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 variants 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 No. 63 / 625,823, filed January 26, 2024, which is incorporated herein by reference in its 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 54462-767 601 SL, created January 24, 2025, which is 3,459,711 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] Disclosed herein are compositions comprising oligonucleotides targeting MTRES1.Disclosed herein, in some aspects, 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 composition disclosed herein to the subject.

[0005] Disclosed herein, in some aspects, are compositions comprising a small interfering RNA(siRNA) comprising a sense strand and an antisense strand, wherein the antisense strand is complementary to at least 10 contiguous nucleotides of MTRES1 ENST00000625458 mRNA. In some embodiments, the antisense strand is complementary to at least 15 contiguous nucleotides of MTRES1 ENST00000625458 mRNA. In some embodiments, the siRNA is selective for binding of MTRES1 ENST00000625458 mRNA. In some embodiments, the selectivity for binding of ENST00000625458 compared to binding of ENST00000311381 or ENST00000405204 mRNA is at least 2:1, 5:1, 10:1, 100:1, 1000:1, or at least 10,000:1. In some embodiments, the antisense strand is not complementary to MTRES1 ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the sense strand comprises no more than 50% identity with MTRES1 ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the sense strand comprises no more than 30% identity with MTRES1 ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the sense strand comprises no more than 10% identity with MTRES1 ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the siRNA is selective for silencing (i.e. knockdown or downregulation) of MTRES1 ENST00000625458 mRNA. In some embodiments, the siRNA silences the expression of the ENST00000625458 mRNA by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least100% more than the silencing of expression of the MTRES1 ENST00000311381 or ENST00000405204 mRNA.

[0006] Disclosed herein, in some aspects, are compositions 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: 1-618. 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. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages. In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2’-O-allyl, 2’-C-allyl, 2'-fluoro, 2'-deoxy, or 2’-O-methyl inosine, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2 ’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises a 2'-O- methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises one or more 2’-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises a 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, l,3-bis-O(hexadecyl)glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3 -propanediol, heptadecyl, palmitic acid, myristic acid, 03- (oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. In some embodiments, the lipophilic moiety comprises a C4-C30 hydrocarbon chain. In some embodiments, the lipophilic moiety comprises a lipid. In some embodiments, the lipid comprises myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, a- tocopherol, or a combination thereof. In some embodiments, the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 12-30 nucleosides in length. In some embodiments, the antisense strand is 12-30 nucleosides in length.

[0007] Disclosed herein, in some aspects, are compositions comprising an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sensestrand 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: 1-618. In some embodiments, any one of the following is true with regard to the sense strand: all purines comprise 2’ -fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O- methyl modified purines, and all pyrimidines comprise a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; all pyrimidines comprise 2’ -fluoro modified pyrimidines, and all purines comprise a mixture of 2’ -fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O-methyl modified purines. In some embodiments, 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-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) 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 ’-0 -methoxy ethyl 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 sensestrand may include a 2’ -deoxy nucleoside. In some embodiments, any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O- methyl modified purines, and all pyrimidines comprise a mixture of 2’ -fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2 ’-fluoro modified pyrimidines; all pyrimidines comprise 2’ -fluoro modified pyrimidines, and all purines comprise a mixture of 2’ -fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines. In some embodiments, the oligonucleotide comprises a phosphate at the 5’ end of the antisense strand. In some embodiments, the oligonucleotide comprises a phosphate mimic at the 5’ end of the antisense strand. In some embodiments, the phosphate mimic comprises a 5'-vinyl phosphonate (VP). In some embodiments, the 3 ’ nucleoside of the sense strand is modified to an A, wherein the 5 ’ nucleoside of the antisense strand is modified to a U. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length.

[0008] Disclosed herein, in some aspects, are compositions comprising: a small interfering RNA(siRNA) comprising a sense strand, an antisense strand complementary to a section of an MTRES1 ENST00000625458 mRNA, and a lipid moiety connected to an end of the sense or antisense strand; 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the lipid moiety comprises the following structure:; wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand. In some embodiments, the lipid moiety comprises a lipid moiety depicted in Table 1.

[0009] Disclosed herein, in some aspects, are compositions comprising an siRNA that targetsMTRES1 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 comprises any one of SEQ ID NOs: 619-670, 723-774, or 847-855 or the antisense strand comprises any one of SEQ ID NOs: 671- 722, 775-826, or 856-864 . In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition is formulated for administration to a central nervous system. In some embodiments, the composition is formulated for delivery to a neural cell.

[0010] Disclosed herein, in some aspects, are methods of treating a subject having a neurological disorder, the method comprising administering an effective amount of a composition disclosed herein to the subject. In some embodiments, the composition is administered systemically. In some embodiments, the composition is administered intrathecally. In some embodiments, the composition is administered systemically.

[0011] Disclosed herein, in some aspects, 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 composition 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, subject is a heterozygous or homozygous carrier of MTRES1 rsl 17058816-G (C.3+1G). 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 fordeveloping 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.

[0012] Disclosed herein, in some aspects, are compositions comprising an siRNA that specifically targets and selectively downregulates a first MTRES1 mRNA transcript compared to a second MTRES1 mRNA transcript. In some embodiments, the siRNA specifically binds to a contiguous nucleotide sequence of the first MTRES1 mRNA transcript that is absent in the second MTRES1 mRNA transcript. In some embodiments, the first MTRES1 mRNA transcript is ENST00000625458. In some embodiments, the second MTRES1 mRNA transcript is ENST00000311381. In some embodiments, the second MTRES1 mRNA transcript is ENST00000405204. In some embodiments, the siRNA downregulates the expression of the ENST00000625458 mRNA by at least 10% more than the downregulation in expression of the ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the siRNA downregulates the expression of the ENST00000625458 mRNA by at least 20% more than the downregulation in expression of the ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the siRNA downregulates the expression of the ENST00000625458 mRNA by at least 30% more than the downregulation in expression of the ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the siRNA downregulates the expression of the ENST00000625458 mRNA by at least 40% more than the downregulation in expression of the ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the siRNA downregulates the expression of the ENST00000625458 mRNA by at least 50% more than the downregulation in expression of the ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the siRNA downregulates the expression of the ENST00000625458 mRNA by at least 60% more than the downregulation in expression of the ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the siRNA downregulates the expression of the ENST00000625458 mRNA by at least 70% more than the downregulation in expression of the ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the siRNA downregulates the expression of the ENST00000625458 mRNA by at least 80% more than the downregulation in expression of the ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the siRNA downregulates the expression of the ENST00000625458 mRNA by at least 90% more than the downregulation in expression of the ENST00000311381 or ENST00000405204 mRNA. In some embodiments, the siRNA downregulates the expression of the ENST00000625458 mRNA by at least 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% more than the downregulation in expression of the ENST00000311381 or ENST00000405204 mRNA, or by a range defined by any of the two aforementioned percentages.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 is a plot of MTRES1 mRNA qPCR data in the CRISPR-engineered wildtype (left two bars, E2-E3 and E4-E5) and MTRES1 c.3+lG>A knock-in cells (right two bars, E2-E3 and E4-E5). The y-axis is labeled fold change from 0.0 to 1.5 at 0.5 unit intervals.

[0014] FIG. 2 is a plot quantifying MTRES1 western blot data in the wildtype (left) andMTRES1 c.3+lG>A knock-in cells (right). The y-axis is labeled normalized to ACTB from 0 to 2.0 at 0.5 unit intervals.DETAILED DESCRIPTION

[0015] 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.”

[0016] 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.

[0017] 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 oftherapeutic 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.

[0018] 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 (encoded by ENST00000311381, SEQ ID NO 827). MTRES1 may include 245 amino acids (encoded by ENST00000625458, SEQ ID NO 828). MTRES1 may include 240 amino acids (encoded by ENST00000405204, SEQ ID NO 865). MTRES1 may be expressed in neural 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. 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). In some embodiments, the oligonucleotide described herein specifically targets ENST00000625458 without targeting ENST00000311381 or ENST00000405204.

