside.

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

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

15. The composition of claim 14, wherein the lipophilic moiety comprises cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1 -pyrene butyric 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.

16. The composition of claim 14, wherein the lipophilic moiety comprises a C4-C30 hydrocarbon chain.

17. The composition of claim 14, wherein the lipophilic moiety comprises a lipid.

18. The composition of claim 17, wherein the lipid comprises myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, a-tocopherol, or a combination thereof.

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

20. The composition of claim 19, wherein the sense strand is 12-30 nucleosides in length.

21. The composition of claim 19, wherein the antisense strand is 12-30 nucleosides in length.

22. A composition comprising an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NOS: 2571, 2633, 2674, 2681, 2683, 2684, 3337, 2790, 2801, 2842, 2856, 2861, 2863, 2865, 2866, 2972, 2983, 3022, 3024, 3143, 3341, 3342, 3343, 3344, 3345, 3346, 3347, 3348, 3349, 3350, 3351, 3352, 3353, 3354, 3355, 3356, 3373, 3374, 3375, 3376, 3377, or 3378.

23. The composition of claim 22, wherein any one of the following is true with regard to the sense strand: all purines comprise 2 ’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’- fluoro and 2’-methyl modified pyrimidines; all purines comprise 2’-methyl modified purines, and all pyrimidines comprise a mixture of 2’- fluoro and 2’-methyl modified pyrimidines; all purines comprise 2 ’-fluoro modified purines, and all pyrimidines comprise 2 ’-methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-methyl modified purines; all pyrimidines comprise 2’-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-methyl modified purines; orall pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-methyl modified purines.

24. The composition of claim 22, wherein any one of the following is true with regard to the sense strand: all purines comprise 2’-fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’- O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O- methyl, and 2’-O-methoxyethyl modified pyrimidines; all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O- methyl, and 2’-O-methoxyethyl modified pyrimidines; all purines comprise 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O- methyl, and 2’-O-methoxyethyl modified pyrimidines; all purines comprise a mixture of 2 ’-fluoro and 2'-O-methyl modified purines and all pyrimidines comprise (i) 2’-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2’-O-methyl and 2’-O- methoxyethyl modified pyrimidines; (iii) a mixture of 2’ -fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; all purines comprise a mixture of 2 ’-fluoro and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-O-methyl modified pyrimidines; (ii) a mixture of 2’-fluoro and 2’-O- methyl modified pyrimidines; (iii) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; all purines comprise a mixture of 2'-O-methyl and 2'-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) a mixture of 2’ -fluoro and 2’-O- methyl modified pyrimidines; (iii) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; or all purines comprise a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2’-fluoro modified pyrimidines; (ii) 2’-O-methyl modified pyrimidines; (iii) 2’-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; (v) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; and with the proviso that in any of the foregoing, the sense strand may include a 2’ -deoxy nucleoside.

25. The composition of claim 22, wherein any one of the following is true with regard to the antisense strand:all purines comprise 2 ’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’- fluoro and 2’-methyl modified pyrimidines; all purines comprise 2’-methyl modified purines, and all pyrimidines comprise a mixture of 2’- fluoro and 2’-methyl modified pyrimidines; all purines comprise 2’-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’-methyl modified purines; all pyrimidines comprise 2’-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-methyl modified purines; or all pyrimidines comprise 2’-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines.

26. The composition of claim 22, wherein the oligonucleotide comprises a phosphate at the 5’ end of the antisense strand.

27. The composition of claim 22, wherein the oligonucleotide comprises a phosphate mimic at the 5’ end of the antisense strand.

28. The composition of claim 22, wherein the phosphate mimic comprises a 5'-vinyl phosphonate (VP).

29. The composition of any one of the preceding claims, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).

30. The composition of claim 29, wherein the ASO is 12-30 nucleosides in length.

31. A composition comprising: a small interfering RNA (siRNA) comprising a sense strand, an antisense strand complementary to a section of an MTRES 1 mRNA, and a ligand connected to an end of the sense or antisense strand.

32. The composition of claim 31, wherein the ligand comprises a peptide or protein.

33. The composition of claim 31, wherein the ligand is selected from a hydrophobic ligand, avP3 ligand, a deltorphin peptide (8 opioid agonist), a dermorphin peptide (p opioid agonist), a Neurotensin peptide, GHRP-6 peptide, a native protein for mediating degradation via Chaperone- Mediated Autophagy, a Nerve Growth Factor-derived peptide binding to tyrosine kinase receptors and to p75 neurotrophin receptors, a 4F peptide that binds LDL, and a ligand for mannose 6-phosphate receptors.

