Methods and compositions for treating metabolic diseases

Abstract

Methods and compositions for treating metabolic diseases are provided herein. In certain aspects, the method includes decreasing, in the cells, the activity of one or more of the TFs presented herein. In certain aspects, the method includes decreasing the activity of one or more of the TFs presented herein using an siRNA targeting the TF.

Description

METHODS AND COMPOSITIONS FOR TREATING METABOLIC DISEASESCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 570,599, filed on March 27, 2024, and U.S. Provisional Application No. 63 / 724,632, filed on November 25, 2024, each of which is incorporated herein by reference in their entireties.BACKGROUND

[0002] Obesity is a significant glob al health challenge that affects millions of people worldwide. It is characterized by excessive fat accumulation that poses a risk to health not only as a condition in and of itself but as a key risk factor for other serious health concerns. Obesity significantly increases the risk of developing Type II diabetes, cardiovascular diseases, hypertension, and some cancers. Therefore, there is a need for interventions targeting obesity.SUMMARY

[0003] Provided herein is a composition comprising an siRNA targeting an ^TFJ pathway, wherein the siRNA comprises (a) a sense strand having a sequence with at least 80% sequence identity to any one sense strand sequence presentedin Tables 1 -6 or 16; (b) an antisense strand having a sequence with at least 80% sequence identity to any one antisense strand sequence presented in Tables 1 -6 or 16. In some embodiments, the siRNA comprises an antisense strand comprising a region of complementarity of at least 8 nucleosides to an ATF3 RNA sequence set forth in any one of SEQ ID NOs: 2148, 17, and 22, and a sense strand that is at least substantially complementary to the antisense strand. In some embodiments, the sense strand is 15-35 nucleosides in length, and / or the antisense strand is 15-35 nucleosides in length. In some embodiments, the antisense strand and the sense strand hybridize to form a duplex region of 15-25 base pairs in length. In some embodiments, the antisense strand comprises a region of complementarity of at least 8 nucleobases to (a) an ATF3 RNA sequence as set forth in SEQ ID NO: 24, or (b) to the sense strand sequence of any one sense strand sequence presented in Tables 1 -6, or 16. In some embodiments, the antisense strand comprises a region of complementary 15-21 nucleobasesto (a) an ATF3 RNA sequence as set forth in SEQ ID NO: 24, or (b) to the sense strand sequence of any one sense strand sequence presented in Tables 1 -6, or 16. In some embodiments, the antisense strand comprises at least 8 consecutive nucleobases of the antisense strand of any one of the antisense strand sequence presented in Tables 1 -6, or 16. In some embodiments, the antisense strand comprises the nucleobase sequences of any one antisense strand sequence presented in Tables 1 -6, or 16. In some embodiments, wherein the sense strand comprises at least 8 consecutive nucleobases of any one sense strand sequence presented in Tables 1 -6, or 16. Insome embodiments, the sense strand comprises the nucleobase sequence of any one sense strand sequence presented in Tables 1 -6, or 16. In some embodiments, the antisense strand comprises at least 8 consecutive nucleobases of any one of SEQ ID NOs: 58 , 66, 68, 274, 356, 358, 370, 378, 380, 386, 392, 408, 414, 416, 444, 446, 478, 486, 488, 694, 776, 778, 790, 798, 800, 806, 812, 828, 834, 836, 864. In some embodiments, the antisense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 58, 66, 68, 274, 356, 358, 370, 378, 380, 386, 392, 408, 414, 416, 444, 446, 478, 486, 488, 694, 776, 778, 790, 798, 800, 806, 812, 828, 834, 836, 864. In some embodiments, the sense strand comprises least 8 consecutive nucleobases of any one of SEQ ID NOs: 57, 65, 67, 273, 355, 357, 369, 377, 379, 385, 391, 407, 413, 415, 443, 445, 477, 485, 487, 693, 775, 777, 789, 797, 799, 805, 811, 827, 833, 835, 863. In some embodiments, the sense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 57, 65, 67, 273, 355, 357, 369, 377, 379, 385, 391, 407, 413, 415, 443, 445, 477, 485, 487, 693, 775, 777, 789, 797, 799, 805, 811, 827, 833, 835, 863. In some embodiments, (a) the antisense strand comprises 15-23 consecutive nucleobases of any one of SEQ ID NOs: 274, 356, 378, 392, 414, 444, 446, 694,776, 798, 812, 834, 864, and (b)the sense strand comprises 15 -21 nucleobases of any one of SEQ ID NOs: 273, 355, 377, 391, 413, 443, 445, 693, 775, 797, 811, 833, and 863 . In some embodiments, the siRNA comprises the nucleobase sequence of any one of siRNA-23, siRNA- 27, siRNA-28, siRNA-131, siRNA-172, siRNA-173, siRNA-179, siRNA-183, siRNA-184, siRNA-187, siRNA-190, siRNA-198, siRNA-201, siRNA-202, siRNA-216, siRNA-217, siRNA- 233, siRNA-237, siRNA-238, siRNA-341, siRNA-382, siRNA-383, siRNA-389, siRNA-393, siRNA-394, siRNA-397, siRNA-400, siRNA-408, siRNA-411, siRNA-412, and siRNA-426. In some embodiments, the siRNA comprises the nucleobase sequence of any one of siRNA-131, siRNA- 172, siRNA-183, siRNA-190, siRNA-201, siRNA-202, siRNA-216, siRNA-217, siRNA-341, siRNA- 382, siRNA-393, siRNA-400, siRNA-411, and siRNA-426. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 273 and an antisense strand having a sequence of SEQ ID NO: 274; a sense strand having a sequence of SEQ ID NO: 355 and an antisense strand having a sequence of SEQ ID NO: 356; a sense strand having a sequence of SEQ ID NO: 377 and an antisense strand having a sequence of SEQ ID NO: 378; a sense strand having a sequence of SEQ ID NO: 391 and an antisense strand havinga sequence ofSEQ ID NO: 392; a sense strandhaving a sequence of SEQ ID NO: 413 and an antisense strand havinga sequence of SEQ ID NO: 414; a sense strand having a sequence of SEQ ID NO: 415 and an antisense strand having a sequence of SEQ ID NO: 416; a sense strand having a sequence of SEQ ID NO: 443 and an antisense strand having a sequence of SEQ ID NO: 444; a sense strand having a sequence of SEQ ID NO: 445 and an antisense strand having a sequence of SEQ ID NO: 446; a sense strand having a sequence of SEQ ID NO: 693 and an antisense strand having a sequence of SEQ ID NO: 694; a sense strand having a sequence ofSEQ ID NO: 775 and an antisense strand havinga sequence ofSEQ ID NO: 776; a sense strandhaving a sequence of SEQ ID NO: 797 and an antisense strand havinga sequence of SEQ ID NO: 798; a sense strand having a sequence of SEQ ID NO: 811 and an antisense strand having a sequence of SEQ ID NO: 812; a sense strand having a sequence of SEQ ID NO: 833 and an antisense strand having a sequence ofSEQ IDNO: 834; ora sense strand havinga sequence ofSEQ ID NO: 863 and an antisense strand having a sequence of SEQ ID NO: 864. In some embodiments, the siRNA comprises a sense strand comprising the nucleobase sequence of any one sense strand sequence presented in column 2 of Tables 2-6 or 16 and an antisense sense strand comprising the nucleobase sequence of the corresponding antisense strand sequence presented column4 of Table 2 -6 or 16. In some embodiments, the siRNA comprises one or more modified nucleosides. In some embodiments, each nucleoside of the antisense strand is a modified nucleoside and each nucleoside of the sense strand is a modified nucleoside. In some embodiments, the one or more modified nucleosides are 2’ modified nucleosides. In some embodiments, the 2 ’-modified nucleoside is selected from 2’-deoxyribonucleoside (DNA), 2 ’-fluoro (2’ -F), 2’-O-methyl (2’-0-Me), 2’-O-methoxyethyl (2’-M0E), 2’-O-aminopropyl (2’-O- AP), 2’-O-dimethylaminoethyl (2’-0-DMA0E), 2’-O-dimethylaminopropyl (2’-0-DMAP), 2’-O- dimethylaminoethyloxyethyl (2’-0-DMAE0E), or 2’-O-N-methylacetamido (2’-0-NMA) modified nucleoside and combinations thereof. In some embodiments, each nucleoside of the antisense strand is selected from a 2’-F modified nucleoside and a 2’-0-Me modified nucleoside, and each nucleoside of the sense strand is a 2’-modified nucleoside selected from a 2’-F modified nucleoside and a 2’-O- Me modified nucleoside. In some embodiments, the nucleosides at one or more positions 9, 10, and 11 (counting 5’ to 3’) of the sense strand are 2’-F modified nucleosides. In some embodiments, the nucleosides at positions 9, 10, and 11 (counting 5’ to 3’) of the sense strand are 2’ -F modified nucleosides. In some embodiments, the nucleoside at position 7 (counting 5’ to 3’) of the sense strand is a 2’-F modified nucleoside. In some embodiments, nucleosides at one or more positions 2, 6, 7, 8, 9, 14 and 16 (counting 5’ to 3’) of the antisense strand are 2’-F modified nucleosides, optionally wherein the nucleosides at positions 2 and 14 of the antisense strand are 2’ -F modified nucleosides. In some embodiments, the antisense strand further comprises one or more of 2’ -deoxy ribonucleosides (DNA), optionally wherein the nucleoside at one of both of positions 5 and 7 (counting 5 ’ to 3 ’) of the antisense strand is a DNA. In some embodiments, the siRNA comprises one or more modified internucleoside linkages. In some embodiments, the siRNA comprises one or more phosphorothioate internucleoside linkages in at least one strand. In some embodiments, the sense strand comprises two phosphorothioate internucleoside linkages. In some embodiments, the two phosphorothioate intemucleoside linkages are the first two internucleoside linkages in the sense strand from 5’ to 3’. In some embodiments, the antisense strand comprises four phosphorothioate intemucleoside linkages. Insome embodiments, the four phosphorothioate internucleoside linkages are the first two intemucleoside linkages and the last two intemucleoside linkages in the antisense strand from 5 ’ to 3’. In some embodiments, the nucleosides at positions 9, 10, and 11 (counting 5 ’to 3’) of the sense strand are 2’-F modified nucleosides, the nucleosides at one or more of positions 2, 6, 7, 8, 9, 14 and 16 (counting 5’ to 3’) of the antisense strand are 2’-F modified nucleosides, the first two intemucleoside linkages in the sense strand from 5’ to 3 ’ are phosphorothioate intemucleoside linkages, and the first two intemucleoside linkages and the last two intemucleoside linkages in the antisense strand from 5’ to 3 ’are phosphorothioate intemucleoside linkages. In some embodiments, the siRNA comprises a sense strand comprisingthe sequenceof any one sense strand sequence presented in column 2 of Tables 4-6 and an antisense sense strand comprising the sequence of the corresponding antisense strand sequence presented column 4 of Table 4-6. In some embodiments, the siRNAis selected from: siRNA- 443, siRNA-447, siRNA-448, siRNA-551, siRNA-592, siRNA-593, siRNA-599, siRNA-603, siRNA- 604, siRNA-607, siRNA-610, siRNA-618, siRNA-621, siRNA-622, and siRNA-636. In some embodiments, the siRNA is selected from: siRNA-551, siRNA-592, siRNA-593, siRNA-599, siRNA- 603, siRNA-610, siRNA-621, and siRNA-636. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 1113 and an antisense strand having a sequence of SEQ ID NO: 1114; a sense strand having a sequence of SEQ ID NO: 1195 and an antisense strand having a sequence of SEQ ID NO : 1196; a sense strand having a sequence of SEQ ID NO : 1197and an antisense strand having a sequence of SEQ ID NO: 1198; a sense strand having a sequence of SEQ ID NO: 1209 and an antisense strand having a sequence of SEQ ID NO: 1210; a sense strand having a sequence of SEQ ID NO: 1217 and an antisense strand having a sequence of SEQ ID NO: 1218; a sense strand having a sequence of SEQ ID NO: 1231 and an antisense strand having a sequence of SEQ ID NO: 1232; a sense strand havinga sequence of SEQ ID NO: 1253 and an antisense strand havinga sequence of SEQ ID NO: 1254; or a sense strand havinga sequence of SEQ ID NO: 1283 and an antisense strand having a sequence of SEQ ID NO: 1284. In some embodiments, the composition further comprisesa targeting agent. In some embodiments, the targeting agent is a peptide. In some embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 11 . In some embodiments, the peptide is covalently linked to the siRNA. In some embodiments, the peptide is covalently linked to the 3’ end of the sense strand of the siRNA. In some embodiments, the targeting agentis a N-acetylgalactosamine (GalNAc). In some embodiments, the GalNAc is covalently linked to the siRNA. In some emb odiments, the GalNAc is covalently linked to the 3 ’ end of the sense strand of the siRNA. In some embodiments, the GalNAc comprises a structure of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d). In some embodiments, the siRNA is selected from the siRNAs listed in Table 16. In some embodiments, the siRNA is selected from: siRNA-1057, siRNA-1058, siRNA-1059, siRNA-1060, siRNA-1061, siRNA-1062, siRNA-1063, siRNA-1064, siRNA-1065, siRNA-1066, siRNA- 1067, siRNA-1069, siRNA-1070, siRNA-1071, and siRNA-1072. In some embodiments, the siRNA is selected from siRNA- 1060, siRNA- 1061, siRNA- 1062, siRNA- 1063, siRNA- 1064, siRNA- 1067, siRNA-1070, and siRNA-1072. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 2132 and an antisense strand having a sequence of SEQ ID NO: 1114; a sense strand having a sequence of SEQ ID NO: 2133 and an antisense strand having a sequence of SEQ ID NO: 1196; a sense strand having a sequence of SEQ ID NO: 2134 and an antisense strand having a sequence of SEQ ID NO: 1198; a sense strand having a sequence of SEQ ID NO: 2135 and an antisense strand having a sequence of SEQ ID NO: 1210; a sense strand having a sequence of SEQ ID NO: 2136 and an antisense strand having a sequence of SEQ ID NO: 1218; a sense strand having a sequence of SEQ ID NO: 2139 and an antisense strand having a sequence of SEQ ID NO: 1232; a sense strand having a sequence of SEQ ID NO: 2142 and an antisense strand having a sequence of SEQ ID NO: 1254; a sense strand having a sequence of SEQ ID NO: 2144 and an antisense strand having a sequence of SEQ ID NO: 1284. In some embodiments, the siRNA is conjugated to a lipid. In some embodiments, the lipid is conjugated to an internal nucleotide of a sense strand or an antisense strand of the siRNA. In some embodiments, the lipid-conjugated internal nucleotide comprises a 2’ - O-docosanoxyl (C22) nucleotide base-3 ’-phosphate. In some embodiments, the lipid-conjugated internal nucleotide comprises a 2’-O-hexadecyl (C16) nucleotide base-3 ’-phosphate. In some embodiments, the nucleotide base is selected from the group consisting of adenine, guanine, cytosine, thymine, uracil and analogs thereof. In some embodiments, the lipid is conjugated to a terminus of a sense strand or an antisense strand of the siRNA. In some embodiments, the lipid comprises a C22 lipid monomer or a Cl 6 lipid monomer.