[0019] 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 the 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. Within neuronal cells, MTRES1 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.

[0020] Here it is shown that loss-of-function M77W.S7 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, vascular dementia, anticholinesterase medication use, and delirium. Therefore, modulation of MTRES1 may serve as a therapeutic for treatment of a neurological disorder such as dementia, Alzheimer’s disease, delirium, cognitive decline, vascular dementia, or Parkinson’s disease.

[0021] Disclosed herein are compositions comprising an oligonucleotide that targets MTRES1. Where inhibition or targeting of MTRES1 is disclosed, it is contemplated that some embodiments may include inhibiting or targeting a MTRES1 protein or MTRES1 RNA. For example, by inhibiting or targeting an RNA (e.g., mRNA) encoded by theMTRESl gene using an oligonucleotide described herein, the MTRES1 protein may be inhibited or targeted as a result of there being less production of the MTRES1 protein by translation of the MTRES1 RNA; or a MTRES1 protein may be targeted or inhibited by an oligonucleotide that binds or interacts with a MTRES1 RNA and reduces production of the MTRES1 protein from the MTRES1 RNA. Thus, targeting MTRES1 may refer to binding aMTRES1 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 MTRES1 to a subject in need thereof.

[0022] 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 rsll7058816-G (C.3+1G). 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

[0023] 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. In some embodiments, the oligonucleotide described herein specifically targets ENST00000625458 without targeting ENST00000311381 or ENST00000405204.

[0024] Some embodiments include a composition comprising an oligonucleotide that decreases mRNA expression of ENST00000625458 at least 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 700%, 1000%, or by a range defined by any of the two aforementioned percentages relative to mRNA expression of ENST00000311381 or ENST00000405204.

[0025] 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.

[0026] 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 about100%, 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 MTRES1 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 MTRES1 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.

[0027] 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 disease may include dementia, Alzheimer’s disease, delirium, cognitive decline, 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.

[0028] 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, 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, about50% 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 to administration. 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.

[0029] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1 and when administered to a subject in an effective amount decreases a marker of neurodegeneration in the subject. Some example markers of neurodegeneration may include central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) beta-amyloid 42, CSF tau, CSF or plasma phospho-tau (such as p-tau217), CSF or plasma neurofilament light chain (NIL), Lewy bodies, or CSF alpha-synuclein. In some embodiments, the marker of neurodegeneration 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 marker of neurodegeneration is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the marker of neurodegeneration 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 marker of neurodegeneration 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 marker of neurodegeneration is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration 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 marker of neurodegeneration 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.

[0030] 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 prior to 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.

[0031] 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.

[0032] 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 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 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.

[0033] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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.

[0034] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 betaamyloid 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 betaamyloid 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 betaamyloid 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.

[0035] 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.

[0036] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) or plasma neurofdament light chain (NIL) in the subject. In some embodiments, the CSF or plasma NIL 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 NIL 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.

[0037] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 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 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.

[0038] 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 decreasedby 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. In some 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.

[0039] 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-sy nuclein 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.

[0040] 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, theLewy 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.

[0041] 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.

[0042] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount reduces or slows cognitive decline in thesubject. 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 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 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. In some embodiments, cognitive decline is measured using tests of cognitive decline, including but not limited to the Mini-Mental State Exam (MMSE, 10-minute test that asks patients to identify everyday objects, count backward, and state the current date); Montreal Cognitive Assessment (MoCA, 10-15 minute test that includes a clock drawing task, as well as questions about attention, language, and short-term memory); mini-Cog (3-minute test that asks patients to draw a clock and recall a list of three words); five Cognitive Tests (5-Cog, a group assessment tool that screens for cognitive decline in older adults); 6-CIT (screening tool for primary care settings that takes 3-4 minutes to administer); GPCOG (screening tool that takes 2-5 minutes to administer); a neurological exam; or other interviews that assess memory, behavior, mood, and functional status.

[0043] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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, themetabolic 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.

[0044] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 prior to 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.

[0045] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 to administration. 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.

[0046] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 thanabout 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.

[0047] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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% 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 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.

[0048] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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.

[0049] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 isimproved 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.

[0050] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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.

[0051] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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-neuron lactate 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.

[0052] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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. Insome 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.

[0053] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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, theastrocyte 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.

[0054] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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.

[0055] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 improvedby 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.

[0056] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 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 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.

[0057] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 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 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.

[0058] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 someembodiments, 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.

[0059] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 about100%, 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.

[0060] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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%, no more 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.

[0061] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 toadministration. 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.

[0062] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 prior to 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 byno 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.

[0063] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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.

[0064] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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.

[0065] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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, the neurotransmitter 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, orabout 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.

[0066] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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%, as compared 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 someembodiments, 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.

[0067] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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.

[0068] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 is improved 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 about100% 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.

[0069] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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 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 amino acid or amino acidmetabolism 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.

[0070] In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 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

[0071] In some embodiments, the composition comprises an oligonucleotide that targetsMTRES1, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In someembodiments, 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.

[0072] 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.

[0073] 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: 827. 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: 827.

[0074] 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.

[0075] 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.

[0076] 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. Insome 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.

[0077] 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 some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human MTRES1 mRNA.

[0078] 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 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.

[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 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 MTRES1 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 MTRES1 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 MTRES1 mRNA and less than or equal to 50 human off-targets, with no more than 3 mismatches in the antisense strand.

[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 andan antisense strand, siRNA binds with a human MTRES1 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%.

[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, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-309, 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: 1-309, 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: 1-309, 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- 309. 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: 1-309 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: 1-309 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 1-309 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 1-309 is modified to an A. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-309 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1- 309 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 1-309 is modified to an A. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs 1-309 ismodified to an T or U. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1- 309 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1-309 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 1-309 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-309 is modified to an G. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-309 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1-309 is modified to an G. In some embodiments, position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs 1-309 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-309 is modified to an C. In some embodiments, position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-309 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 1-309 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 1-309 is modified to an C.

[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 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: 310-618, 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: 310-618, 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: 310-618, 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: 310-618. 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 mayinclude 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: 310-618 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: 310-618 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 310-618 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 310-618 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: 310-618 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: 310-618 is modified to an A. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 310-618 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 310-618 is modified to an A. In some embodiments, position 1 (from the 5’ end of any one of SEQ ID NOs: 310-618 is modified to a T or U. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 310-618 is modified to a T or U. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 310-618 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 310- 618 is modified to a T or U. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 310-618 is modified to an G. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 310-618 is modified to an G. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 310-618 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 310-618 is modified to an G. In some embodiments, position 1 (from the 5’ end) of any one of SEQ ID NOs: 310-618 is modified to an C. In some embodiments, position 14 (from the 5’ end) of any one of SEQ ID NOs: 310-618 is modified to an C. In some embodiments, position 19 (from the 5’ end) of any one of SEQ ID NOs 310-618 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 310-618 is modified to an C.

[0083] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in any one of Tables 3-6, 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 Tables 3-6, 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 Tables 3-6. 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 ofTables 3-6 is modified by substitution of the 3’ nucleoside to an A. In some embodiments, a sense strand sequence of an siRNA in any one of Tables 3-6 is modified by substitution of the nucleoside to an A at position 19 (from the 5’ end). In some embodiments, an antisense strand sequence of an siRNA in any one of Tables 3-6 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.

[0084] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 3, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 3, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 3. 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. The siRNA may include a moiety such as 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 is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22 or ETL28. 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.

[0085] 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.

[0086] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 4, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 4, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 4. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or moreintemucleoside linkages and / or one or more nucleoside modifications. The siRNA may include a moiety such as 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 is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22 or ETL28. 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.

[0087] 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.

[0088] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 5, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 5, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 5. 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. The siRNA may include a moiety such as 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 is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22 or ETL28. 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.

[0089] 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.