34. The composition of claim 31, wherein the ligand is selected from cycloRGDfK(N3- PEG4), YaFDVV-N3K, YaFGYPK, KPPPAGSSPGLYENKPRRPYIL, -PEG2-CH2CO-GHwAWfK- NH2, PEG2-CH2CO-GKFERQQKILDQRFFE, PEG2-CH2CO-GTFVKALTMDGKQAAWR, PEG2- CH2CO-GDWFKAFYDKVAEKFKEAF-NH2, and alpha-Mannose 6-phosphate PEG3.

35. The composition of any one of claims 31-34, wherein the ligand is connected to an end of the sense or antisense strand via linker.

36. The composition of claim 35, wherein the linker is formed through a conjugation a reaction.

37. The composition of claim 36, wherein the conjugation a reaction comprises a cycloaddition reaction.

38. The composition of claim 36, wherein the conjugation a reaction comprises reaction of an azide and an alkyne.

39. The composition of claim 31, wherein the composition comprises the structure:

40. The composition of claim 31, wherein the ligand comprises a lipid moiety connected to an end of the sense or antisense strand.

41. The composition of claim 40, wherein the lipid moiety comprises (a) a phenyl or cyclohexanyl linker, and (b) a lipid, wherein the linker is connected to the lipid and to the end of the sense or antisense strand.

42. The composition of claim 40, wherein the lipid and the end of the sense or antisense strand are connected to the phenyl or cyclohexanyl linker in the 1,4; 1,3; or 1,2 substitution pattern.

43. The composition of claim 41 or 42, wherein the lipid and the end of the sense or antisense strand are connected to the phenyl or cyclohexanyl linker in the 1,4-substitution pattern.

44. The composition of any one of claims 40-43, wherein the lipid moiety comprises the following structure:wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, with the proviso that R is not an octane.

45. The composition of any one of claims 40-43, wherein the lipid moiety comprises the following structure:wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, n is 1-3, and R is an alkyl group containing 4-18 carbons.

46. The composition of any one of claims 40-43, wherein the lipid moiety comprises the following structure:wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, n is 0-3, and R is an alkyl group containing 4-18 carbons.

47. The composition of any one of claims 40-43, wherein the lipid moiety comprises the following structure:wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand.

48. The composition of claim 40 wherein the lipid moiety comprises a lipid moiety depicted in Table 1.

49. The composition of claim 31, wherein the ligand comprises a ligand depicted in Table 115.

50. A composition comprising an siRNA that targets MTRES1 and when administered to a cell modulates the expression of MTRES1, wherein the siRNA comprises a sense strand and an antisense strand; and wherein the sense strand or the antisense strand comprises any of modification patterns 64S to 83S or 41AS to 45AS.

51. The composition of claim 50, wherein the oligonucleotide comprises any one of SEQ ID NOS: 2571, 2633, 2674, 2681, 2683, 2684, 2790, 2801, 2842, 2856, 2861, 2863, 2865, 2866, 2972, 2983, 3022, 3024, 3143, 3341, 3342, 3343, 3344, 3345, 3346, 3347, 3348, 3349, 3350, 3351, 3352, 3353, 3354, 3355, 3356, 3373, 3374, 3375, 3376, 3377, or 3378.

52. A composition comprising an siRNA that targets MTRES1 and when administered to a cell modulates the expression of MTRES1, wherein the siRNA comprises a sense strand and an antisense strand; and wherein the sense strand or anti sense strand comprises any one of SEQ ID NOs: 2571, 2633, 2674, 2681, 2683, 2684, 2790, 2801, 2842, 2856, 2861, 2863, 2865, 2866, 2972, 2983, 3022, 3024, 3143, 3341, 3342, 3343, 3344, 3345, 3346, 3347, 3348, 3349, 3350, 3351, 3352, 3353, 3354, 3355, 3356, 3373, 3374, 3375, 3376, 3377, or 3378; or wherein the sense strand or the antisense strand comprises any one ofSEQ ID NOs: 2399, 2484, 2501, , 3051, 3095, 3106, 3119, 3177, 3183, 3194, 3207, 3239, 3241, 3242, 3243, 3244, 3248, 3296, 3306, 3326, 3337, 3357,3358, 3359, 3360, 3361, 3362, 3363, 3364, 3365, 3366, 3367, 3368, 3369, 3370, 3371, 3372, 3379, 3380, 3381, 3382, 3383, 3384, 3385, 3386, 3387, 3388, 3389, 3390, 3391, 3392, 3393, 3394, 3395-3414.