[0004] Also provided herein is a nanoparticle composition comprising the siRNA of any one of the foregoing embodiments. In some embodiments, the nanoparticle composition comprises an adipose targeting peptide having a sequence set forth in SEQ ID NO: 11 . In some embodiments, the adipose targeting peptide is modified to bind to the therapeutic agent. In some embodiments, the adipose targeting peptide is modified such that at least one positive charged amino acid is added to C -terminus of the adipose targeting peptide. In some embodiments, the at least one positive charged amino acid comprises arginine, lysine, or histidine. In some embodiments, the positive charged amino acid is arginine. In some embodiments, a ratio of the adipose targeting peptide to the siRNA is at least 10:1, 20: 1, 30:1, or 40:1 . In some embodiments, the pH of the nanoparticle composition is from about 5.5 to about 7.5. In some embodiments, the pH is from about 6 to about 6.5. In some embodiments, the pH of the nanoparticle composition is about 6.

[0005] Also provided herein is a pharmaceutical composition comprising (a) the composition of any one of the foregoing embodiments or the nanoparticle composition of any one of the foregoing embodiments; and (b) a pharmaceutically acceptable excipient.

[0006] Also provided herein is a method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of the foregoing embodiments. In some embodiments, the subject is a human. In some embodiments, the disease or condition is a metabolism -related disease or condition. In some embodiments, the disease or condition is a kidney disorder, a diabetes or a diabetes -related disorder, a cancer, an obesity or an obesity -related disorder, a liver disease, a cardiovascular disease (CVD), dyslipidemia, hypertension, systemic inflammation, or a neurodegenerative disorder. In some embodiments, the liver disease is a non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH), primary sclerosing cholangitis (PSC), or primary biliary cholangitis (PBC). In some embodiments, the diabetes is Type II diabetes. In some embodiments, the disease or condition is associated with fibrosis. In some embodiments, the cancer comprises colon cancer, breast cancer, or endometrium cancer. In some embodiments, the neurodegenerative disorder comprises dementia, depression, or anxiety. In some embodiments, the method results in a lowering of an mRNA level of ATF3 or a protein level of ATF3.INCORPORATION BY REFERENCE

[0007] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0009] FIG. 1 depicts qPCR results quantifying the percent change in expression of metabolism- related genes in HepG2 human liver cells treated with siRNA targeting ATF3 normalized to results obtained by treating cells with nontargeting control siRNA.

[0010] FIG. 2 depicts qPCR results quantifying the percent change in expression of metabolism- related genes in human or mouse adipose cells treated with siRNA targeting ATF3 normalized to results obtained by treating cells with nontargeting control siRNA.

[0011] FIGs. 3A-3D depict exemplary GalNAc moieties that can be covalently linked to siRNAs. FIG. 3 A depicts a GalNAc L96. FIG.3B depicts a GalNAc-7. FIG. 3C depicts a GalNAc-6. FIG.3D depicts a GalNAc- 1.

[0012] FIGs. 4A-4D depict exemplary lipid moieties that can be covalently linked to siRNAs. FIG. 4A depicts a 2’-O-docosanoxyl (C22) nucleotide base -3 ’-phosphate. “B” can be any nucleotide base or nucleotide base analog. FIG.4B depicts a 2’-O-hexadecyl (Cl 6) nucleotide base-3’-phosp hate. “B” can be any nucleotide base or nucleotide base analog. FIG. 4C depicts a C22 lipid monomer. FIG.4D depicts a Cl 6 lipid monomers.

[0013] FIGs. 5A-5C depict results of a glucose tolerance test in a mouse model using ATF3 siRNAs. FIG. 5A is a quantification of percent change in body weight. FIG. 5B is a quantification of an area under the curve (AUC) of glucose concentration over time. FIG. 5C is a quantification of insulin concentration.

[0014] FIGs. 6A-6B depicts results of a body composition assay using mice treated with ATF3 siRNAs. FIG. 6A shows relative composition of fatmass. FIG.6B shows relative composition of lean mass.

[0015] FIGs. 7A-7C depict results of experiments measuring fibrosis in mice treated with ATF3 siRNAs . FIG. 7 A shows levels of collagen buildup measured using Masson’ s trichrome staining. FIG. 7B depicts a metabolic dysfunction-associated steatohepatitis (MASH) activity score. FIG.7C depicts fibrosis scoring.

[0016] FIG. 8 depicts results of an experiment measuring hydroxyproline (HYP) levels in livers of mice in a mouse model of fibrotic disease.DETAILED DESCRIPTION

[0017] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0018] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context cl early dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassedwithin the invention, subjectto any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0020] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the fibroblast” includes reference to one or more fibroblast and equivalents thereof known to those skilled in the art, and so forth. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0021] The publications discussedherein are provided solely fortheir disclosurepriorto the filingdate of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publicationby virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.Definitions

[0022] The terms “polypeptide,” “peptide,” and “protein”, used interchangeably herein, refer to a polymeric form of amino acids of any length, which can include genetically coded and non -genetically coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified polypeptide backbones. The terms include fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence, fusion proteins with heterologous and homologous leader sequences, with or without N-terminus methionine residues; immunologically tagged proteins; and the like. In specific embodiments, the terms refer to a polymeric form of amino acids of any length which include genetically coded amino acids. In particular embodiments, the termsrefer to a polymeric form of amino acids of any length which include genetically coded amino acids fused to a heterologous amino acid sequence.

[0023] The term “heterologous” refers to two components that are defined by structures derived ftom different sources. For example, “heterologous” polynucleic acids include expression constructs in which a polynucleic acid comprising a coding sequence is operably linked to a regulatory element (e.g., a promoter) that is from a genetic origin different from that of the coding sequence (e.g., to provide for expression in a host cell of interest, which may be of different genetic origin than the promoter, the coding sequence or both).

[0024] The term “operably linked” refers to linkage between molecules to provide a desired function. By way of example, a polynucleic acid expression control sequence (such as a promoter, signal sequence, or array of transcription factor binding sites) may be operably linked to a second polynucleotide, wherein the expression control sequence affects transcription and / or translation of the second polynucleotide.

[0025] The terms “polynucleotide,” “polynucleicacid,” “nucleic acid,” and “oligonucleotide” are used interchangeably. They refer to a polymer containing at least two nucleotides (e.g., deoxyribonucleotides or ribonucleotides), e.g., in either single- or double-stranded form, and includes DNA and RNA, hybrids of DNA and RNA, and combinations thereof. The term “nucleic acid” as used herein also refers to a polymer containing at least two chemically modified nucleotides (e.g., deoxyribonucleotides or ribonucleotides), e.g., in either single- or double-stranded form and includes DNA and RNA, hybrids of DNA and RNA, and combinations thereof.

[0026] The term “nucleotide” refers to a molecule that contains a sugar deoxyribose (DNA) or ribose (RNA), a base, and a phosphate group. Nucleotides are linked together through the phosphate groups. “Bases” include purines and pyrimidines, which further include natural compounds adenine, thymine, guanine, cytosine, uracil, inosine, and natural analogs, and synthetic derivatives of purines and pyrimidines, which include, but are notlimited to, modifications whichplace new reactive groups such as, but not limited to, amines, alcohols, thiols, carboxylates, and alkylhalides.

[0027] A nucleic acid includes any oligonucleotide or polynucleotide, with fragments containing up to 60 nucleotides generally termed oligonucleotides, and longer fragments termed polynucleotides. A deoxyribo-oligonucleotide consists of a 5-carbon sugar called deoxyribose joined covalently to phosphate at the 5 ’ and 3 ’ carbons of this sugar to form an alternating, unbranched polymer. A ribooligonucleotide consists of a similar repeating structure where the 5 -carbon sugar is ribose. Accordingly, the terms “polynucleotide” and “oligonucleotide” can refer to a polymer or oligomer of nucleotide or nucleoside monomers consisting of naturally -occurring bases, sugars and inter-sugar (backbone) linkages. Additionally, nucleic acids include nucleic acids containing known nucleotideanalogs or modified backbone residues or linkages, which are synthetic, nonstandard, and / or non- naturally occurring, and which have similar binding properties as the reference nucleic acid. The nucleic acid may be modified at the base moiety (e.g., at one or more atoms that typically are available to form a hydrogen bond with a complementary nucleotide and / or at one or more atoms that are not typically capable of forming a hydrogen bond with a complementary nucleotide), sugar moiety, or phosphate backbone. Backbone modifications can include, but are not limited to, a phosphorothioate, a phosphorodithioate, a phosphoroselenoate, a phosphorodiselenoate, a phosphoroanilothioate, a phosphoraniladate, a phosphoramidate, and a phosphorodiamidate linkage. A phosphorothioate linkage substitutes a sulfur atom for a non-bridging oxygen in the phosphate backbone and delays nuclease degradation of oligonucleotides. A phosphorodiamidate linkage (N3’— >P5’) allows preventing nuclease recognition and degradation. Backbone modifications can also include having peptide bonds instead of phosphorous in the backbone structure (e.g., N-(2-aminoethyl)-glycine units linked by peptide bonds in a peptide nucleic acid), or linking groups including carbamate, amides, and linear and cyclic hydrocarbon groups. Oligonucleotides with modified backbones are reviewed in Micklefield, Backbone modification of nucleic acids: synthesis, structure and therapeutic applications, Curr. Med. Chem., 8 (10): 1157-79, 2001 and Lyer et al., Modified oligonucleotides-synthesis, properties and applications, Curr. Opin. Mol. Ther., 1 (3): 344-358, 1999.

[0028] Nucleic acid molecules described herein may contain a sugar moiety that comprises ribose or deoxyribose, as present in naturally occurring nucleotides, or a modified sugar moiety or sugar analog The examples of modified sugar moieties include, but are not limited to, 2’ -O-methyl, 2’-O- methoxyethyl, 2’ -O -aminoethyl, 2’-Flouro, N3’— >P5’ phosphoramidate, 2 Mim ethylaminooxy ethoxy, 2’ 2 'dimethylaminoethoxy ethoxy, 2'-guanidinidium, 2'-O-guanidinium ethyl, carbamate modified sugars, and bicyclic modified sugars. 2’-O-methyl or 2’-O-methoxy ethyl modifications promote the A-form or RNA-like conformation in oligonucleotides, increase binding affinity to RNA, and have enhanced nuclease resistance. Modified sugar moieties can also include having an extra bridge bond (e.g., a methylene bridge joining the 2’-0 and 4’-C atoms of the ribose in a locked nucleic acid) or sugar analog such as a morpholine ring (e.g., as in a phosphorodiamidate morpholino). Examples of such analogs and / or modified residues include, but are not limited to diaminopurine, 5 -fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5- (carboxyhydroxylmethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5- carboxymethylaminom ethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6- isopentenyladenine, 1-methylguanine, 1 -methylinosine, 2,2— dimethylguanine, 2-methyladenine, 2- methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5- methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D- mannosylqueosine, 5’-methoxycarboxymethyluracil, 5-methoxyuracil, 2— methylthio-N6- isopentenyladenine, uracil— 5- oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2- thiouracil, 4-thiouracil, 5-methyluracil, uracil- 5- oxyacetic acid methylester, 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, 2,6-diaminopurine, methyl phosphonates, chiral-methyl phosphonates, 2’-O-methyl ribonucleotides, peptide-nucleic acids (PNAs), and the like. In some cases, nucleotides may include modifications in their phosphate moieties, including modifications to a triphosphate moiety. Non-limiting examples of such modifications include phosphate chains of greater length (e.g., a phosphate chain having, 4, 5, 6, 7, 8, 9, 10 or more phosphate moieties) and modifications with thiol moieties (e.g., alpha-thiotriphosphate and betathiotriphosphates). Such modified or substituted oligonucleotides are often preferred over native forms because of properties such as, for example, enhanced cellular uptake, reduced immunogenicity, and increased stability in the presence of nucleases. Thus, the terms “polynucleotide” and “oligonucleotide” can also include polymers or oligomers comprising non -naturally occurring monomers, or portions thereof, which function similarly.