[0090] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 6, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 6, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA in Table 6. 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. The siRNA may include a moiety such as 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 is ETL3, ETL7, ETL8, ETL9, ETL10, ETL12, ETL13, ETL15, ETL16, ETL18, ETL19, ETL20, ETL21, ETL22 or ETL28. 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.. 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.

[0091] 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 internucleoside linkages and / or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3 ’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3 ’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.

[0092] In some embodiments, the siRNA comprises the sense strand and / or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and / orthe 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.

[0093] 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.

[0094] 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.B. ASOs

[0095] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, 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 14-30nucleosides 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.

[0096] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, 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: 827, 828, or 865; 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: 827.C. Modification patterns

[0097] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, 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.

[0098] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, 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 modifiedintemucleoside linkages, 9 or more modified internucleoside 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.

[0099] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, 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'-O-alkyl group. In some embodiments, the modified nucleoside comprises a 2'-O-allyl group. In some embodiments, the modified nucleoside comprises a 2'-fluoro group. In some embodiments, the modified nucleoside comprises a 2'-deoxy group. In some embodiments, the modified nucleoside comprises a 2'-O- methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2'-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2’- fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2’-O-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics.

[0100] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure:3’ nucleotidewherein the base can be any pyrimidine or purine.

[0101] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:K or Jare independently an H or a 3’ or 5’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.

[0102] 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).

[0103] 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, thesense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothioates at the 5’ and 3’ ends.

[0104] 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.

[0105] 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 group consisting of a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O- methoxy ethyl. In some embodiments, the sense strand comprises at least a 2 ’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2 ’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2 ’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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 each branch 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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 a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’ -fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise 2 ’-fluoro modified purines.

[0121] 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 modifiedpyrimidines. 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.

[0122] In some cases, the oligonucleotide comprises a particular modification pattern. In some embodiments, position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification. In some embodiments, when position 9 of a strand of the oligonucleotide is a pyrimidine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between 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 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.

[0123] In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’Fmodifications 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.

[0124] In some cases, position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.

[0125] In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’- fluoro-modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’- fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine; all purines of the sense strand comprises 2’-O- methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’ -fluoromodified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row; the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxy ribonucleotides.

[0126] 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 deoxy ribonucleotide. 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 strandcomprise 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.

[0127] In some embodiments, position nine of the sense strand comprises an unmodified deoxy ribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2’-fluoro-modified purines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxy ribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O-methyl modified purines or 2’-fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides.

[0128] In some embodiments, position nine of the sense strand comprises an unmodified deoxy ribonucleotide. 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 deoxy ribonucleotide; 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’ -fluoromodified nucleotides and unmodified deoxy ribonucleotide.

[0129] 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.

[0130] 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.

[0131] In some embodiments, the oligonucleotide includes a phosphate mimic. In some embodiments, the phosphate mimic comprises vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises a trans- vinylphosphonate. In some embodiments, the vinyl phosphonate comprises a cis- vinylphosphonate. An example of a nucleotide that includes a vinyl phosphonate is shown below.5’ vinylphosphonate 2’-0 Methyl Uridine

[0132] 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.

[0133] 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 avinyl 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

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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. Thelipophilic 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 O3-(oleoyl)lithocholic acid. The lipophilic moiety may include 03- (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.

[0138] 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.

[0139] 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 octanolwater partition coefficient, logP, exceeds 0.

[0140] 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 CT-Cix hydrocarbon chain (e.g., a linear CT-Cix alkyl or alkenyl). In some embodiments, the lipophilic moiety contains a saturated or unsaturated Cis hydrocarbon chain (e.g., a linear Cis alkyl or alkenyl). In some embodiments, the lipophilic moiety contains two or more carbon-carbon double bonds.

[0141] 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. Thehydrocarbon 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.

[0142] 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.

[0143] 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.

[0144] In some embodiments, a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and / or an antisense strand of a siRNA). In some embodiments, a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl.

[0145] 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.

[0146] 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 oligonucleotide comprises any aspect of the following structure:some embodiments, the oligonucleotide comprises any aspect of the following structure: The aspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown. In some embodiments, n is 1-3. In some embodiments, n is 1, 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 anoctane (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. 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. Ligands of Table 1 may also be attached via a 3’ terminus of an oligonucleotide.Table 1: Hydrophobic moiety examples

[0147] 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.

[0148] 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.

[0149] The lipid moiety may comprise or consist of the following structure:In some embodiments, the lipid moiety comprises or consists of thesome embodiments, the lipid moiety comprises the following structure:some embodiments, the lipid 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 is0. 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.

[0150] In some embodiments, the 5 ’ hydrophobic moiety comprises any one of the following structures: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 is 0-3. 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.

[0151] 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 tothe phenyl or cyclohexyl linker in the 1,4-substitution patern (e.g., the para phenyl configuration). The lipid may be atached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be atached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be atached to the carbocycle in the meta orientation relative to the oligonucleotide. The lipid may be atached to the carbocycle in the in the 1,4 orientation relative to the oligonucleotide. The lipid may be atached to the carbocycle in the in the 1,3 orientation relative to the oligonucleotide. The lipid may be atached to the carbocycle in the in the 1,2 orientation relative to the oligonucleotide.

[0152] In some embodiments, when the lipid moiety comprises the structure: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 group. In some embodiments, the polyunsaturated fatty acyl group is unsaturated at least at the omega-3, omega-5, omega-6, omega-7, omega-, omega-9 position, or a combination thereof.

[0153] The lipid moiety may be atached at a 5’ end of the oligonucleotide. The 5’ end may have one phosphate linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have two phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have three phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide. The 5’ end may have one phosphate connected to the 5’ carbon of a sugar of the oligonucleotide, where the one phosphate is connected to the lipid moiety. The 5’ end may have two phosphates connected to the 5 ’ carbon of a sugar of the oligonucleotide, where the one of the two phosphates is connected to the lipid moiety. The 5’ end may have three phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the three phosphates is connected to the lipid moiety. The sugar may include a ribose. The sugar may include a deoxyribose. The sugar may be modified a such as a 2’- modified sugar (e.g., a 2’-O-methyl or 2’-fluoro ribose). A phosphate of the 5’ end may include a modification such as a sulfur in place of an oxygen. Two phosphates of the 5 ’ end may include a modification such as a sulfur in place of an oxygen. Three phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen.

[0154] In some embodiments, the oligonucleotide includes 1 lipid moiety. In some embodiments, the oligonucleotide includes 2 lipid moieties. In some embodiments, the oligonucleotide includes 3 lipid moieties. In some embodiments, the oligonucleotide includes 4 lipid moieties.

[0155] Some embodiments relate to a method of making an oligonucleotide comprising a hydrophobic conjugate. A strategy for making hydrophobic conjugates may include use of a phosphoramidite reagent based upon a 6-membered ring alcohol such as a phenol or cyclohexanol. The phosphoramidite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, andthereby produce the hydrophobic conjugate. Some examples of phosphoramidite reagents that may be used to produce a hydrophobic conjugate are provided as follows:. n some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. Any one of the phosphoramidite reagents may be reacted to a 5’ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety. In some embodiments, the phosphoramidite reagents is reacted to a 5 ’ end of a sense strand of an siRNA. The sense strand may then be hybridized to an antisense strand to form a duplex. The hybridization may be performed by incubating the sense and antisense strands in solution at a given temperature. The temperature may be gradually reduced. The temperature may comprise or include a temperature comprising an annealing temperature for the sense and antisense strands. The temperature may be below or include a temperature below the annealing temperature for the sense and antisense strands. The temperature may be below a melting temperature of the sense and antisense strands.

[0156] The lipid may be atached to the oligonucleotide by a linker. The linker may include a polyethyleneglycol (e.g., tetraethyleneglycol).