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

54. The composition of claim 53, wherein the composition is formulated for administration to a central nervous system.

55. The composition of claim 53 or 54, wherein the composition is formulated for delivery to a neural cell.

56. A composition comprising an oligonucleotide of any one of claims 1-55 that targets MTRES1 and when administered to a subject in an effective amount increases cognitive function or slows cognitive decline.

57. The composition of claim 56, wherein the cognitive function is increased by about 10% or more, as compared to prior to administration.

58. The composition of claim 56, wherein the cognitive decline is slowed by about 10% or more, as compared to prior to administration.

59. A composition comprising an oligonucleotide of any one of claims 1-55 that targets MTRES1 and when administered to a subject in an effective amount improves a marker of neurodegeneration.

60. The composition of claim 59, wherein the wherein the marker of neurodegeneration comprises a central nervous system (CNS), cerebrospinal fluid (CSF), or plasma marker of neurodegeneration.

61. The composition of claim 59, wherein the wherein the marker of neurodegeneration comprises a measurement of amyloid plaques, tau accumulation, beta-amyloid 42, beta-amyloid 40, the ratio of beta-amyloid 42 to beta-amyloid 40, tau, phospho-tau, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), alpha-synuclein, or Lewy bodies.

62. The composition of any one of claims 59-61, wherein the marker of neurodegeneration is improved by about 10% or more, as compared to prior to administration.

63. A composition comprising an oligonucleotide of any one of claims 1-55 that targets MTRES1 and when administered to a subject in an effective amount improves a marker of mitochondrial function or mitochondrial energy metabolism.

64. The composition of claim 63, wherein the wherein the marker of mitochondrial function or mitochondrial energy metabolism comprises a central nervous system (CNS), cerebrospinal fluid (CSF), or plasma marker of mitochondrial function or mitochondrial energy metabolism.

65. The composition of claim 63, wherein the wherein the marker of mitochondrial function or mitochondrial energy metabolism comprises a measurement of metabolic dysfunction, mitochondrial dysfunction, mitochondrial respiration, oxidative phosphorylation, glycolysis, a ATP or ATP production,ketones or ketone metabolism, lipids or lipid metabolism, the astrocyte -neuron lactate shuttle (ANLS), neuron metabolism, astrocyte metabolism, glial cell metabolism, oligodendrocyte metabolism, CNS glucose or CNS glucose consumption, CNS oxygen or CNS oxygen consumption, the TCA or Krebs cycle, the electron transport chain, mitophagy or autophagy, mitochondrial fission or fusion, mitochondrial transcription or translation, mitochondrial biogenesis, gliotransmitter release or function, neurotransmitter release or function, connexin 43, lactate or lactate metabolism, pyruvate or pyruvate metabolism, amino acids or amino acid metabolism, or lipoprotein particle composition or concentration.

66. The composition of any one of claims 63-64, wherein the mitochondrial function or mitochondrial energy metabolism is improved by about 10% or more, as compared to prior to administration.

67. A method of treating a subject having a neurological disorder, the method comprising administering an effective amount of the composition of any one of claims 1-55 to the subject.

68. The method of claim 67, wherein the neurological disorder comprises dementia, Alzheimer’s disease, delirium, cognitive decline, cognitive impairment, vascular dementia, or Parkinson’s disease.

69. The method of claim 67, wherein the composition is administered intrathecally.

70. A method of treating a subject having a neurological disorder or who is at risk for developing the neurological disorder, the method comprising evaluating a subject’s risk for developing a neurological disorder and administering an effective amount of the composition of any one of claims 1-55 to the subject.

71. The method of any one of claims 67-70, wherein the subject has a genotype at risk for developing Alzheimer’s disease or dementia.

72. The method of claim 71, wherein the subject is a heterozygous or homozygous carrier of APOE4.

73. The method of claim 67, wherein the subject is a heterozygous or homozygous carrier of MTRES1 rsl 17058816-G (c.3+lG).

74. The method of any one of claims 67-73, wherein evaluating a subject’s risk for developing a neurological disorder comprises calculating a polygenic risk score for developing Alzheimer’s disease or dementia.

75. The method of claim 74, wherein the subject has a polygenic risk score in the 40th percentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia.

76. The method of claim 74, wherein the subject has a polygenic risk score in the 20th percentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia.

77. The method of claim 74, wherein calculating a polygenic risk score comprises providing genomic data comprising one or more genotypes of the subject, wherein the one or more genotypes is associated with a high risk for developing Alzheimer’s disease or dementia.

78. A composition comprising an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases central nervous system (CNS) MTRES1, wherein the oligonucleotide comprises any one of SEQ ID NOS: 3595-3599.

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