[0029] Unless otherwise indicated, a particular nucleic acid sequence encoding a protein or a peptide can also encompass conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences that encode the same protein or peptide. Specifically, degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed -base and / or deoxyinosine residues (Batzeretal., Nucleic AcidRes., 19:5081 (1991); Ohtsukaetal., J. Biol. Chem., 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes, 8:91 -98 (1994)).

[0030] The term “at least” prior to a number or series of numbers is understood to include the number adjacent to the term “at least”, and all subsequent numbers or integers that could logically be included, as clear from context. For example, the number of nucleotides or nucleosides in a nucleic acid molecule must be an integer. For example, “at least 19 nucleotides of a 21 nucleotide nucleic acid molecule” means that 19, 20, or 21 nucleotides have the indicated property. When at least is present before a series of numbers or a range, it is understood that “at least” can modify each of the numbers in the series or range.

[0031] The term “complementary,” as used herein, refers to the capacity for base pairing between two nucleobases or two nucleobase sequences. In particular, complementary is a term that characterizes an extent of hydrogen bond pairing that brings about binding between two nucleobases or two nucleobase sequences. For example, if a base at one position of a nucleobase sequence (e.g., antisense strand of an RNAi agent) is capable of hydrogen bonding with a base at the corresponding position of another nucleobase sequence (e.g., RNAi agent sense strand or target mRNA), then the bases areconsidered to be complementary to each other at that position. The nucleic acid molecules (e.g., antisense strand and sense strand of an siRNA molecule) whose nucleobase sequences are complementary may comprise one or more modified nucleosides and modified intemucleoside linkages, which do not affect the capacity of base paring between the nucleobases and do not affect the “complementarity” between two nucleobase sequences . The nucleic acidmolecules (e.g., antisense strand and sense strand of an siRNA molecule) whose nucleobase sequences are complementary may also comprise nucleobase analogous that result in bases at certain positions not being complementary, butthe nucleobase sequences of thetwo molecules mustbe sufficiently complementary over the entire length to result in a desired biological activity (e.g., RNA interference).

[0032] Complementary sequences include Watson-Crick base pairs or non-Watson-Crick base pairs (e.g., Wobble base pairs and Hoogsteen base pairs) and may include natural or modified nucleosides or nucleoside mimics. For example, in some embodiments, for complementary base pairings, adenosine-type bases (A) are complementary to thymidine-typebases (T) or uracil-type bases (U), that cytosine-type bases (C) are complementary to guanosine-type bases (G), and that universal bases such as 3 -nitropyrrole or 5 -nitroindole can hybridize to and are considered complementary to any A, C, U, or T. Inosine (I) has also been considered in the art to be a universal base and is considered complementary to any A, C, U or T.

[0033] Complementarity is independent of modifications in the sugar of a nucleoside. For example, 2’-modified A, as defined herein, are complementary to U (or T) and identical to A for the purposes of determining identity or complementarity.

[0034] The term “perfectly complementary” or “fully complementary” means that all (100%) of the nucleobases, nucleosides, or nucleotides in a contiguous sequence of a first nucleotide sequence (e.g, antisense strand of an siRNA) will hybridize with the same number of nucleobases, nucleosides, or nucleotides in a contiguous sequence of second nucleotide sequence (e.g., RNAi agent sense strand or target mRNA). The contiguous sequence may comprise all or a part of a first or second nucleotide sequence. The term “partially complementary” means that in a hybridized pair of nucleobase, nucleosides, or nucleotide sequences, at least 70%, but not all, of the bases in a contiguous sequence of a first nucleotide sequence (e.g., antisense strand of an siRNA) will hybridize with the same number of bases in a contiguous sequence of a second nucleotide sequence (e.g., siRNA sense strand or target mRNA). The term “sufficiently complementary” or “substantially complementary” means that in a hybridized pair of nucleobase, nucleosides, or nucleotide sequences, at least 85%, but not all, of the bases in a contiguous sequence of a first nucleotide sequence (e.g., antisense strand of an siRNA) will hybridize with the same number of bases in a contiguous sequence of a second nucleotide sequence (e.g., siRNA sense strand or target mRNA). The terms “complementary,” “fully complementary,”“partially complementary,” and “sufficiently / substantially complementary” herein are used with respect to the nucleobase, nucleosides, or nucleotide matching between the sense strand and the antisense strand of an siRNA, or between the antisense strand of an RNAi agent and a target mRNA sequence (e.g., ATF3 mRNA).

[0035] The term “contiguous” in the context of an oligonucleotide (e.g., siRNA) refers to nucleosides, nucleobases, sugar moieties, or internucleoside linkages that are immediately adjacent to each other. For example, “contiguous nucleobases” means nucleobases that are immediately adj acent to each other in a sequence.

[0036] The term “GalNAc” refers to N-Acetylgalactosamine (GalNAc), which is a monosaccharide and amino sugar derivative of galactose. GalNAc may also be referred to in the art as 2 -(Acetylamino)- 2-deoxy-D-galactopyranose, 2-(Acetylamino)-2-deoxy-D-galactose, N-Acetylchondrosamine, and N- Acetyl-D-galactosamine. Galactose derivatives such as GalNAc have been used to target molecules to hepatocytes in vivo through their binding to the asialoglycoprotein receptor expressed on the surface of hepatocytes. Binding of asialoglycoprotein receptor ligands to the asialoglycoprotein receptors) facilitates cell-specific targeting to target cells (e.g., hepatocytes) and endocytosis of the molecule into the target cells (e.g., hepatocytes). In some embodiments, any one of the targeting moieties described herein includes an asialoglycoprotein receptor ligand comprising GalNAc. In some embodiments, the asialoglycoprotein receptor ligand comprises a GalNAc trimer. Asialoglycoprotein receptor ligands can be monomeric (e.g., having a single GalNAc) or multimeric (e.g., having multiple GalNAcs). The targeting moiety may comprise one or more GalNAcs attached to the 3 ’ or 5 ’ end of the sense or antisense strand of the RNAi agent using methods known in the art. In some embodiments, the targeting moiety comprises one or more (e.g., 1, 2, 3, 4, or more) GalNAc, each of which are linked via phosphorothioate linkages. GalNAc targeting moieties, which comprise one or more GalNAc, have been described, for example, in the following references:

[0037] The disclosures in these references related to GalNAc are hereby incorporated herein by reference.

[0038] The terms “hybridize” and “hybridization” refer to the pairing of complementary compounds (e.g., an siRNA and its target nucleic acid). While not limited to a particular mechanism, the most common mechanism of pairing involves hydrogen bonding, which may be Watson -Crick, Wobble, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.

[0039] The term “internucleoside linkage,” as used herein, means a covalent linkage between adjacent nucleosides in an oligonucleotide (e.g., siRNA such as an siRNA described herein). An internucleoside linkage may be a natural phosphodiester intemucleoside linkage, or may be a modified (non-natural) intemucleoside linkage. Modified internucleoside that may be used in an RNAi agent disclosed herein include, but are not limited to, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphorates comprising 3 ’alkylene phosphorates and chiral phosphonates, phosphinates, phosphoramidates comprising 3 ’-amino phosphoramidate and aminoalky Iphosphoramidates, mesyl phosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3 ’-5’ linkages, 2’-5’ linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3 ’ -5’ to 5 ’-3’ or 2 ’-5’ to 5’- 2’; see US patent nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5, 177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455, 233; 5,466,677; 5,476,925; 5,519,126; 5,536,821 ; 5,541,306; 5,550, 111; 5,563, 253; 5,571,799; 5,587,361; and 5,625,050.

[0040] The term, “nucleoside,” as used herein, refers to a compound comprising a nucleobase moiety and a sugar moiety. Nucleosides include, but are not limited to, naturally occurring nucleosides (as found in DNA and RNA) and modified nucleosides. Nucleosides may be linked to a phosphate moiety. The term “nucleoside” encompasses a natural nucleoside and chemically modified nucleosides (e.g., with modifications in the base and / or sugar moiety).

[0041] The term “nucleotide,” as used herein, refers to a compound comprising a nucleoside linked to a phosphate group. As used herein, “linked nucleosides” may or may not be linked by phosphate linkages and thus includes, but is not limited to “linked nucleotides.” As used herein, “linked nucleosides” are nucleosides that are connected in a continuous sequence (i.e., no additional nucleosides are present between those that are linked). The term “nucleotide” encompasses a natural nucleotide and chemically modified nucleotides (e.g., with modifications in the base, sugar moiety, and / or phosphate group).

[0042] The term “nucleobase,” as used herein, refers to nitrogen -containing compounds that can be linked to a sugar moiety to create a nucleoside that is capable of incorporation into an oligonucleotide, and wherein the compound is capable of bonding with a complementary naturally occurring nucleobase of another oligonucleotide ornucleicacid. Nucleobases may be naturally occurring or may be modified. As used herein a “naturally occurring nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). The term “nucleobase” encompasses 5 ’-methylated bases (e.g., 5’- methyl cytosine or 5 ’-methyl guanine).

[0043] The term “modified intemucleoside linkage” refers to a linkage between two nucleosides (e.g., in an oligonucleotide or in a strand of an siRNA) that is not the natural phosphodiester linkage. Nonlimiting examples of modified internucleoside linkages include phosphorothioates, phosphorodiamidates, phosphotriesters, methyl phosphonates, short chain alkyl or cycloalkyl intersugar linkages or short chain heteroatomic or heterocyclic intersugar linkages.

[0044] The term “nucleoside modification” or “modified nucleoside” means a nucleoside that has one or more modifications to the nucleoside, including modifications to the nucleobase moiety and / or the sugar moiety. Any of the modified chemistries or formats of nucleosides described herein can be combined with each other. Non-limiting examples of modified nucleosides includes 2’ -fluoro (2’-F), 2’-O-methyl (2’-O-Me), 2’-O-methoxyethyl (2’-MOE), 2’-O-aminopropyl (2’-O-AP), 2’-O- dimethylaminoethyl (2’-0-DMA0E), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-O- dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-O-N-methylacetamido (2’-0-NMA), locked nucleic acid (LNA, methylene-bridged nucleic acid), unlocked nucleic acid (UNA), ethylene-bridged nucleic acid (ENA), and (S)-constrained ethyl-bridged nucleic acid (cEt) modified nucleosides. Further non-limiting examples of modified nucleosides include a conformationally restricted nucleoside, an abasic nucleoside, a 2’ -amino-modified nucleoside, a morpholino nucleoside, a phosphoramidate, a non-natural base comprising nucleoside, a tetrahydropyran modified nucleoside, a 1,5-anhydrohexitol modified nucleoside (HNA), a cyclohexenyl modified nucleoside (CeNA), a nucleoside comprising a phosphorothioate group, a nucleoside comprising a methylphosphonate group, a nucleoside comprising a 5 ’-phosphate, a nucleoside comprising a 5’ -phosphate mimic, a thermally destabilizing nucleoside, a glycol modified nucleoside (GNA).

[0045] The term “2 ’-modified nucleoside” refers to a nucleoside having a sugar moiety modified at the 2’ position, meaning the sugar moiety comprises at least one 2’ -substituent group other than H or OH. Non-limiting examples of2’-modifiednucleosides include: 2’-fluoro (2’-F), 2’-O-methyl (2’-O- Me), 2’-O-methoxyethyl (2’-M0E), 2’-deoxy, 2’-O-aminopropyl (2’-O-AP), 2’-O- dimethylaminoethyl (2’-O-DMAOE), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-O- dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-O-N-methylacetamido (2’-0-NMA) modifiednucleosides. In some embodiments, any one of the 2’ -modified nucleosides described herein are high- affinity modified nucleosides and a modified RNAi agent has increased affinity to target sequences, relative to an unmodified RNAi agent. In some embodiments, at least one modified nucleoside is a 2’ modified nucleoside. In some embodiments the 2’ modified nucleoside is a 2’ -O-methyl (2’-0-Me) modified nucleoside or a 2’-fluoro (2’-F) modified nucleoside or combinations thereof.

[0046] The term “modified oligonucleotide” or “modified siRNA molecule” or “modified siRNA” refers to oligonucleotides or modified siRNAs that comprise one or more modified nucleosides and / or one or more modified internucleoside linkages. In some embodiments, a modified oligonucleotide” or “modified siRNA molecule” or “modified siRNA” comprises a mix of modified nucleosides and unmodified nucleosides and / or a mix of modified internucleoside linkages and unmodified modified internucleoside linkages. In some embodiments, each nucleoside of a modified oligonucleotide” or “modified siRNA molecule” or “modified siRNA” is a modified nucleoside, and / or each internucleoside linkage of a “modified oligonucleotide” or “modified siRNA molecule” or “modified siRNA” is a modified intemucleoside linkage.

[0047] The term “antisense strand” or “guide strand,” as used herein, refers to a single stranded nucleic acid molecule, which is one strand of a double stranded siRNA, and which comprises a region of complementarity to a target sequence (e.g., a target gene sequence, RNA sequence, or mRNA sequence). The antisense strand may contain modified nucleosides with base analogs and is not necessarily 100% complementary over its entire length to the target sequence, but must at least be sufficiently complementary to hybridize with a target RNA and result in RNA interference.