[0157] The modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition. The modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue.2. Sugar moieties

[0158] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N-acetyl galactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylghicosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be atached at a 3’ or 5’ terminus of the oligonucleotide. The sugar moiety may include an N-acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N-acetyl glucose moiety. The sugar moiety may include N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages when they target or bind a mannose receptor such as CD206. The sugar moiety may be useful for binding or targeting an asialoglycoprotein receptor such as an asialoglycoprotein receptor of a hepatocyte. The GalNAc moiety may bind to an asialoglycoprotein receptor. The GalNAc moiety may target a hepatocyte.

[0159] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting. The GalNAc moiety may include a bivalent or trivalent branched linker. The oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be atached at a 3’ or 5’ terminus of the oligonucleotide.

[0160] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is atached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is atached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is atached to the sense strand (e.g., atached to a 5’ end of the sense strand, or atached to a 3’ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the GalNAc ligand is atached to the antisense strand (e.g., atached to a 5’ end of the antisense strand, or atached to a 3’ end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand atached at a 3’ or 5’ terminus of the oligonucleotide.

[0161] Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (I) or (II):or a salt thereof, whereinJ is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR6, or if z is 1, Y is C(R6)2;Q is selected from:C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, -S(O)R7, and C1-6 alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, - SH, -NO2, and -NH2;R1is a linker selected from:-O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-_ -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O- , -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O’)O-, -SP(O)(O’)O-, -OP(S)(O’)O-, -OP(O)(S’)O-, -OP(O)(O’ )S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, -OP(N(R7)2)O-, -OP(OR7)N(R7)-, and - OPN(R7)2NR7-; each R2is independently selected from:C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, - N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7;R3and R4are each independently selected from:-OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, - N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R5is independently selected from:-OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -N(R7)C(O)OR7, -C(O)R7, -C(O)OR7, and -C(O)N(R7)2; each R6is independently selected from: hydrogen; halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, - OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, - N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7; each R7is independently selected from: hydrogen; C1-6 alkyl, C2-6 alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O-C1-6 alkyl, -S- C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocycle, and 3- to 10-membered heterocycle; and C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -N02, -NH2, =0, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C1-6 alkyl, C2.& alkenyl, C2-6alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl.

[0162] In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, -C(O)N(R7)2, - N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, and -S(O)R7. In some embodiments, Q is selected from C5-6 carbocycle optionally substituted with one or moresubstituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, - OP(O)(OR7)S-, -OP(O)(O’)O-, -SP(O)(O’)O-, -OP(S)(O’)O-, -OP(O)(S’)O-, -OP(O)(O’)S-, - OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, -OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2. NR7. In some embodiments, R1is selected from -OP(O)(OR7)O-, -SP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O’)O-, -OP(S)(O’)O-, -OP(O)(S’)O-, -OP(O)(O’ )S-, and -OP(OR7)O-. In some embodiments, R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, - OP(O)(O')O-, -OP(S)(O')O-, -OP(O)(S')O-, and -OP(OR7)O-. In some embodiments, R1is selected from -OP(O)(OR7)O- and -OP(OR7)O-. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR7, -OC(O)R7, -SR7, -N(R7)2, -C(O)R7, and -S(O)R7. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7, -OC(O)R7, -SR7, and -N(R7)2. In some embodiments, R2is selected from C1-3 alkyl substituted with one or more substituents independently selected from -OR7and -OC(O)R7. In some embodiments, R3is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, - OC(O)R7, and -S(O)R7.In some embodiments, R3is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2. In some embodiments, R3is selected from -OR7- and -OC(O)R7. In some embodiments, R4is selected from halogen, -OR7, -SR7, -N(R7)2, -C(O)R7, -OC(O)R7, and -S(O)R7.In some embodiments, R4is selected from -OR7-SR7, -OC(O)R7, and -N(R7)2.In some embodiments, R4is selected from -OR7- and - OC(O)R7. In some embodiments, R5is selected from -OC(O)R7, -OC(O)N(R7)2, -N(R7)C(O)R7, - N(R7)C(O)N(R7)2, and -N(R7)C(O)OR7. In some embodiments, R5is selected from -OC(O)R7and - N(R7)C(O)R7. In some embodiments, each R7is independently selected from: hydrogen; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, - SH, -NO2, -NH2, =0, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocycle, or 3- to 10-membered heterocycle. In some embodiments, each R7is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, - SH, -NO2, -NH2, =0, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, and -NH(C1-6 alkyl). In some embodiments, each R7is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH. In some embodiments, w is 1 ; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, and Ci- 3 alkyl; R1is selected from -OP(O)(OR7)O-, -OP(S)(OR7)O-, -0P(0)(0’)0-, -OP(S)(O’)O-, -OP(O)(S’)O- , and -OP(OR7)O-; R2is Ci alkyl substituted with -OH or -OC(O)CH3;some embodiments, thesome embodiments, the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified intemucleoside linkages. In some embodiments, the one or more modified intemucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate,phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified intemucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets a hepatocyte.

[0163] Some embodiments include the following, where J is the oligonucleotide:include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0164] Some embodiments include the following, where J is the oligonucleotide:. J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

[0165] Some embodiments include the following, where J is the oligonucleotide:may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or morephosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0166] Some embodiments include the following, where J is the oligonucleotide:. The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0167] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[0168] Some embodiments include the following, where the phosphate or “5”’ indicates a connection to the oligonucleotide:

[0169] Some embodiments include the following, where J is the oligonucleotide:include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

[0170] Some embodiments include the following, where J is the oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include aphosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g., oligonucleotide) represented by Formula (III), (IV), or (V):Formula V, or a salt thereof, whereinJ is an oligonucleotide; each w is independently selected from any value from 0 to 20; v is independently selected from any value from 0 to 20; each n is selected from any value from 0 to 20; each m is selected from any value from 0 to 20; each p is selected from any value from 0 to 1 ; each w is selected from any value from 0 to 20; t is selected from any value from 0 to 1 ; x is selected from any value from 0 to 1; r is selected from any value from 0 to 20; u is selected from any value from 0 to 20;Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR7, -SR7, -N(R7)2, -C(O)R7, - C(O)N(R7)2, -N(R7)C(O)R7, -N(R7)C(O)N(R7)2, -OC(O)N(R7)2, -N(R7)C(O)OR7, -C(O)OR7, -OC(O)R7, - S(O)R7, and C1-6 alkyl, wherein the C1-6 alkyl, is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2;R1is a linker selected from: -O-, -S-, -N(R7)-, -C(O)-, -C(O)N(R7)-, -N(R7)C(O)-_ -N(R7)C(O)N(R7)-, -OC(O)N(R7)-, -N(R7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR7)O-, - SP(O)(OR7)O-, -OP(S)(OR7)O-, -OP(O)(SR7)O-, -OP(O)(OR7)S-, -OP(O)(O )O-, -SP(O)(O’)O-, -OP(S)(O’)O-, -OP(O)(S’)O-, -OP(O)(O’)S-, -OP(O)(OR7)NR7-, -OP(O)(N(R7)2)NR7-, -OP(OR7)O-, - OP(N(R7)2)O-, -OP(OR7)N(R7)-, and -OPN(R7)2NR7-; each R7is independently selected from: hydrogen, C1-6 alkyl, C2-6 alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O- C1-6 alkyl, -S- C1-6 alkyl, -N(C1-6 alkyl)2, -NH( C1-6 alkyl), C3-10 carbocycle, and 3- to 10-membered heterocycle, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N( C1-6 alkyl)2, -NH(C1-6 alkyl), C1-6 alkyl, C2.& alkenyl, C2-6alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, and C1-6 haloalkyl.

[0171] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0172] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “L96,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0173] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0174] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “NAG37,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0175] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0176] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GluGalNAc,” and is an example of a GalNAc moiety. J in some instances comprises oneor more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0177] Provided herein are sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides:

[0178] The structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide. In some instances, 2-4 GalNAc moieties are attached to theoligonucleotide. The placement of the GalNAc moieties in some instances is at the 3 or 5’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K may in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0179] Provided herein are sugar moieties comprising the following structure, where R is an oligonucleotide:

[0180] The structure in this compound attached to the oligonucleotide (R) in some instances is referred to as Hl, H2, H3, H4, H5, H6, H7, or H9, and are examples of GalNAc moieties. R in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. R in some instances comprises one or more phosphates linking to the oligonucleotide. R in some instances comprises a phosphate linking to the oligonucleotide. R in some instances comprises one or more phosphorothioates linking to the oligonucleotide. R in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0181] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) may be referred to as “K2 GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0182] Provided herein are sugar moieties comprising the following structure, where J is anThe structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0183] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0184] Provided herein are sugar moieties comprising the following structure, where J or K comprises an oligonucleotide:

[0185] The structures in these compounds in some instances are attached to the oligonucleotide (J or K), referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties. In some instances, 2-4 GalNAc moieties are attached oligonucleotide. The placement of the GalNAc moieties may be at the 3 or 5 ’ ends (J or K = H) or internal (J and K are oligonucleotides) of the oligonucleotide strand. J and K in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J and K in some instances comprises one or more phosphates linking to the oligonucleotide. J and K in some instances comprises a phosphate linking to the oligonucleotide. J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0186] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0187] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “THA,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0188] Provided herein are sugar moieties comprising the following structure, where Nu is an oligonucleotide:

[0189] The structure in this compound attached to the oligonucleotide (Nu) in some instances is referred to as “L-9” and is an example of a GalNAc moiety. Nu in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. Nu in some instances comprises one or more phosphates linking to the oligonucleotide. Nu in some instances comprises a phosphate linking to the oligonucleotide. Nu in some instances comprises one or more phosphorothioates linking to the oligonucleotide. Nu in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0190] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0191] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Sirius GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0192] Provided herein are sugar moieties comprising the following structures, where J is an oligonucleotide:

[0193] The structures in this compound attached to the oligonucleotide (J) in some instances are referred to as GLS-5 and GLS-15 and are examples of GalNAc moieties. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0194] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0195] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Olix GalNAc,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0196] Provided herein are sugar moieties comprising the following structure, where J and J’ is an oligonucleotide or a GalNAc moiety:

[0197] The structure in this compound attached to the oligonucleotide or a GalNAc moiety (J or J’) in some instances is referred to as “GalNAc Gib,” and is an example of a GalNAc moiety. J or J’ in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphates linking to the oligonucleotide. J or J’ in some instances comprises a phosphate linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0198] Provided herein are sugar moieties comprising the following structure, where B is a nucleic acid base, and J and J’ is an oligonucleotide or a GalNAc moiety:

[0199] The structure in this compound attached to the oligonucleotide or a GalNAc moiety (J or J’) in some instances is referred to as “lgT3,” and is an example of a GalNAc moiety. J or J’ in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphates linking to the oligonucleotide. J or J’ in some instances comprises a phosphate linking to the oligonucleotide. J or J’ in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J or J’ in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0200] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide and X is an optional linker:

[0201] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “5gn2c6,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide. X is a carbon or heteroatom linker to J. In some instances, the heteroatom in linker X is an N or O.

[0202] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0203] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “[Gal-6]s[Gal-6]s[Gal-6],” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

[0204] Provided herein are sugar moieties comprising the following structure, where J is an oligonucleotide:

[0205] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Janssen,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.

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

[0207] The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Arbutus,” and is an example of a GalNAc moiety. J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide. J in some instances comprises one or more phosphates linking to the oligonucleotide. J in some instances comprises a phosphate linking to the oligonucleotide. J in some instances comprises one or more phosphorothioates linking to the oligonucleotide. J in some instances comprises a phosphorothioate linking to the oligonucleotide.3. siRNA modification patterns