[0048] The term “passenger strand” or “sense strand,” as used herein, refers to a single stranded nucleic acid molecule which is one strand of a double stranded siRNA, and which has a sequence that is at least substantially complementary (e.g., at least 85% complementary) to that of the guide strand / antisense strand. The sense strand need not be fully complementary over the entire length of the antisense strand, but must at least be sufficiently complementary to hybridize with the antisense strand and result in RNA interference.

[0049] The term “region of complementarity,” as used herein, refers to a nucleobase sequence, e.g, of an siRNA, that is sufficiently complementary to a cognate nucleobase sequence, e.g., of a target nucleic acid, such that the two nucleobase sequences are capable of annealing to one another under physiological conditions (e.g., in a cell). In some embodiments, a region of complementarity is fully complementary to a cognate nucleobase sequence of target nucleic acid. However, in some embodiments, a region of complementarity is partially complementary to a cognate nucleobase sequence of target nucleic acid (e.g., at least 80%, 90%, 95% or 99% complementarity). In someembodiments, a region of complementarity contains 1, 2, 3, 4, or 5 mismatches compared with a cognate nucleobase sequence of a target nucleic acid.

[0050] The term “RNAi agent,” or “RNA interference agent” means a composition that contains an RNA or RNA-like (e.g., chemically modified RNA) oligonucleotide molecule that is capable of degrading or inhibiting translation of messenger RNA (mRNA) transcripts of a target mRNA in a sequence specific manner. As used herein, RNAi agents may operate through the RNA interference mechanism (i.e., inducing RNA interference through interaction with the RNA interference pathway machinery (RNA-induced silencing complex or RISC) of mammalian cells), or by any alternative mechanism(s)orpathway(s). While itis believed thatRNAi agents, as that term is used herein, operate primarily through the RNA interference mechanism, the disclosed RNAi agents are not bound by or limited to any particular pathway or mechanism of action. An RNAi agent modulates, e.g., inhibits, the expression of ATF3 in a cell, e.g., a cell within a subject, such as a mammalian subject. RNA agents include, but are not limited to: single -stranded oligonucleotides, single-stranded antisense oligonucleotides, short interfering RNAs (siRNAs), double -strand RNAs (dsRNA), micro RNA (miRNAs), short hairpin RNAs (shRNA), and dicer substrates. Any one of the RNAi agents described herein comprises a strand thatis at least partially complementary to the mRNAbeing targeted. In some embodiments, an RNAi agent is single stranded (e.g., it can be an antisense oligonucleotide). In some embodiments, an RNAi agent is double stranded. In some embodiments, the double stranded RNA agent is a double stranded siRNA.

[0051] In some embodiments, an RNAi agent (e.g., siRNA) described herein is double-stranded, and comprises an antisense strand and a sense strand, wherein the antisense strand is at least partially complementary to the mRNA being targeted (e.g., ATF mRNA), and the sense strand is at least partially complementary to the antisense strand. It is not necessary that there be perfect complementarity between the RNAi agent (e.g., siRNA) and the target, but the correspondence is preferably sufficient to enable the RNAi agent to direct sequence specific silencing, e.g., by RNAi cleavage of the target RNA, e.g., ATF3 mRNA. An RNAi agent (e.g., siRNA) described herein may comprise one or more modified nucleosides and / or one or more modified (e.g., non -phosphodiester) internucleoside linkages.

[0052] Modification to stabilize one or more 3 ’ - or 5 ’-terminus of an siRNA, e g., against exonucleases may also be present in an RNAi agent described herein. Other modifications can include C3 (or C6, C7, C12) amino linkers, thiol linkers, carboxyl linkers, non-nucleotidic spacers (C3, C6, C9, C12, abasic, triethylene glycol, hexaethylene glycol), special biotin or fluorescein reagents that come as phosphoramidites and that have another DMT -protected hydroxyl group, allowing multiple couplings during RNA synthesis. Modifications can also include, e.g., the use of modifications at the 2’ OHgroup of the ribose sugar, e.g., the use of deoxyribonucleosides, e.g., deoxythymidine, instead of ribonucleosides, and modifications in the intemucleoside linkages, e.g., phosphothioate internucleoside linkages. In some embodiments, the different strands will include different modifications. In some embodiments, an RNAi agent of the disclosure includes a short interfering RNA (siRNA) that interacts with a target RNA sequence, e.g., an ATF3 target sequence, to direct the cleavage of the target RNA. In some embodiments, an RNAi agent described herein is a small interfering RNA (siRNA).

[0053] The term “siRNA,” as used herein, refers to a complex of ribonucleic acid molecules, having a duplex structure comprisingtwo anti -parallel and substantially complementary (e.g., at least 85% complementary) nucleic acid strands, referred to as having “sense” and “antisense” orientations with respect to a target sequence, i.e., an ATF3 sequence. Each strand of the siRNA may optionally and independently comprise ribonucleosides (RNA), RNA analog(s) (e.g., chemically modified ribonucleosides), and / or deoxyribonucleosides (DNA). Each strand of an siRNA comprises between 15 and 30 nucleosides (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 , 29, or30 nucleosides). In some embodiments, each strand of an siRNA comprises between 18 and 28 nucleosides (e.g., 18-28, 19-25, 19-23, 19-21). In some embodiments, each strand of an siRNA is 19, 20, 21, 22, or 23 nucleosides in length. . In some embodiments of the disclosure, an siRNA induces the degradation of a target RNA, e.g., an mRNA, through a post-transcriptional gene-silencing mechanism referred to herein as RNA interference or RNAi.

[0054] In some embodiments, any one of the siRNAs disclosed herein comprises a duplex region of 10-30 base pairs in length (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, or 30 base pairs in length). In some embodiments, an RNAi agent of the present disclosure is blunt ended. In some embodiments, an RNAi agent of the present disclosure has overhangs on one or both strands. The overhang may include 1 - 10 (e.g., 1-10, 1-8, 1-5, 1-3, 1 -2) nucleosides, such thatthe duplex region in the RNAi agent comprises 17-21 nucleosides, or 19 nucleosides. The overhangs can be the result of one strand being longer than the other, or the result of two strands of the same length being staggered.

[0055] Without wishing to be bound by any particular theory, it is believed that long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease -Ill-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3’ overhangs (Bernstein, et al., (2001) Nature 409:363). The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Uponbindingtothe appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elb ashir, et al., (2001) Genes Dev. 15: 188).

[0056] In one aspect, the disclosure relates to a single stranded RNA generated within a cell and which promotes the formation of a RISC complex to effect silencing of the target gene, i.e., ATF3 gene. In some embodiments, an RNAi agent may be a single-stranded RNA (ssRNAi) that is introduced into a cell or organism to inhibit a target mRNA. Single -stranded RNAi agents bind to the RISC endonuclease, Argonaute 2, which then cleaves the target mRNA. The single -stranded RNAi agents are generally 15-30 nucleosides and may be chemically modified. The design and testing of singlestranded RNAi agents are described in U.S. Patent No. 8, 101,348 and in Lima et al., (2012) Cell 150:883-894, the entire contents of each of which are hereby incorporated herein by reference.

[0057] The term “target sequence,” as used herein, refers to a nucleoside sequence whose expression or activity is to be modulated. In some embodiments, the target sequence is a contiguous portion of the nucleoside sequence of a gene, a cDNA, or an mRNA molecule formed during the transcription of a target gene, e.g., ATF3 gene, including an unprocessed pre-mRNA transcript and mRNA that is a product of RNA processing of a primary transcription product. The target portion of the sequence will be at least long enough to serve as a substrate for RNAi-directed cleavage at or near that portion of the nucleoside sequence of an mRNA molecule formed during the transcription of the target gene, e.g., ATF3 gene. In some embodiment, the target sequence is within the protein coding region of the target gene, e.g., ATF3.

[0058] A “gene,” for the purposes of the present disclosure, includes a DNA region encoding a gene product, as well as all DNA regions which regulate the production of the gene product, whether or not such regulatory sequences are adjacentto coding and / or transcribed sequences. Accordingly, a gene includes, but is not necessarily limited to, promoter sequences, terminators, translational regulatory sequences such as ribosome binding sites and internal ribosome entry sites, enhancers, silencers, insulators, boundary elements, replication origins, matrix attachment sites and locus control region.

[0059] “Gene expression” refers to the conversion of the information, contained in a gene, into a gene product. A gene product can be the direct transcriptional product of a gene (e.g., mRNA, tRNA, rRNA, antisense RNA, ribozyme, structural RNA, shRNA, RNAi, miRNA or any other type of RNA) or a protein produced by translation of a mRNA. Gene products also include RNAs which are modified, by processes such as capping, polyadenylation, methylation, and editing, and proteins modified by, for example, methylation, acetylation, phosphorylation, ubiquitination, ADP-ribosylation, myristylation, and glycosylation.

[0060] As used herein, the term “sequence identity” refers to a degree of identity. Determination of sequence identity is described in the following example: a sequence of 20 nucleobases in lengthwhich is otherwise identical to another 20 nucleobase sequence but having two non -identical residues has 18 of 20 identical residues (18 / 20 = 0.9 or 90% sequence identity). In another example, a sequence of 15 nucleobases in length having all residues identical to a 15 nucleobase segment of a sequence of 20 nucleobases in length would have 15 / 20 = 0.75 or 75% sequence identity with the 20 nucleobase sequence. As used herein, sequence identity is meant to be properly determined when the query sequence and the subject sequence are both described and aligned in the 5 ’ to 3’ direction. Sequence identity may also encompass alternate or modified nucleobases that perform in a functionally similar manner to the regular nucleobases adenine, thymine, guanine and cytosine. The sequence identity can be determined by online tools such as EMBOSS Needles (https: / / www.ebi.ac.uk / jdispatcher / psa / emboss_needle). The sequence identity is determined without consideration of chemical modification.

[0061] The terms “treat”, “treating”, treatment” and the like refer to a course of action initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition afflicting a subject, or at least one of the symptoms associated with a disease, disorder, condition afflicting a subject.

[0062] The terms “prevent”, “preventing”, “prevention” and the like refer to a course of action initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.

[0063] By “treating or preventing a condition,” for example, as compared with an equivalentuntreated control, alleviating a symptom of a disorder may involve reduction or degree of prevention at least 3%, 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.9%, or 100% as measured by any standard technique. In some embodiments, alleviating a symptom of a disorder may involve reduction or degree of prevention by atleast 2, 3, 4, 5, 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or 10000 fold as compared with an equivalent untreated control.

[0064] As used therein, “delaying” the development of a disease means to defer, hinder, slow, retard, stabilize, and / or postpone progression of the disease. This delay can be of varying lengths of time, depending on the history of the disease and / or individuals being treated. A method that “delays” oralleviates the development of a disease, or delays the onset of the disease, is a method that reduces probability of developing one or more symptoms of the disease in a given time frame and / or reduces extent of the symptoms in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a number of subjects sufficient to give a statistically significant result.

[0065] “Development” or “progression” of a disease means initial manifestations and / or ensuing progression of the disease. Development of the disease can be detectable and assessed using standard clinical techniques as well known in the art. However, development also refers to progression that may be undetectable. For purpose of this disclosure, development or progression refers to the biological course of the symptoms. “Development” includes occurrence, recurrence, and onset.

[0066] As used herein “onset” or “occurrence” of a disease includes initial onset and / or recurrence.

[0067] “Administering” and its grammatical equivalents as used herein can refer to providing pharmaceutical compositions described herein to a subject or a patient. Conventional methods, known to those of ordinary skill in the art of medicine, can be used to administer the composition to the subject, depending upon the type of disease to be treated or the site of the disease. For example, the composition can be administered, e.g., orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, or via infusion. One or more such routes can be employed.

[0068] The phrase “therapeutically effective amount” refers to the administration of an agent to a subject, either alone or as a part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount that is capable of having any detectable, positive effect on any symptom, aspect, or characteristics of a disease, disorder or condition when administered to a patient. The therapeutically effective amount can be ascertained by measuring relevant physiological effects.

[0069] The term “vector,” as used herein, refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. In some examples, a vector is an expression vector that is capable of directing the expression of nucleic acids to which they are operatively linked. The term “operably linked,” as used herein, means that the nucleotide sequence of interest is linked to regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence. The term “regulatory sequence,” as used herein, includes, but is not limited to promoters, enhancers and other expression control elements. Such regulatory sequences are well known in the art and are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990). Examples of expression vectors include, but are not limited to, plasmid vectors, viral vectors based on vaccinia virus, poliovirus, adenovirus, adeno -associated virus, SV40, herpes simplex virus, human immunodeficiency virus, retrovirus (e.g., Murine Leukemia Virus, spleennecrosis virus, and vectors derived from retroviruses such as Rous Sarcoma Virus, Harvey Sarcoma Virus, avian leukosis virus, a lentivirus, human immunodeficiency virus, myeloproliferative sarcoma virus, and mammary tumor virus) and other recombinant vectors.