[0208] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of target nucleic acid, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern IS: 5’- NfsnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3. In some embodiments, the sense strand comprises modification pattern 2S: 5’-nsnsnnNfnNfNfNfnnrmrmrmnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 3S: 5’-nsnsnnNfnNfnNfrmnrmrmrmnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 4S: 5’-NfsnsNfiiNfiiNININfiiNfnNfnNfiiNfiiNfsnsnN-moiety-3’. In some embodiments, the sense strand comprises modification pattern 5S: 5’-nsnsnnNfiiNfNfNfimnnnnnnnnsnsnN-moiety-3’. In some embodiments, the moiety in modification pattern 4S or 5S is a lipophilic moiety. In some embodiments, the moiety in modification pattern 4S or 5S is a lipid moiety. In some embodiments, the sense strand comprises modification pattern 6S: 5’-NfsnsNfiiNfiiNfiiNfiiNfiiNfiiNfiiNfiiNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 7S: 5’- nsnsnnNfNINfNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 8S: 5’-nsnsnnnNININfNfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 9S: 5’-nsnsnnnnNININfNfimnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 10S: 5’-NfsnsnnNfiiNfiiNfiiNfiiNfiiNfiiNfnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 11 S: 5’- nsnsNfiiNfiiNfiiNfiiNfiiNfimnNfiiNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 12S: 5’-NfsnsNfiiNfiiNfiiNfiiNfimnNfiiNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 13 S: 5’-nsnsnnnnNfiiNfiiNfiiNfiiNfiiNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 14S: 5’- snnnnnnNfNfNINfiinnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 15 S: 5’-snnnnNININININfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 16S: 5’-snnnnNfiiNfNfdNnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 17S: 5’-snnnnnNINfiiNfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 18S: 5’-snnnnnnNfiiNfNfimnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 19S: 5’- snnnnNfiiNfiiNfiiNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 20S: 5’-snnnnNfiiNfiiNfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 2 IS: 5’-snnnnNINfimNfNfimnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 22S: 5’-snnnnNfimNININfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 23S: 5’-snnnnnNfiiNfNfimnnnnnnnnsnsn- 3’. In some embodiments, the sense strand comprises modification pattern 24S: 5’- snnnnnnnNfNINfNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 25 S: 5’-snnnnnNININININfimnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 26S: 5’-snnnnnNINININfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 27S: 5’-snnnnnnnNINfiiNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 28S: 5’- snnnnNINfiiNfNfiiNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 29S: 5’-snnnnnnnnNfiiNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 3 OS: 5’-snnnnNINfimNfiiNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 3 IS: 5’-snnnnNINfiiNINfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 32S: 5’-snnnnnnNfNfdNNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 33S: 5'-snnnnNfiiNfiiNfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 34S: 5'-snnnnNfiiNINfdNNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35S: 5'-snnnnnnNINININfiiNfiinnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 36S: 5'- snnnnnNINININfiiNfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 37S: 5'-snnnnNfiiNINfdTNfiinnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 38S: 5'-snnnnNfiiNINfNfimnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 39S: 5'-snnnnNfiiNINfdTnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 40S: 5'- snnnnNfiiNINfdNnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 4 IS: 5’-snnnnnnnnNfNfimnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 42S: 5'-snnnnNfiiNINfdTnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 43S: 5'-snnnnnnNfiiNfiiNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 44S: 5'- snnnnNfiiNINININfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 45S: 5'-snnnnnNfimNINfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 46S: 5'-snnnnnnNINININfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 47S: 5'-snnnnnNINfiiNfiiNfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 48S: 5'- nnNfiiNfiiNfiiNfiiNfiiNfimnNfiiNfsnsn-3'. In some embodiments, the sense strand comprises modification pattern 49S: 5'-NfiiNfiiNfiiNININfiiNfiiNfnNfnNfnNfsnsn-3'. In some embodiments, the sense strand comprises modification pattern 50S: 5'-nnnnnNINININfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 5 IS: 5'- nnnnNINININfNfimnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 52S: 5'-snnnnmnNINININfimnnnnmnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 53S: 5'-snnnnmnNININfNfimnnnmnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 54S: 5'-snnnnmnNINfNfNfimnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 55S: 5'- snnnnmnNINININfimnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 56S: 5'-snnnnnmNININfNfimnmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 57S: 5'-snnnnnmNININfNfimnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 58S: 5'-nnnnmnNININfNfimnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 59S: 5'- snsnnnnNINININfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 60S: 5'-snnnnmnnNININfNfimnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 61S: 5'-snnnnmNfiiNINININfimnmnnnnnnsnsn-3'. In someembodiments, the sense strand comprises modification pattern 62S: 5'- snnnnmnNfNfNfNfnnnnmnnnninsnsn-3'. In some embodiments, the sense strand comprises modification pattern 63S: 5'-snnnnmnNfNfNfNfimnnmnninnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 64S: 5'-nnnnmnnNININfNfimnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 65S: 5'-nsnsnnmnN(C16)NININfimnnmnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 66S: 5'- nnnnnnnnNfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 67S: 5'-nnnnNfiiNINfdNNfiinnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 68S: 5'-nnnnnnnNINfiiNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 69S: 5'-nnnnnNfimNfiiNfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 70S: 5'-nnnnnNfiiNfNfimnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 71 S: 5'-nnnnnNfiiNINfiiNfnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 72S: 5'- nnnnnnNfiiNfNfnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 73S: 5'-nnnnNfiiNfiiNfimnnnnnnnnsnsn-3. In some embodiments, the sense strand comprises modification pattern 74S: 5'-nnnnNINfimNfimnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 75S: 5'-nnnnNfimnNfiiNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 76S: 5'-nnnnNINfimNfiiNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 77S: 5'-nnnnnnNfiiNfiiNfiinnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 78S: 5'- nnnnnNINfiiNfiiNfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 79S: 5'-nnnnnNININfNfimnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 80S: 5'-nnnnnNINININfiiNfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 81 S: 5'-nnnnNfimNfNfimnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 82S: 5'-nnnnNfimNINfiiNfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 83 S: 5'-nnnnNfiiNfiiNfiiNfnnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 84S: 5'- nnnnNINfiiNINfimnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 85S: 5'-nnnnNINfiiNINfiiNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 86S: 5'-nnnnnnnNININfNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 87S: 5'-nnnnnnNININfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 88S: 5'-nnnnnnNININININfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 89S: 5'-nnnnnNfimNfNfiinnnnnnnnsnsn- 3'. In some embodiments, the sense strand comprises modification pattern 90S: 5'- nnnnnNfiiNININfNfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 91 S: 5'-nnnnnNINfiiNfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 92S: 5'-nnnnNfimnNfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strandcomprises modification pattern 93S: 5'-nnnnNfimNfNfNfNfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 94S: 5'-nnnnNfiiNfiiNfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 95S: 5'- nnnnNfiiNINININfiinnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 96S: 5'-nnnnNINfimNINfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 97S: 5'-nnnnnnnNINfimnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 98S: 5'-nnnnNfiiNINfdNnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 99S: 5'-nnnnnnnnNfiiNfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 100S: 5'- nnnnNfiiNfNfdTnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 101 S: 5'-nnnnNfiiNINfdNnNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 102S: 5'-nnnnNfiiNfNfdTnnnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 103S: 5'-snnnnnNfiiNINfiiNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 104S: 5'- snnnnNINfimNfimnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 105S: 5'-snnnnNfimNINfiiNfnnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 106S: 5'-snnnnNfimNfNfimnnnnnnnnsnsnm-3'. In some embodiments, the sense strand comprises modification pattern 107S: 5'-snnnnNfimnNfNfimnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 108S: 5’- snNfiiNfiiNfiiNfNfimnnnNfiiNfNfnsnsn-3’.. In some embodiments, the sense strand comprises modification pattern 109S: 5’-snnnnnmNININfNfimnnnmnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 110S: 5'-nnnnnNINfiiNfimnnnnnnnnsnsn-3' In some embodiments, the sense strand comprises modification pattern 11 IS: 5’- NfsnNfiiNfiiNfiiNfiiNfiiNfiiNfiiNfnNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 112S: 5’-NfiiNfiiNfiiNfiiNfiiNfiiNfiiNfiiNfiiNfsnsn-3’. In some embodiments, the sense strand comprises modification pattern 113S: 5’-nnnnnnNfiiNfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 114S: 5’- snnnnmnNfNfNfNfnnmnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 115S: 5’-nNfiiNfiiNfiiNINfimnnnNfiiNfNfnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 116S: 5’-snnnnnNfimNfiiNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 117S: 5’- snnnnnNINfNfdNnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 118S: 5’-snnnnNfimNINfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 119S: 5’-snnnnNfimnNfiiNfnnnnnnnnsnsn-3’.In some embodiments, the sense strand comprises modification pattern 120S: 5’-snnnnnNINfiiNfNfimnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 121 S: 5’- nsnsnnnnNfiiNfiiNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modificationpattern 122S: 5’-nsnsnnnNfnnNfnNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 123S: 5’-nsnsnnnNfNfiiNfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 124S: 5’-nsnsnnnNINfiiNfiiNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 125S: 5’- nsnsnnNfimnNfiiNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 126S: 5’-nsnsnnNfiiNfiiNfiiNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 127S: 5’-nsnsnnNINfimNfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 128S: 5’-nsnsnnnnnnNINfiinnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 129S: 5’- nsnsnnnnnNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 130S: 5’-nsnsnnnNfimNfNfimnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 13 IS: 5’-nsnsnnNfimnNfNfimnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 132S: 5’-nsnsnnNINfimNfNfimnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 133S: 5’- nsnsnnnnnNfNfiiNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 134S: 5’-nsnsnnnNfiiNfNfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 135S: 5’-nsnsnnnNfiiNINfiiNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 136S: 5’-nsnsnnnNINININfiiNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 137S: 5’- nsnsnnNfimNfNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 138S: 5’-nsnsnnNfimNfNfiiNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 139S: 5’-nsnsnnNfNfimNfiiNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern MOS: 5’-nsnsnnNINfiiNINfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 141 S: 5’- nsnsnnnnNfiiNfnnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 142S: 5’-nsnsnnnNfimNfimnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 143S: 5’-nsnsnnnnnNININfNfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 144S: 5’-nsnsnnnnNfiiNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 145S: 5’- nsnsnnnnNINfNfNfNfnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 146S: 5’-nsnsnnnNfiiNINININfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 147S: 5’-nsnsnnnNINININfNfimnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 148S: 5’-nsnsnnNfimNINININfiinnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 149S: 5’- nsnsnnnNfNfiiNINfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 150S: 5’-nsnsnnNfiiNfiiNfNfnnnnnnnnnsnsn-3’. In some embodiments, the sense strand comprises modification pattern 15 IS: 5’-nsnsnnNfiiNININfNfimnnnnnnnsnsn-3’. In some embodiments,the sense strand comprises modification pattern 152S: 5'-snnnnnNfNfNfNfimnnnnmnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 153S: 5'- snnnnNfiidNnNfiiNfiinnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 154S: 5'-snnnnmNfiiNININfNfimmnnnnnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 155 S: 5'-snnnnmNfiiNINININfimnnmnnnnnsnsn-3'. In all the above modification pattern, wherever they occur, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “dN” is a 2 ’-deoxy -modified nucleoside or a 2’ -deoxy nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, “i” is an inosine, “ni” is a 2’-O-methyl inosine nucleoside, N(C16) is 2’-O-hexadecate modification and N comprises one or more nucleosides. In some modifications N(C16) is a 2'-O-hexadecyl adenylate.

[0209] In some embodiments, the composition comprises an oligonucleotide that inhibits or reduces the expression of PLG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern IAS: 5’- nsNfsnNfiiNfiiNfiiNfimnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 2 AS: 5’-nsNfsnnnNfiiNfNfimnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 3AS: 5’-nsNfsnnnNfimnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 4 AS: 5’- nsNfsnNfiiNfimnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 5AS: 5’-nsNfsnnnnnnnnnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 6 AS: 5’-nsNfsnnnNfimNfimnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 7AS: 5’- nsNfsnNfiiNfiiNfiiNfiiNfiiNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 8 AS: 5’-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 9AS: 5’-nsNfsnnnNfiiNfimnnnNfnNfnnnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 10AS: 5’- nsNfsnNfsnNfiiNfiiNfiiNfiiNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern HAS: 5'-nsNfsnnnNfiiNfiiNfimnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 12AS: 5'-nsNfsnnnNfiiNfiiNfiiNfiiNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 13AS: 5'- nsNfsnnNfiiNfimNfiiNfiiNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 14AS: 5'-nsNfsnnNfiiNfiiNfimnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 15AS: 5'-nsNfsnNfimNfiiNfimnnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 16AS: 5'- nsNfsnnnNfiiNfimnNfiiNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 17AS: 5'-nsNfsnNfimNfimNfiiNfiiNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 18AS: 5'-nsNfsnNfimNfimNfimnNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 19AS: 5'-nsNfsnnnnNfnnNfnNfnNfnNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 20AS: 5'-nsNfsnnnnNfiiNfimNfiiNfiiNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 2 IAS: 5'-nsNfsnnnnNfiiNfimnnNfiiNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 22AS: 5'- nsNfsnNfiiNfiiNfimnnnNfiiNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 23 AS: 5 WPnsNfsnnnNfiiNfimnnnNfiiNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 24 AS: 5'-VPnsNfsnNfiiNfiiNfiiNfiiNfiiNfiiNfiiNfiisnsn- 3'. In some embodiments, the sense strand comprises modification pattern 25AS: 5'- VPnsNfsnnnNfiiNfiiNfiiNfiiNfiiNfiiNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 26AS: 5 WPnsNfsnnNfiiNfimNfiiNfiiNfiiNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 27AS: 5'-VPnsNfsnNfimNfiiNfimnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 28AS: 5'- nsNfsnnNfiiNfimNfimnNfiiNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 29AS: 5'-nsNfsnnNfiiNfimNfimnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 30AS: 5'-nsNfsnnnNfiiNfiiNfiiNfiiNfiiNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 3 IAS: 5'- nsNfsnnNfiiNfimNfiiNfiiNfiiNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 32AS: 5'-nsNfsnnnNINfimNfiiNfiiNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 33AS: 5'-nsNfsnnNfiiNINfiiNfimnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 34AS: 5'- nsNfsnnNfiiNINfimnNfiiNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 35AS: 5'-nsNfsnnnNINfimNfimnNfnNfiinnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 36AS: 5'-nsNfsnnnnNINfiiNfimnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 37AS: 5'- nsNfsnnNfii[NUNA]nnNfimnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 38AS: 5'-nsNfsnnNf[NUNA]NfimNfimnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 39AS: 5'-5VPnsNfsnnNfiiNfimNfimnNfnNfnnnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 40 AS: 5'- 5VPnsNfsnnNfiiNfimNfiiNfiiNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 41AS: 5'-nnnNfiiNfiiNfiiNfiiNfiiNfiiNfiiNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 42AS: 5'-nsNfsnnnNfiiNfiiNfimnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 43 AS: 5'- nsNfsnnnNINfimNfiiNfiiNfiiNfiiNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 44AS: 5'-nsNfsnnnNfimnNfimnNfiiNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 45 AS: 5'-nsNfsnnnNINfimNfimnNfiiNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 46AS: 5'- nsNfsnnnnNfimNfimnNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprisesmodification pattern 47AS: 5'-nsNfsnnnnNfNfiiNfiiNfiiNfiiNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 48AS: 5'-nsNfsnnNfiiNfNfiiNfiiNfiiNfiiNfiiNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 49 AS: 5'- nsNfsnnNfiiNINfimnNfiiNfiiNfiiNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 50AS: 5'-nsNfsnnNfiiNfiiNfimNfiiNfiiNfnNfnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 5 IAS: 5'-nsNfsnNfiiNfiiNfiiNfiiNfiiNfiiNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 52AS: 5'- nsNfsnNfiiNf[UNA]NfiiNfiiNfiiNfiiNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 53AS: 5'-nsNfsnnnnNINfiiNfiiNfiiNfiiNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 54AS: 5'-nsNfsnnnnNINfimnNfiiNfnNfiinnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 55AS: 5'- nsNfsnnnn[UNA]NfimnNfiiNfnNfnnnsnsn-3'. In some embodiments, the antisense strand comprises modification pattern 56AS: 5’-nsnsnNfiiNfiiNfiiNfiiNfiiNfnNfnNfnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 57AS: 5’-nsNfsnNfimNfimNfiiNfiiNfnnnnnsnsn 3’. In some embodiments, the antisense strand comprises modification pattern 58AS: 5’-nsNfsnnnNfiiNfiiNfiiNfiiNfnnnnnsnsn 3’. In some embodiments, the antisense strand comprises modification pattern 59 AS: 5’-nsNfsnNfimNfimnnNfiiNfnNfnNfnsnsn 3’. In some embodiments, the sense strand comprises modification pattern 60 AS: 5'-nsNfsnNfiiNfimNfimnnNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 6 IAS: 5'- nsNfsnNfiiNfimNfiiNfimNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 62AS: 5'-nsNfsnNfimNfiiNfiiNfimNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 63 AS: 5'-nsNfsnnNfiiNfiiNfiiNfimNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 64AS: 5'- nsNfsnNfiiNfiiNfimnNfiiNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 65AS: 5'-nsNfsnNfimnNfiiNfiiNfiiNfnNfnNfnsnsn-3'.In some embodiments, the sense strand comprises modification pattern 66AS: 5'-nsNfsnNfimNfiiNfimNfiiNfnNfnNfnsnsn-3'. In some embodiments, the sense strand comprises modification pattern 67AS: 5'- nsNfsnnnNfimnNfiiNfnNfiiNfiiNfnsnsn-3'.In some embodiments, the antisense strand comprises modification pattern 68AS: 5'-nsNfsnnNfiiNfiiNfimnnNfnNfiinnsnsn-3’. In some embodiments, the antisense strand comprises modification pattern 69 AS: 5'-nsNfsnnn[NUNA]nNfiiNfimnNfnNfnnnsnsn- 3’. In all the above modification pattern, wherever they occur, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, “dN” is a 2’- deoxy -modified nucleoside or a 2’-deoxy nucleoside, “nm” is a 2’-O-methoxyethyl modified nucleoside, “i” is an inosine, “ni” is a 2’-O-methyl inosine nucleoside, N(C16) is 2’-O-hexadecate modification, VP is a 5'-vinyl phosphonate, “[NUNA]” is an unlocked nucleic acid, “[UNA]” is an unlocked nucleic acid and N comprises one or more nucleosides. In some modifications N(C16) is a 2'-O-hexadecyl adenylate.