[0070] The term “diabetes,” as used herein, refers to a group of metabolic disorders characterized by a high blood sugar level over a prolonged period of time. Diabetes can be type 1 diabetes that results from the pancreas’s failure to produce enough insulin due to loss of beta cells. Diabetes can be type 2 diabetes characterized by insulin resistance, a condition in which cells fail to respond to insulin properly. Diabetes can be gestational diabetes that occurs when pregnant women without a previous history of diabetes develop high blood sugar levels.ATF3 Pathway

[0071] Activating transcription factor 3 (ATF3), also known as cyclic AMP-dependent transcription factor, is a member of the ATF / cAMP response element -binding (CREB) family, which can bind to the cyclic AMP response element (CRE) in numerous promoters. ATF3 can also interact with proteins via its basic leucine zipper (bZIP) domain and modulate cellular functions independently of its transcriptional activity. The ATF3 gene consists of four exons that encode a 181 -amino acid protein with a molecular weight of 22 kDa. See, Hui-Chen Ku, Ching-Feng Cheng, Master Regulator Activating Transcription Factor 3 (ATF3) in Metabolic Homeostasis and Cancer , Front Endocrinol (Lausanne). 2020; 11 : 556. TheHTFJ gene can be a human HTFJ gene (NCBI Reference Sequence: NG 029871.1). In some embodiments, the ATF3 gene comprises a nucleic acid sequence of: ACAGTCGCACGCAGCCAGGCGCGCACTGCACAGCTCTCTTCTCTCGCCGCCGCCCGAGC GCACCCTTCAGCCCGCGCGCCGGCCGTGAGTCCTCGGTGCTCGCCCGCCGGCCAGACAA ACAGCCCGCCCGACCCCGTCCCGACCCTGGCCGCCCCGAGCGGAGCCTGGAGGTGAGC GCTGGAAGCCGAGGGAGTGAGCGCGACGAGGGCTGCTCGCCTTCATTCCCTTCGCGCCC CTCTAAGTAACCAGTCCGCCGACCCCTGACCCACCCCGGATCCGCGCCCCCAGCCTCCG GCTTGGAAATAACTCTGGCTTAAACTTCTTCTAAGCCACCGCTGCTCCTCGGCGCTTCGA AAAGTTTCCCGCAAAGCGAAAGAACTAACTTTCTCTTTTGACTTGGGGCGCGAAAGGTT CCTGGTGACGGAGGTCGGGCGTCCACTCTGCCGCCAGCCTCGAGCGCCGCTTCTCTCCG CCGACGGCGCTGGCTTGCCCGGCTGGGAGAGGGCGTAAGGTGGGTGGGCGGGTGCGTT GGGGTGTCCGAGGCTGCCTCGCTCGCCGTCCCGCTCCATCCCTCGCTTCGAGACACGGC ACTGTGGGAGCCGATCCTTCCCGGGTGGGGGGGGGGGGGCGCAGAGAGGCACGAAGGC CGGAGGCTTGCGGGAGGGCTGCCCCACGCGCCGAGAGGAATGAATGGGGAAGGGGCGA GAGGGCGGGAGGCGTCCCGGGCGCGGCCGCTGGGGGTCGCCCTGGGTACCCCGCAGCA CTGGCGGCAGGACCGTGAAGGCAACCCCGAGAAAAAGTTAGCTGGGATAAGCTTGGAAGTGGCGAGCGCTGGTGTCGCGCTGTCCCGGGGCGGAAGACGGGGAGGGCTCCCGGCAACGGCTGGTGTCCGGACCCCGAGCCCGGGACTCCCACACACCTGGGACTCTCACTCTGGCTTTTCCTTCGGCGGGTCCGCGGGAGACCCACCGTGGCGGGGAAGCGAGGGTGTGGAGCCACTTGTGCAGATATTTGAGAGAATGGCTTTGTGGTCTAGTGCCAGGACTCTGAGCGCTTACACTGCAATCGATGTCGTTGGGCCTCAGTATGCGGAGCCGGGAAATAAGGGCACATGGGCAGTACCGGCCCCCTCTGCGTGTTGGAGGGCACAATGCAGTGGTTGGACCAGATAACTACTAAGGTCCTTTCTGTCTGGAGATTTTCAGATTTTGGAGTGGTGTAGTGGGGAGAAAAGGAGCCAGTGAGGGGACTTGAATGGGGTGGGTCTCTATCTAATGTCATTCACCAGTGTCCAGACAGTGGGGGAAAGGGGACTTTTCTGCAGGGCATCTTTTCCCTCACCAGCTTTCTTTCCACTGGATTCGTTCTCCTTCTCTGCTCCCCCCACTCCCATTTTCATTTCTCATCTACTTCCTTTCCTCCTAAACATTTTCTTTTCCCTAATTTCATTGCATAGGTCACATATGCTTTCTTACAAATAAAATAGTTACTAAATCCTTGATGAACCCAGAAAGAAAAGGAGAGCCAGAAAATCTGGATGTTCTCTCAGTGTACCCCTTTCGTTGTAGGTGACAGTCATATCTTCTGTTCGAAGTTTCTGTCTCTGTAACTTAAAGTGAAGGCAAAAAATTGGTATTACTGTCCCCATTGTTTTGCAGTTAGCATTGGTTGTAGAATAATGCTACAACATACAGGCTCCTGCTTTGAGGATATCCTGGGCAAAGATGGGATGGGGTGAGGATTGCAGTTACTGTCGGAATGGTTTCAGAGACAGCAAAGAAGGCAGCACCCCACGCCCGCAGTGGGGATAAGATACAGCACCCAGCATCTGTGGCAGTGATGGGAGCCTTCTTTTTCTCTCTCTCTTCCTCCTTGCCCTTTAGCCATTATAGAATTCCTTTTTCTCCATGGCCGTTTTCTTCGATAGCCCCTCCCTATCTCAGTCCTGTCAAAGTCTCCTCTGTGATTGGTACCAGGTGCCAGGACTCTTGACCCCTTATCTACCTGGCTAATGGCTCTGTTCTCTGGTTGCCTTGTTGGTTGATCCCTTGAGGCGGTCGATACCTATTGGTGATGGAGCAAAATGAGCAGTCGGTGGGTGTTCAGCAGCTTGGCATGGGCTGGGCCACTCACCAGCTTTATGACCTCAGGCAAGTCATTTTTACCTCCCTGGACCAATGTACTCATTATGAAATGAGAATCTGACCTAGATGATTCTAATATTGAGAGGGTGTGATTTCCATTAGATAGAGTCCATGATTCCTTCCTTTTTAAAATTGGCTGGGCATGGGACAGGGCCAGTGGCTTCGAGTGTTTACCCAGCCAGGGGAGGAGGAAGGACATAGCCAAGATGCCTCAGAAGCTTTCCAAGGGAGAAATGGTTTATATGTGAGAATTGGTTCTCTTTCAAATATGTAATGCAGAAATGCTGGCATCAGCAAATAGTGGGGTGAAACCTACCTGGTCTGTGAAGAACTTGGGGTCAATGAGAGTACAAAAGAGGCTCTGACTGACCTGAATGTCTTGAAGGTTCCAGTTAATTCCTCACTAACAGGGCTTTATTGAATTGATAACAACAGAATGAGTTTTTCCTGAAATGGAGAAGATGGAGTCACAGTAGTAATGACTACCCGGTGTGTATGTAAATCTCATATGTCCTTCTCAACAGCCCTTTGGGGAAGGCAGTTTTGATCTCAAATTACAGAGGAAGAGAATGAGAGGCCCAGAAAGCCTAAGTGATTTGTTGGTGGATGCTCAGCTTATGAGTGGCACTGATAGGCTTAGAAACATTGTCTCTGGCCCTTGATGCCCAGCTTTGCACCTCTTCAAGAGGTCTGGGAGGAAGACCAAGATATGAAGAGTTAGTGAAAGGCCAGTACTGGCTTCCTAGTAACATAAGATGGTTAGCAAGCAATGCTTAGTGGAAAGAGGATGAAAATTAAAAGTGAAAATTCAATGTAGCTGTAGCTACTAGGAAATAAAAATCTGGGAGCTGAATTTCCAGTTAAAGGAATACATGAGTAAACTTTCACTTTCTTGAAAATGATGAAACTGCCAATGATACAACATGATTTCTGATTGGAAATAATCAAGCAGAAACAAAATGCAAGTTCTTGGTAGCAAGTCTGAACAATTTTATGATCAGCATAGAAAGTCAACTCTGATCTGAGGTCCCCAAACAATTTTTTTCAATGACCGGGATGTTTGAGGATCTCAACTTTCTGAAAAATTGTGTGAAGATTTAACTTCATTTCCTTGTGGGGACACAGCCGTAGTCTAGGCTGAATCATACCTCGAGAGACTGAGTAAAGGAATAACTAGAAAGTATCCCGAGAAGTTAAGCTTTAGCCTAGTGCCGAGAAAACCCAAATCTCGACAGATACATCTGTTTTATTTTCTGAAAGGCTTTTAACATTTTTACAACCATTTATGTCCCCAAGGAAGCCCACCCAATGCTTTTCATAAAAGCATTCCATACCACTGACATTCTTCAGCTTCTTTCATTGGGACTGCTGACTTTACATAAGAAGAAGGGTAGGGGGCGGGAGTCATAAACAGCAGACCCCAAGCCCTGAGAGCTCATTAATAAACCTAGTTGGATGGCAAAATGGAACTACACTCTACTGCAGTGGAATTCAAAGTCCCCGTGTAGAAGGGAGCCATCCAGGCCTCCAAACAAAGACCAGCCCAGTGGCAGCTCTGAATGTCATCCCCGAATCACTGAGTTTTTAATAAACTTGGAAAGGGAAGGGAAACATGAATGCATGGGAGAATCTTAAGCCTCTGGCTTTAGAAGGCTAGTTTCTCAGAGTTTATTGCCTGACAGCGACAAGTATCCTCCCAGCATCCTAAGATTATAGGATTAAATTGAGAGAAGAACTTCAGTTCTGACTCATGACACAGGGCTTTGGGAAAAGAATTACATACATAGCCTGGGTTTCTTTGACTAGTCAAGGGCAGATTTCATTGGCCTGGAAGTCTTGCCTCCATTGGTGTATGTTAGATCTCCAGGGGGAGTTTGAAGTCAGGGTATTCTATTCAGAAGCCTTTGAGATCAAAGTGGGTGACCAGCTGCCCTCCTTCCTGGACTCCACAGAGCCTCTGTCAGAGAGCCAGCCCTGGGCTGGAGAGATCTCTGGGAGGCCTAGTAATCATGGAGCTCCTGGCCAAAGAATGTTTTCCAGGGCATATTCATGTATTAGTTCCTCAATTCCTCATAGGATATTATGGGAAAATAGGGCGATTATTACAAGCCCTCTTTAACAGAGGAGAAAAAGCCACGGGGAGGTACAATGATAACACATAATGGAGTAAGTGGGCTTCAAATCTTCATCTTCTGACCTCAGTCTGGGAATTTTGTGGATAAGAGACCCACTTGCTCACACTCCCAGAAGGCAGTTAGCAAGCAGCCTGGGTATGCACCGTGACATAAAGATTAGCAGTTCATTAAACAGAGTTCAGTTTATCCCGAGGAATCTTTACTTAGCCTCCCCTCTATCACTTCATTTCCAGGCCTCCCACCTACCTTAAGGCCTGCCCCGAGAAAATTTGCTCTGGTTTTTTGTTTGTTTGTGCAATATAACATAATGCTTGTTTGTTTTTGTAATGTAGAATAATATTTGTTTGTTTTTTGCAATGTACAAATTAAGGGCATGAATCCTGGAGCCAAACTAACTTAATTCCAAATCCTGATGCTGCCCCATATTAATTCTGTGAATTCGGGCAAATGACTTAGTTTGTCTAAACCTCAATTATCTCATCTATAAAAGGCAGCTAGATCTTAACTCACTGGGTTCTCGTGAGGATTAAATGAGATAGTGCCCCTAAGGTTTCTGGTATGAAGGAGGCACTCCTTAAATGTTCGAGACTTGCCAGAGGGCTTCTTCTCTGTCTGGACTGTGCTAATGACCACAGATCCCCGGTTGAGAGGAATGCCCAGACCACACTCATCCTACACTCATCCCTATACTCATTGTCCCTTGGGAACCAACTGCAGGGAGGAGGGGAAATGGCCACCACTGGAGGGAGTACACAGCAGGCCAAGACTTATGGGGGACTCTTCCAAATTGGGGCCATGGAACTGTCACTATTTCTACTCTTTATTTTCCTTTTGTCATCCTTTTGGGTTCACCGAGCTATAGAATAACAGAGGGAGATGAATTTAGCAAATACATCACTGAAGCTTCTCCCTCGGAAGTTGGGCCCAAGCAATGGGAATGAGAAAGGTAACCTTGGACCGTGGGGGCCATTTGATTTGATGACCCCATCCCCACTTCATTTATCAGTTGGCCAATGAGGCATGGCGAGTCAGGCATTGGGCCAGGCTCTGGGTAAAGCAATGGTGGAGACTCAATGCTTGCATTGGAGGAGCTGTCAGTCATTTACCAGACACAGACTGGGTCCTAGAGAGCTGAAATTACTAGCTCAAGTCACTGCTGTTTAGTGCCAGAGCCAGCCCCAGGGTTCCCTGCCCCCACACCCAGCCTAAGTCTATCCCTATACCACAGGCCTGAACAACTCCCCCACAATACAGTGCCTCACTTTTCTTTAAGACCTTTTGCTTTGCCAACCTTAACCTTAAGAATCCACCTCCCCATCCCCTGCCAAAGACTGGGGTGAAGAAACGCACCTGGCTACAGTTACCTTTCTCATTCCCATTGCTTGGGCCCAACTTCGGGGGAGAAGCTTCAGAGATGTATTTGCTAAATTCAAGGATTCCCCACTTTTTGCTTTTACTTCCACTCACTGATAGTTTCAGCTTGACGTCAAGCCTCTTTGAAAAAGAGGCTTTTTTTTTTAAGTGAAAGAAACTTTATTTTGAGTAATATACAAAAAAAAAAAAAGAGAGAGAGAGAGAAAGAAAAAGAAGCTGAAAATGAGATTACTCATGATTTTTAAAATGGCCTCACTGATTTTTAAAAAATGTTCTTCCTCTTTCAGGACTGTTTGTGGCCACATTTGCACATAGGCACACCAGCCAAAACTCATAGATCTTGTGAATTCAGAGTAGCCTGAAACATCATCCCTTATAAATTTCAAATAGGCATTTTGTTCATGTCACTGAGCTATGTGTATTTTAAGAACCTGCTTTACTTAAGATGAGGATGGCATGAAATGAAAACAAAACAGAAACCCAAGGGCTTATGGGACTTTTCTCTGAGGGTGGGGCTCTGGTGTTGGAGGTCTGGTGGGGGAGGGGGACTTGATCCCATGCCCCAGAGCCCCTGAAACAGTTTGGGTTTCAATGTGTCTTTCAGCAAAATGATGCTTCAACACCCAGGCCAGGTCTCTGCCTCGGAAGTGAGTGCTTCTGCCATCGTCCCCTGCCTGTCCCCTCCTGGGTCACTGGTGTTTGAGGATTTTGCTAACCTGACGCCCTTTGTCAAGGAAGAGCTGAGGTTTGCCATCCAGAACAAGCACCTCTGCCACCGGATGTCCTCTGCGCTGGAATCAGTCACTGTCAGCGACAGACCCCTCGGGGTGTCCATCACAAAAGCCGAGGTGGGTTCTATCACAGGTATTCATTCTTTCGGCACATGTTTCGCTCGCAGCCACTGTGTGTTGGGCATGTTCTAGGCAGGGGGCTGTTGTTGAGAGTGAAACAAACAAAACCACTGCCCTCAGGGAGCTTACCTTCTCCTGGGAGGAGACAGAAGTACATAACATACGTAAGTACACGTTAAGAGATGAGTGCAAAGGAGAAAAAAGCAGGGAGCGGGGCAGAGAGAACGGGTAGGGATGGGGTTGCTGGGTTTAAAAACTTTTCAGGCCAGGCATGGTGGCCCACGCTTATAATCCCAGCACTTTGAGAGGCCAAGATGGGATTATCGCTTGAGTCCAGGAGTTTGAGACCAGCCTGGGCAACACAATGAAACCCAATCTCTATGACAGTATTAGCTGGGCAAGGTGGTACATGGCCTATAGTCTCATCTACTTGCGAGGCTGAGGTGGGAGGACCGCTTGAGCCCAGGAGGTTGAGGCTGCAATGAGCCGTGATCACCTCACTGCACTCCAGCCTGGGTGATGGAGCAAGACTCATTTTGCTTTTAGAGACAGTGTTGCTCCATCACCCAGGCTGGGGTGCAGTGGGGTGATCACGGCTCATTGTAGCCTCAGTCTCCTGGGCTCAAGCGATCCTCCTGCTTCAGCCTCCCAAAACACTGGGATCACAGGGATGAGCCATTGCACCCAGCCGGGGTTGCTGTTTTAAATTAGGAAGTCAGGTAAGGATTCACTGATAGTGACTTTTGAGCAGAGGTCAAAAGGAAAGGAAGAAGGAAAGAGGAGAGGGAAGAAGCCACGTGGGTATCTGGTAAAAGAAATTAAGGGCACTGAGGTGGAAGTATTGGTGCCTGGTGGGCTGTGCAGTGGGGCAGAGTATAGGGGTGGGAGATAAATAGGGGCTGGTCATATTGGGTCTTACAGATTATTATTGTATAGATGCAGCCCTGGGCTCAAAGTGAGGTGGGAAACCACAGAAGGCTTTTGAGCAGAGAAGCAACAAGATTCAACACACACACACACACACAGATACACACACACACTTTTTTTTTTGAGACAGAGTCTTGTTCTGTCACCCAGACTGGAGTGCAGTGGCATGATCTTGGCTCACTGCAACCTCTGCCTCCCAGGTTCAAGGGATTCTCATGCCTCAGTCTTCCAAATAGCTGGGATTACAGGTGCCCGCCACACGTCTGGCTAATTTTTGAATTTTTTTAGTAGAGACGGGGTTTCTCCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTAATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACCACGCCCAGCCTTGATTTATATTTTTAAATGATCACCCTGGCTGTCATGTTGAGAATGGGCAGTAGGGGTAAGACAGAAGCTGAGTGCACAGAAAGGAGGCCGTGGCAGGAATCCACGTGAGTCAGGGGGCCTGCAGCAGGAGGGAGCAGTGCAGGTGCTGAGAAGTGGTTGGCTTTGGATCTGACTTGAAGGTAAAGCTGATTTGCTGATAGATTGGATGTGGGGTGTAAGAGAAAGGGAAGACTCAAGGGTGACTGAGTTTTCTGGCCAGCATAGCTGTAAGAATGGAGCGTCCATTTGCTGCTGAGATTTGGGATTATAGGGGTTAGGGTGGTGGCAAGAGCAGGAGGTCTGTCCTATTCTGCAGACCCCTGTGGAGATGTCAAGCAGGCAGTTGGATATGTGAGTCTGGAGTTCAGAGGACAGTCTGGGCTAGAGATAATAGAGTTGGAAATTATCGGCATATAGATGGCACTTAAAGCCATGAGTCAGGATGAGGCCACCTTCTGTGTCCAGTTGTTCTGAAGAAGCTTGGAGCGTGGTGGTCCCTGTTTTTATCACTACTAGGACCCAAGCACCCAGACAGTAGAGCAAGGACCAGGCAGCCTGCCCCACCCTTCCCTGTAGCAATGTTCACAGCCTTGGGACCAGGTGTTGCTCCAGGTTCACTTCTGTCTGACACACTTGCACTGTTCCACGCTTGGCAACCTTGGGTAAGACTCCTGGAATAATAAACATGGTGAGAAGTCTGGGAGGTGGCTTCTGGCGATGCCATAGTGGCTTAAGGATGTCAGAGCTGAGGTTCCACCATTTTATTGGCCTTTTCCTCATGGTGGCAAGTGGAAGTGTTTCAGGCTTACTCAACTGGCATGATTGCAGCCTTTGGGCAAGGAGTAGTGGGACTGACCTAAAAGACTGTCCTAGTTCACCACTTGCAGGTGGCACCCCAGCATGGGCCGATTAATGCCGCTTTGGTTGGGAATGGGCTTAGGTGCCTTTTCTACAGGAGCATCATGGGCTTCTCCCAAATTTGGGAAGCTGGTGCTCTGATGCTCCAGGTGAAGTCAGAGGTGAATGGGGTTGCCCTTGGGTCTTGAATTGAAGAAGAGGCCGGGAGTGGGTGGCTAGGTAATGATCCTGAGATCATTCCTGGTTCTCAAAGAAAGGAGATGTTTACCAGACAGAATCTGTTTCGGCTTTAAATGATTATAGTTAATACCAATAGTTATCAATTTGCATATTATCCTCATCTCAAAATCCAAATGCATTTTTAAAATTGGCTAACTTTTAATTTACTAATATATTGCCGGTATAATTTTAACTTTGATTTTTGTTGTTCACTCACGTGTGTGTGTGTGCGTGTGTGTGTGTGTGTGTGTAGGGGTTTTCACACAAAAGTCTAGAGCTTTAGTATTTCGGGGTCTTTTAGCGCTAGCATTGCCCTTGTCTGCCAGCTTTTGCTGGCAGTAAAAGGCAGTGTATTTGAGGTAGGTGGCATTTCTTACTGCCCTTTAAATGTGTTTCTTTTGGATTTTACAGGTAGCCCCTGAAGAAGATGAAAGGAAAAAGAGGCGACGAGAAAGAAATAAGATTGCAGCTGCAAAGTGCCGAAACAAGAAGAAGGAGAAGACGGAGTGCCTGCAGAAAGTGAGTGCCTTCTAGCCTTACCCTTCCTCTCGCTCACGCCTGTCTTCACCAGCTTCATGTGGCTATCAGAAGAAGAGTTAGAAAACCCCCTACTTGGTTATAGTTTCCCAAGAAGGGCCTTGTAGCTGGTAGCAGAAATGCCAGTTGCAGAATGAGGAGGTGGCAAAGCAGTTAACACAATGGATGTGACGGTGGATGTATAAAAACAGGTGTGTGAATTCGTCTGATGCCTGACTCCCAGCAGCCTCGGCCGGTTCATACATGTCCATCAGCTTCCAGGCTGCAGGACATGCCAGCCCAGTTAAAGAGGCTTCACTTGACTGTTTTCCTGAGAAAAGGAAGCTGCCAGCTCTCATTTGGCTCACTATGAAAAGCCTTTAATTAATCTCTTCAAACAAGTTATTTCCTTAATCCACAAGCAGTGGTTACACTTGCTTTGCATTCTTGTCTGGTTCCTAACTCTAGAGCCCTTCTCCCTGGCTTAGCCAGTAAGCTGAGCCCCTGGCTGCGTTCAGCCGGCCCGCCTGAGAGACACTAGGGGAAATAGCTTTTGTGGGCAAGCAGGGTGGCCGGTGGTGCTCAGCAGTCTTTCCAGTGGCTGTGTCCCTCCTCCAAATGTGGACAGGCCATGACAGAGTCTTAGCCCAAGTCCCACAGATCCCCAAAAGTTCTGTTGATTGCTTCAGGGGATCAGTGAAAATTAGGGAATTTTGTGTGTTGCTATATACATTTTTTCTGGGGAGATGAGCTTCTCATTGAGATCTGTGACTCAGAATCGACTAAGCCACCATAAGTCTGGATTTCTCCCCAGCTCCCAAGGCCCTTTTGGGTCCAGAAGACCTGCATATGGGCTGTTGACTCATGCAAATGAGGTATCTGAACTGCAGCTTCAGTATTAGCAGAGCCACAGGCCGCCTCTGTGGCATCACCAGGGTTTCTCTGAAGAAGAGGGTCTGCATTTTCCTAAACCCAGTGCTGCTCTCCCATCTCCCATCTTCCTCTCGCAGCTTGATGAGCCCCGGTGTGTCCCAGGTACACCCCTGCATCCAGGCAGCAGCCCAGGCCACCCCCTCCTCACTGGCCCTTGGCTCCTTTCTTGATGCCTCTGTTGCTTGTCCCCCAGGAGTCGGAGAAGCTGGAAAGTGTGAATGCTGAACTGAAGGCTCAGATTGAGGAGCTCAAGAACGAGAAGCAGCATTTGATATACATGCTCAACCTTCATCGGCCCACGTGTATTGTCCGGGCTCAGAATGGGAGGACTCCAGAAGATGAGAGAAACCTCTTTATCCAACAGATAAAAGAAGGAACATTGCAGAGCTAAGCAGTCGTGGTATGGGGGCGACTGGGGAGTCCTCATTGAATCCTCATTTTATACCCAAAACCCTGAAGCCATTGGAGAGCTGTCTTCCTGTGTACCTCTAGAATCCCAGCAGCAGAGAACCATCAAGGCGGGAGGGCCTGCAGTGATTCAGCAGGCC CTTCCCATTCTGCCCCAGAGTGGGTCTTGGACCAGGGCAAGTGCATCTTTGCCTCAACTC CAGGATTTAGGCCTTAACACACTGGCCATTCTTATGTTCCAGATGGCCCCCAGCTGGTGT CCTGCCCGCCTTTCATCTGGATTCTACAAAAAACCAGGATGCCCACCGTTAGGATTCAG GCAGCAGTGTCTGTACCTCGGGTGGGAGGGATGGGGCCATCTCCTTCACCGTGGCTACC ATTGTCACTCGTAGGGGATGTGGAGTGAGAACAGCATTTAGTGAAGTTGTGCAACGGCC AGGGTTGTGCTTTCTAGCAAATATGCTGTTATGTCCAGAAATTGTGTGTGCAAGAAAAC TAGGCAATGTACTCTTCCGATGTTTGTGTCACACAACACTGATGTGACTTTTATATGCTT TTTCTCAGATCTGGTTTCTAAGAGTTTTGGGGGGCGGGGCTGTCACCACGTGCAGTATCT CAAGATATTCAGGTGGCCAGAAGAGCTTGTCAGCAAGAGGAGGACAGAATTCTCCCAG CGTTAACACAAAATCCATGGGCAGTATGATGGCAGGTCCTCTGTTGCAAACTCAGTTCC AAAGTCACAGGAAGAAAGCAGAAAGTTCAACTTCCAAAGGGTTAGGACTCTCCACTCA ATGTCTTAGGTCAGGAGTTGTGTCTAGGCTGGAAGAGCCAAAGAATATTCCATTTTCCTT TCCTTGTGGTTGAAAACCACAGTCAGTGGAGAGATGTTTGGAAACCACAGTCAGTGGAG CCTGGGTGGTACCCAGGCTTTAGCATTATTGGATGTCAATAGCATTGTTTTTGTCATGTA GCTGTTTTAAGAAATCTGGCCCAGGGTGTTTGCAGCTGTGAGAAGTCACTCACACTGGC CACAAGGACGCTGGCTACTGTCTATTAAAATTCTGATGTTTCTGTGAAATTCTCAGAGTG TTTAATTGTACTCAATGGTATCATTACAATTTTCTGTAAGAGAAAATATTACTTATTTAT CCTAGTATTCCTAACCTGTCAGAATAATAAATATTGGAACCAAGACATGGTAAA (SEQ ID NO: 16). In some embodiments, the ATF3 gene comprises a sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% sequence identity to SEQ ID NO: 16.

[0072] A transcript of ATF3 gene is provided herein (NCB I Reference Sequence: NM_001030287.4, with all T’s replaced with U’s to represent mRNA sequence):GUGACAAGAAGAGAAAUCCUCCUCUAUAUAGGAUGCUCUGCUGUUUCCUAAGGAUUUUCAGCACCUUGCCCCAAAAUCAAAAUGAUGCUUCAACACCCAGGCCAGGUCUCUGCC UCGGAAGUGAGUGCUUCUGCCAUCGUCCCCUGCCUGUCCCCUCCUGGGUCACUGGUG UUUGAGGAUUUUGCUAACCUGACGCCCUUUGUCAAGGAAGAGCUGAGGUUUGCCAUC CAGAACAAGCACCUCUGCCACCGGAUGUCCUCUGCGCUGGAAUCAGUCACUGUCAGCGACAGACCCCUCGGGGUGUCCAUCACAAAAGCCGAGGUAGCCCCUGAAGAAGAUGAAAGGAAAAAGAGGCGACGAGAAAGAAAUAAGAUUGCAGCUGCAAAGUGCCGAAACAA GAAGAAGGAGAAGACGGAGUGCCUGCAGAAAGAGUCGGAGAAGCUGGAAAGUGUGA AUGCUGAACUGAAGGCUCAGAUUGAGGAGCUCAAGAACGAGAAGCAGCAUUUGAUA UACAUGCUCAACCUUCAUCGGCCCACGUGUAUUGUCCGGGCUCAGAAUGGGAGGACUCCAGAAGAUGAGAGAAACCUCUUUAUCCAACAGAUAAAAGAAGGAACAUUGCAGAGC UAAGCAGUCGUGGUAUGGGGGCGACUGGGGAGUCCUCAUUGAAUCCUCAUUUUAUAC CCAAAACCCUGAAGCCAUUGGAGAGCUGUCUUCCUGUGUACCUCUAGAAUCCCAGCA GCAGAGAACCAUCAAGGCGGGAGGGCCUGCAGUGAUUCAGCAGGCCCUUCCCAUUCU GCCCCAGAGUGGGUCUUGGACCAGGGCAAGUGCAUCUUUGCCUCAACUCCAGGAUUU AGGCCUUAACACACUGGCCAUUCUUAUGUUCCAGAUGGCCCCCAGCUGGUGUCCUGC CCGCCUUUCAUCUGGAUUCUACAAAAAACCAGGAUGCCCACCGUUAGGAUUCAGGCA GCAGUGUCUGUACCUCGGGUGGGAGGGAUGGGGCCAUCUCCUUCACCGUGGCUACCA UUGUCACUCGUAGGGGAUGUGGAGUGAGAACAGCAUUUAGUGAAGUUGUGCAACGG CCAGGGUUGUGCUUUCUAGCAAAUAUGCUGUUAUGUCCAGAAAUUGUGUGUGCAAG AAAACUAGGCAAUGUACUCUUCCGAUGUUUGUGUCACACAACACUGAUGUGACUUUU AUAUGCUUUUUCUCAGAUCUGGUUUCUAAGAGUUUUGGGGGGCGGGGCUGUCACCAC GUGCAGUAUCUCAAGAUAUUCAGGUGGCCAGAAGAGCUUGUCAGCAAGAGGAGGACA GAAUUCUCCCAGCGUUAACACAAAAUCCAUGGGCAGUAUGAUGGCAGGUCCUCUGUU GCAAACUCAGUUCCAAAGUCACAGGAAGAAAGCAGAAAGUUCAACUUCCAAAGGGUU AGGACUCUCCACUCAAUGUCUUAGGUCAGGAGUUGUGUCUAGGCUGGAAGAGCCAAA GAAUAUUCCAUUUUCCUUUCCUUGUGGUUGAAAACCACAGUCAGUGGAGAGAUGUUU GGAAACCACAGUCAGUGGAGCCUGGGUGGUACCCAGGCUUUAGCAUUAUUGGAUGUC AAUAGCAUUGUUUUUGUCAUGUAGCUGUUUUAAGAAAUCUGGCCCAGGGUGUUUGC AGCUGUGAGAAGUCACUCACACUGGCCACAAGGACGCUGGCUACUGUCUAUUAAAAU UCUGAUGUUUCUGUGAAAUUCUCAGAGUGUUUAAUUGUACUCAAUGGUAUCAUUAC AAUUUUCUGUAAGAGAAAAUAUUACUUAUUUAUCCUAGUAUUCCUAACCUGUCAGA AUAAUAAAUAUUGGAACCAAGACAUGGUAAA(SEQ ID NO: 17). In some embodiments, the ATF3 transcript (i.e., mRNA) comprises a sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% sequence identity to SEQ ID NO: 17.

[0073] Another transcript of ATF3 gene is provided herein (NCBI Reference Sequence: NM 001674.4, with all T’s replaced with U’s to represent mRNA sequence):ACAGUCGCACGCAGCCAGGCGCGCACUGCACAGCUCUCUUCUCUCGCCGCCGCCCGAG CGCACCCUUCAGCCCGCGCGCCGGCCGUGAGUCCUCGGUGCUCGCCCGCCGGCCAGAC AAACAGCCCGCCCGACCCCGUCCCGACCCUGGCCGCCCCGAGCGGAGCCUGGAGCAAA AUGAUGCUUCAACACCCAGGCCAGGUCUCUGCCUCGGAAGUGAGUGCUUCUGCCAUC GUCCCCUGCCUGUCCCCUCCUGGGUCACUGGUGUUUGAGGAUUUUGCUAACCUGACG CCCUUUGUCAAGGAAGAGCUGAGGUUUGCCAUCCAGAACAAGCACCUCUGCCACCGGAUGUCCUCUGCGCUGGAAUCAGUCACUGUCAGCGACAGACCCCUCGGGGUGUCCAUC ACAAAAGCCGAGGUAGCCCCUGAAGAAGAUGAAAGGAAAAAGAGGCGACGAGAAAG AAAUAAGAUUGCAGCUGCAAAGUGCCGAAACAAGAAGAAGGAGAAGACGGAGUGCC UGCAGAAAGAGUCGGAGAAGCUGGAAAGUGUGAAUGCUGAACUGAAGGCUCAGAUU GAGGAGCUCAAGAACGAGAAGCAGCAUUUGAUAUACAUGCUCAACCUUCAUCGGCCC ACGUGUAUUGUCCGGGCUCAGAAUGGGAGGACUCCAGAAGAUGAGAGAAACCUCUUU AUCCAACAGAUAAAAGAAGGAACAUUGCAGAGCUAAGCAGUCGUGGUAUGGGGGCG ACUGGGGAGUCCUCAUUGAAUCCUCAUUUUAUACCCAAAACCCUGAAGCCAUUGGAG AGCUGUCUUCCUGUGUACCUCUAGAAUCCCAGCAGCAGAGAACCAUCAAGGCGGGAG GGCCUGCAGUGAUUCAGCAGGCCCUUCCCAUUCUGCCCCAGAGUGGGUCUUGGACCA GGGCAAGUGCAUCUUUGCCUCAACUCCAGGAUUUAGGCCUUAACACACUGGCCAUUC UUAUGUUCCAGAUGGCCCCCAGCUGGUGUCCUGCCCGCCUUUCAUCUGGAUUCUACA AAAAACCAGGAUGCCCACCGUUAGGAUUCAGGCAGCAGUGUCUGUACCUCGGGUGGG AGGGAUGGGGCCAUCUCCUUCACCGUGGCUACCAUUGUCACUCGUAGGGGAUGUGGA GUGAGAACAGCAUUUAGUGAAGUUGUGCAACGGCCAGGGUUGUGCUUUCUAGCAAA UAUGCUGUUAUGUCCAGAAAUUGUGUGUGCAAGAAAACUAGGCAAUGUACUCUUCCG AUGUUUGUGUCACACAACACUGAUGUGACUUUUAUAUGCUUUUUCUCAGAUCUGGUU UCUAAGAGUUUUGGGGGGCGGGGCUGUCACCACGUGCAGUAUCUCAAGAUAUUCAGG UGGCCAGAAGAGCUUGUCAGCAAGAGGAGGACAGAAUUCUCCCAGCGUUAACACAAA AUCCAUGGGCAGUAUGAUGGCAGGUCCUCUGUUGCAAACUCAGUUCCAAAGUCACAG GAAGAAAGCAGAAAGUUCAACUUCCAAAGGGUUAGGACUCUCCACUCAAUGUCUUAG GUCAGGAGUUGUGUCUAGGCUGGAAGAGCCAAAGAAUAUUCCAUUUUCCUUUCCUUG UGGUUGAAAACCACAGUCAGUGGAGAGAUGUUUGGAAACCACAGUCAGUGGAGCCUG GGUGGUACCCAGGCUUUAGCAUUAUUGGAUGUCAAUAGCAUUGUUUUUGUCAUGUA GCUGUUUUAAGAAAUCUGGCCCAGGGUGUUUGCAGCUGUGAGAAGUCACUCACACUG GCCACAAGGACGCUGGCUACUGUCUAUUAAAAUUCUGAUGUUUCUGUGAAAUUCUCA GAGUGUUUAAUUGUACUCAAUGGUAUCAUUACAAUUUUCUGUAAGAGAAAAUAUUA CUUAUUUAUCCUAGUAUUCCUAACCUGUCAGAAUAAUAAAUAUUGGAACCAAGACAU GGUAAA (SEQ ID NO: 2148). In some embodiments, the ATF3 transcript (i.e., mRNA) comprises a sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, atleast 98%, atleast 99%, atleast 99.5%, or at least 99.9% sequence identity to SEQ ID NO: 2148.

[0074] As used herein, the term “ATF3 protein” refers to Activating Transcription Factor 3 and functional variants thereof. For example, the ATF3 protein may encompass proteins that have at least80% amino acid sequence identity to the amino acid sequence set forth as UniProt Accession No. Pl 8847 and / or has ATF3 activity of binding to a regulatory region of the genes that can be activated by a wildtype ATF3 protein and activating gene expression. In certain embodiments, the ATF3 protein is a human ATF3 protein. In certain embodiments, the ATF3 protein is a mouse ATF3 protein or a non-human primate ATF3 protein. The wildtype human ATF3 protein can comprises an amino acid sequence of MMLQHPGQVSASEVSASAIVPCLSPPGSLVFEDFANLTPFVKEELRFAIQNKHLCHRMSSAL ESVTVSDRPLGVSITKAEVAPEEDERKKRRRERNKIAAAKCRNKKKEKTECLQKESEKLESV NAELKAQIEELKNEKQHLIYMLNLHRPTCIVRAQNGRTPEDERNLFIQQIKEGTLQS (SEQ ID NO: 18). In some embodiments, the ATF3 protein comprisesan amino acid sequence of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% sequence identity to SEQ ID NO: 18.