[0210] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of PLG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern IS and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 5OAs, 5 IAS, 52AS, 53AS, 54AS 55 AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61 AS, 62AS, 63 AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 5OAs, 5 IAS, 52AS, 53 AS, 54AS 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, 69AS, 70AS, 71AS, or 72AS. In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 5S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 6 IAS, 62AS, 63 AS, 64AS, 65 AS, 66 AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 6S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 7S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS.14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 9S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern IOS and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 11 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55 AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 12S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 13S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or69 AS. In some embodiments, the sense strand comprises pattern 14S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 2 IAS, 22AS, 23 AS, 24 AS, 25 AS, 26 AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55 AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 15S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35 AS, 36AS, 37AS, 38AS, 39AS, 40 AS, 41 AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 16S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40 AS, 41 AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 6 IAS, 62AS, 63 AS, 64 AS, 65 AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 17S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 18S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55 AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 19S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55 AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61 AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 20S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS,42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55 AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 21S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 22S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 23 S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 2 IAS, 22AS, 23 AS, 24 AS, 25 AS, 26 AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55 AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 24S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40 AS, 41 AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 25S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40 AS, 41 AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 6 IAS, 62AS, 63 AS, 64 AS, 65 AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 26S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 27S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS.14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55 AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 28S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 29S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55 AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 30S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 51AS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 31S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65 AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 32S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55 AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 33 S and the antisense strand comprises pattern IAS, 2AS, 3 AS, 4AS, 5 AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40 AS, 41 AS, 42As, 43 AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63AS, 64AS, 65AS, 66AS, 67AS,68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 34S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41AS, 42As, 43AS, 44AS, 45 AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53 AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69AS. In some embodiments, the sense strand comprises pattern 35S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, I3AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21 AS, 22AS, 23 AS, 24AS, 25 AS, 26AS, 27AS, 28AS, 29 AS, 30AS, 3 IAS, 32AS, 33 AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, 41 AS, 42As, 43 AS, 44AS, 45AS, 46AS, 47AS, 48AS, 49 AS, 50AS, 5 IAS, 52AS, 53AS, 54AS, 55AS, 56AS, 57AS, 58AS, 59AS, 60AS, 61AS, 62AS, 63 AS, 64AS, 65AS, 66AS, 67AS, 68AS, or 69 AS. In some embodiments, the sense strand comprises pattern 36S and the antisense strand comprises pattern IAS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, HAS, 12AS, 13 AS. 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23 AS...

Claims

CLAIMSWhat is claimed is:

1. A composition comprising a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the antisense strand is complementary to at least 10 contiguous nucleotides of MTRES1 ENST00000625458 mRNA.

2. The composition of claim 1, wherein the antisense strand is complementary to at least 15 contiguous nucleotides of MTRES1 ENST00000625458 mRNA.

3. The composition of claim 1, wherein the selectivity for binding of ENST00000625458 compared to binding of ENST00000311381 or ENST00000405204 is at least 2:1, 5:1, 10:1, 100:1, 1000:1, or at least 10,000:1.

4. The composition of claim 1, wherein the antisense strand is not complementary to MTRES1 ENST00000311381 or ENST00000405204 mRNA.

5. The composition of claim 1, wherein the sense strand comprises no more than 50% identity with MTRES1 ENST00000311381 or ENST00000405204 mRNA.

6. The composition of claim 1, wherein the sense strand comprises no more than 30% identity with MTRES1 ENST00000311381 or ENST00000405204 mRNA.

7. The composition of claim 1, wherein the sense strand comprises no more than 10% identity with MTRES1 ENST00000311381 or ENST00000405204 mRNA.

8. The composition of claim 1, wherein the siRNA is selective for the downregulation of MTRES1 ENST00000625458 mRNA.

9. 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: 1-618.

10. The composition of any one of claims 1-9, wherein the oligonucleotide comprises a modified internucleoside linkage.

11. The composition of claim 10, wherein the modified intemucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.

12. The composition of claim 10, wherein the modified intemucleoside linkage comprises one or more phosphorothioate linkages.

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, or 20 modified intemucleoside linkages.

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

15. The composition of claim 14, wherein 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, 2'-deoxy, or 2’-O-methyl inosine, or a combination thereof.

16. The composition of claim 15, wherein the modified nucleoside comprises an LNA.

17. The composition of claim 15, wherein the modified nucleoside comprises a 2 ’,4’ constrained ethyl nucleic acid.

18. The composition of claim 15, 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'-0-DMAE0E) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof.

19. The composition of claim 15, wherein the modified nucleoside comprises one or more 2’- fluoro modified nucleosides.

20. The composition of claim 15, wherein the modified nucleoside comprises a 2'-O-alkyl modified nucleoside.

21. 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.

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

23. The composition of claim 22, 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, dimethoxy trityl, or phenoxazine.

24. The composition of claim 22, wherein the lipophilic moiety comprises a C4-C30 hydrocarbon chain.

25. The composition of claim 22, wherein the lipophilic moiety comprises a lipid.

26. The composition of claim 25, wherein the lipid comprises myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, a-tocopherol, or a combination thereof.

27. 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.

28. The composition of claim 27, wherein the sense strand is 12-30 nucleosides in length.

29. The composition of claim 27, wherein the antisense strand is 12-30 nucleosides in length.

30. 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 theantisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NOS: 1-618.

31. The composition of claim 30, 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’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2 ’-fluoro modified purines, and all pyrimidines comprise 2’-O- methyl modified pyrimidines; all pyrimidines comprise 2’ -fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise 2’-O- methyl modified purines.

32. The composition of claim 30, 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-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’- fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines;(b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (i) 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-methoxy ethyl 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.

33. The composition of claim 30, 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’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’- fluoro modified pyrimidines; all pyrimidines comprise 2’ -fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2 ’-fluoro and 2’-O-methyl modified purines; or all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise 2’-fluoro modified purines.

34. The composition of claim 30, wherein the oligonucleotide comprises a phosphate at the 5 ’ end of the antisense strand.

35. The composition of claim 30, wherein the oligonucleotide comprises a phosphate mimic at the 5’ end of the antisense strand.

36. The composition of claim 30, wherein the phosphate mimic comprises a 5'-vinyl phosphonate (VP).

37. The composition of claim 30, wherein the 3’ nucleoside of the sense strand is modified to an A, wherein the 5 ’ nucleoside of the antisense strand is modified to a U.

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

39. The composition of claim 38, wherein the ASO is 12-30 nucleosides in length.

40. A composition comprising: a small interfering RNA (siRNA) comprising a sense strand, an antisense strand complementary to a section of an MTRES1 ENST00000625458 mRNA, and a lipid moiety connected to an end of the sense or antisense strand; 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.

41. 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.

42. The composition of claim 40 or 41, 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.

43. The composition of any one of claims 40-42, 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.

44. The composition of any one of claims 40-42, 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.

45. The composition of any one of claims 40-42, 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.

46. The composition of any one of claims 40-42, 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.

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

48. 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 comprises any one of SEQ ID NOs: 619-670, 723-774, or 847-855, or the antisense strand comprises any one of SEQ ID NOs: 671-722, 775-826, or 856-864.

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

50. The composition of claim 49, wherein the composition is formulated for administration to a central nervous system.

51. The composition of claim 49 or 50, wherein the composition is formulated for delivery to a neural cell.

52. 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 1-51 to the subject.

53. The method of claim 52, wherein the composition is administered systemically.

54. The method of claim 52, wherein the composition is administered intrathecally.

55. 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- 51 to the subject.

56. The method of any one of claims 52-55, wherein the subject has a genotype at risk for developing Alzheimer’s disease or dementia.

57. The method of claim 56, wherein the subject is a heterozygous or homozygous carrier of APOE4.

58. The method of claim 56, wherein the subject is a heterozygous or homozygous carrier of MTRES1 rsll7058816-G (C.3+1G).

59. The method of any one of claims 55-58, wherein evaluating a subject’s risk for developing a neurological disorder comprises calculating a polygenic risk score for developing Alzheimer’s disease or dementia.

60. The method of claim 59, 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.

61. The method of claim 59, 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.

62. The method of claim 59, 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.

63. A composition comprising an siRNA that specifically targets and selectively downregulates a first MTRES1 mRNA transcript compared to a second MTRES1 mRNA transcript.

64. The composition of claim 63, wherein the siRNA specifically binds to a nucleotide sequence of thefirst MTRES1 mRNA transcript that is absent in the second MTRES1 mRNA transcript.

65. The composition of claim 63, wherein the first MTRES1 mRNA transcript is ENST00000625458.

66. The composition of claim 63, wherein the second MTRES1 mRNA transcript is ENST00000311381 or ENST00000405204.

67. The composition of claim 63, wherein the siRNA downregulates the expression of the ENST00000625458 mRNA by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or at least 100% more than the downregulation of expression of the ENST00000311381 or ENST00000405204 mRNA.

68. 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 63-67 to the subject.

69. The method of claim 68, wherein the composition is administered systemically.

70. The method of claim 68, wherein the composition is administered intrathecally.

71. 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 63- 67 to the subject.

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