[0075] A genomic ATF3 nucleic acid sequence in mouse is provided herein (NCBI Ref: NC_000067.7): CTGGGATTGGTAACCTGGAGTTAAGCGGGCTCCCTGCCAACGCGAGGGCTTTAAAAGGG GTGATGCAACGCGCTCCCAGCCACAGTCTCACTCAGCGAGACGCCGCGCACGGTGCTTC CCCAGTGGAGCCAATCGGCTAACCCGCGCTCCGGCAGAGTCCTTGGCGCTCGCCCGCCG GCGGGACAGACCACCCGCCTCTGGCCGCTCTCTGGACCCTGGCCGCCCCGAGCGAAGAC TGGAGGTGAGTTAGAGCCACACCGAGGAGCGCTGCCCTCCTCACCCTAAGTTCCCCTCT GGTGACCAGTCCCGGGACCCTTGCGCCACCGGAGACTGAAGCCCTAGTGTCCGTGCCAC AGTCGCTCGGCTGAGCCGCTCTTTGCCGCTGCCGTTCTTAGCTGGTAAAAAGTTTCTGGT AAAGTGAAAGAACGAACTTTCTCTTTTGACTCGAGGCGTGAAAGATGCCCAGGGACGG AGGAGTTGCGCTCTCAGTTTGCAACTAGGAGAGGTCGTCTGGGTGGAAGGTGGGTGCTG GTGCGCGGAGGTGACTCACACTCTGGCGATCGGGGTCCCCTCTTCCATCCATCACTTCTT GTCCCGGACCCTGGACTCGGAGCGGGTCCCTCCTAAGTCCGCGTAGAGGCGCAGTGGCC GCGGCTTGTTGAAGCGCTGCTCCCGGTATCGAGCTAAATGAATGAAGACCGGACGCTCG AACGGAGGTCCGGCACAGCCGCTGGAGGTCGCCTTGCGCTCCCCGGAGCAGAGATCTG GGCAGCATGACCGCGTAGAGCGCTGTGAGCGAAAGTGTGTTAGGATAAGTTTGGAGGC GGCGAGCCCTGGTGTGGCGCTGTCCCGGGGCTGAAGGCCGAGAGGTCTCCGCACCAGCT AACTTCGGACCGCTAGGTTTGAGACGTCACTTCCAGCCTCACTCGCTGTTGTGACTTGCT GTGCTCTGGCTGACTTTTAACCGGCCCTTGAGTTTCTTTATGTATTGGAAGGGAAGCGAA GGAATCGGATCAAGCGGGTGGAGGGACCAGGGTGTGGAACCACTTGTACTTGGGGGGG GGGGCGTGCGGGGGGGGGGTTGTTTGTATTCTCGTGACAGAGTCTCACTCTGTAATCCA GACTGCCCATAAAAACTCCGGCCAATCCTCCTGCCTCAGCCTCCCAAGTGCTGAAATTACAGGCCCACACGCCCAGCACCTTTCTGTGCGCTGTGTGCTTCAGATAGCCAGCTTTTGACAGATTTGTTTCTAGACTAAAATAATTAAAGTAAAAGGAGCCAGGGAGGGATGTTCAGTGTGGAGGCTCCCCCACCCAGCGTTCCTAGCCGGTCTCTGAGACAGGACAGGAAAGGGGGCCTCTCTTACATCTCTGTCTCCTAGCTCTCTCCCGTTGGATTGATTCCCTGCTTCGACCCCATGCTCATTTTCAACTCCCATTTCTGTATTTTCCTCTTAGCCATTTTATTTGATTTAATCATGTAGCTCACGAGCTTTCTTATAAATTAAAGGAGTTGCCAAGCCCGATTATTTAAAAGGTTTATTCTCCCCTCCTGTTGTTCCACTCTTTTGAGACAAAGTCTCCCTATGTAACTGGGGCTTGCTTTAAACTTATGGCAGTCTTCTAGCCTCGGTCCCCAAGTGCTGAGATTACAGGCATGTGTCACCAAGAAGGGAGCACATGTTTTGCATGTTGCATTTGTTATGGGATAATGTTACCACATACAGGCTCTTGCTTGGAGCGGGTGGGGCTGGGGTGGGGGTTGCTGTTGCTTCTATCAAGAGGTTTCAGAGGCTGCTGACCAGGTTCCCAGAGTGAAGAAGGCATTGCCCAGCACCTGTGGCTATCTAAATCCCTTCTTGGCACACCAGTTTCTTCTGGTCTTCATTCTGTCAGAGCCTCCTCTATGAGGGGTGCCAGGTATGGGTCTCTTCAGCCCTCAGTTGCCCCCCTGGCAGGCAGCTCTCTCTGTGGTTGCTTATTTGGTTGATCTATTGAACTAACTGATGGGTCCTCCTGGTAGTGCAGAATGAGTAGAGGGTGGGTGTGGGCAGCTTGGCTGGACTGGACCACACCCATCTCTGTGAGTTTAGTTAGGCAAGTGCTTTCCTTCTGGGACCTCAGTTTATTCAATGACAAAATGGGGGTTTGAGCTAGACAATTCTAATGCTGGGAGTCCCGTTGAGTTCCTTTAGCCAAAGTCTGTGATTCTTTAAGGAACTGGCTACAGGGGTTCCTTGTCAAGGGAGGAGGGACATAGCCAGGACCCCCCAGAAACTTCAAGAGAGAAATGGTTTCCTATGTGAGAACTCACAATCTTGGCCAATCCAACCCTAATGGAGGAATGCTGATGTCAGCCAATTGGGTGTAATTCACCTGGTGTCTTAGGAACTCGGGGGTCAACCACCAGTTGTGACAGACTGGCTTGAAATTCTTGAGGGTTCCAGTCAATTCCTGATGACTAGAACTAAACTGAACTGAACTAGATCAGGGTCCCTGAGGGGCAGGGAGAATGTGAATGTATGGATCCTAATTTCCTTATGTTTTAAAGTTTGTGCATGTGATGTGTTGTTCCCCACAGCCCTGGGAGGGAACTGGTCAGTTCAGATAGGAACTGAAGGTCAGAAAGCCTCTGGCTCGGGAGTGGGTGCCCAACTAGTGAGAACCAGAGGCAGACCTGGAAATGCTGTCTCTGACCCTCAAGCCCAGCCTCCCGCCTCCAGCCTTCAAACAGGAGAAAGGACAGGATGTAGAGTCAGGAAGGAGTACTGGTTCCCTAGTACTACAGGACAGTTTGCAGACAGCTTGGTGGAAGGAAGTGGAAATCAAAAGTGAAAATTCAAAGCCATCATAAGCTACTAGGAGATAAAAATCTAGGAGCTGAATTTCCAGTTAAGTGAGGGAAGTTTCATTTTCTTGAAAATGGCGAGATTGCCGATGGTGCGGCATAATTTCTGGTTGGAAGTCATGAAGCAGCATCTGGAAGCATATCTGAAAGACAGCTTTATGATCAGTGTAGAAAGTTCACTCAGCTCACCCCAAATCTCCCCTCTTTGGGGCCTCAGCTCCTGAAATCAAGTTGAAACTTTCAACTTTCTTTCCCTGGAGGACACAGCCTGGCTCTGCCTGACTCTCTGGAGACCTCTGTGCAAGACAAACCAGAAAAGACAAGAGCCCAAATCTTACAGAGTGTGCCCCCATGGGGGCTTCTTAACAGCTTTCTAACATGCTTGTGTCCCCAAGTAAGCCCCACCCCCAGCTCTTCACAGAAACATTCCATACCACTGACATTCCTCAGTTTCTTCCTGACTTTACACTAAGAATGCTGTTGGGGGAAGTCCTATACAGCGGACTTTAACCTCAAAGGGCTCGTTAATAAACTTAACTGGGCTGCTAAAGGCTCATGCTCAACTGCTGTGGCTCAAGCTAGTTAAGTATAGATGAACTAGTTAAGTATAGATGAACTATTCAGTCCTACAAATGATGGCCAGGCCAGTGGCAGCCCTGAATTCCACCCCTGGACTGTTGGGGTTTTTGTTTGTTTGTCTGTATTTCCAATAAAATGCAAAGGAGAATATATAGGAGGATGCCGAGCCTCTGGCTTCAGAAGTCATAGAAACATCCCCCAGGTACAAGGTTACAGCTTCCAATTAAGAGACCTTCAGTTCTTACTCCTGTCTGGAAAAGAATTGTATACATCTTTTTGAGTTCTTTTACTGCTCTGGAATTTCTGCCTCCACCAGTGGGCCTTAATATCCAGGGAAAGGGATCTTCAGGAAGGGCTCAAGAAGGTGACCAGACCCCAGGGAGTCTCCGTAGGAGAGCAGCCATCCCTCTGTGGGAGCTCCTGGGAGACCCAGAGTAGCTCCTCATGGCAGAATGCTTTCCAGGGCATTTCTTGTATTATTTCCCAAATTGCTTCCACCACTCTTGGGGAATTAGGGTACTCATTACCAGCCTTCCTTTACAGAAGAGATAGTACACCAGGGTACTATCACCACACATAACTGAGCAGTCTTCAAATCTCAGTTAACAAACAAACAAACAAACAAATTCTGGTATAGGGATTTTATGGAAGGCTGTGAGTTCTGAAACCACGCAAAACAAATCCCAGTGCCCCATACTATCCCATGTTAATGTGATCTGACTAAATCTCAGTAAGTTCATGTCTAAAATGGGACTAGTTTTCACAACGCTGGCTGCAAAGCTCAAGGGAGACAAGGTAGATAGATTTCTCCTTAAATGTTAGAGATTTGCCAAAAGGCTCACTGCCCTCTGGGACTTGGCTGATGACCAGTGTAGCCGAGGACGGTCCCTATACCGCTCCTGCTTTGGGAAAAGGCCCGTGGGGGCGATGGGGGCAGCAAGTCTGCAGCAGAAAGAGGCACCAGAACACTCTTCCTAGATTGCTTCTGCCCGTGGTTCCCCCTGTCACCCCTGTGGGTTTGCTGACCTATAGACTGATGAGGTCATCTGCTTCGGCCACCTCGGCTGCACTTTATTTATTCAGTTGTTTAACTGGCCAGCCGGGACAGAGCTTCAGCAATGGTTTGCTCGCTTTCTCAGCCAACTTCCACATGTAGACTGAGTCCCATAGGGCCAAATTGCCTGCTCCTTCATCCTAGATCTTTCTTTGGCCCTGTTCCAAGCTTTGCTCCTTGCATGTCAAAGCTAAACAACACCCCCATAAAACCAGAACTTTGCTCCTGGCTTTTGCCTGCTGAGTGAGGTCCTTTGCTTTGCCAGCCATCTCGTTAAGAAGGGGCTCCGTATTCCTGCATGACCTGAGTTACCACCACTACCGCCGTTCCCTGCCAGTGACTGGGGCAAAGAAACATACCCCACGGTGTGTTTACCTTCTTCATTCGGACCCAGTTTCCTCCAGGAGAAAGTTCTGCCACAGAGTTGTTGAATTCAGGGCCCCAGCTTCCACTGGCTAACAGATGTGGCCCAATTCAAGTGTCTTCCCGATTCTTTTTGAAAGGAGACTGAAAATGGGATCACGGCAGGCGCTGTACTTTTTTTTTCCTTCCTTCCTTTTGGGACCGAGGCCACATTTGTATATTCTGCATACCGGCCACAGAAGAGCCTGAAATGAGGACCCCCTTGAGCCTTATTTTAGATGTGTCTCTGAGCTGTGTGTTTTAAGGATCTGTTTTACTCACAGTGAGGATAGCATAACATTTTTTTTGATGGTGCATTGAATTTAATTAGCATTGTTTGCACGGGTGTGGGGATAGTTATTGGCACATGGGCAACTTAACTACTGAATAAATGTTCCCTTTAACTGTCAGGGTTCACTGCTAATAGCTCCTGGGTTAGGGTTGGGACTGCATCTTCCCTCTACAGGTCCTGTGCAGGTAACCAGAGCTGCTGGGTTCATGAGAGAAACTGCCGTGTCACATCCAGAAAGCAGCACTTCCCAGAAGTCTCCTACCCTCCTGAGCTTACCTCCTTTTAGCCCCGATGTTCCCTGAGCTATGAATGTGTGTGTGTGGGGGGGTGCTGTTTAGGATGGGACATGGAACAGCCACTTATTCTCAGCACCTTGTACAGTTATGAATCTCTGCATTAGCTGCTGCCTGTTGCAAAAGGAAACTGACCAAGGTTGTATTGCTAATCTGTGGGCCAGAACATAAAGGAGGCAGTTTTACAACACATATGTTTAGCAAAACAACAGTAATATGTTCTCCTTTACTTCCTATAATTTCTCCAGGCATGGGCAAGGCATGGGCATGGGCATAAAGTAATAAGAAACCTGAAGCCTCAGGGCTGATGGGATTTGTTTCTGAGGTAGGCTGTCAGACCCCATGCCCCAGGACGCCTGAAGCAGTGTGTGCTTATTCTTTTTTCTTTCAGCAAAATGATGCTTCAACATCCAGGCCAGGTCTCTGCCTCAGAAGTCAGTGCGACCGCCATTGTCCCCTGCCTCTCACCTCCTGGGTCACTGGTATTTGAGGATTTTGCTAACCTGACACCCTTTGTCAAGGAAGAGCTGAGATTCGCCATCCAGAATAAACACCTCTGCCATCGGATGTCCTCTGCGCTGGAGTCAGTTACCGTCAACAACAGACCCCTGGAGATGTCAGTCACCAAGTCTGAGGTGCGTTCTGCAACACATGATCCTTTCTTCAGCTCATGCTTGTCACACATGCTCCACATTCCAGCACATTCAGAAGGCTTAAAGTTGGGGATAAGAACCATCCAAAGCTCTGGGCTCTGGGAGGTTAAAGTCTAAAGATAACAGAGTAAAGACTATAATACACGAATGAGCAGGTATAGTGTGCACCCGAGAATGGGCAGATAGAGTGTGTGCATGTGTGTGTGCGCATGCAGGTACATGCATGTGTATGTGTCTGTGCATATGTGTGTATGGATGTGCATACATGTGCGTGCGTGCATGTGTGTGTGTGTGTGTGTGTGTGATATCAAGAAACTGAAACAGGAAGATCAAGAGAGTGGTGAGTTTGAGGGAAATCTGAGGTACATTTCCATACTGTCTTTTAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGCACTCAGCAGTTAATAGCACTTGCTGCTCCTGCAGAGGACACAGGTTCAATTCCCAGTACCCACATGGTGGCTCACAGCTATCTGTACCTTCAATTTCAGGAAATCCAACATCCTCTGCAGGCAACTGCATAAACATGTCACAAATACATAAATGCAGGTAAATACTCATACATGCAAAATAAAAATTATGTCTCTTTTAAAACAACAACAAAAGGAAGACAGAAGCAAGCAACTGCACAAACTCAGACACACACAGGCAAAGGCTGGTGTGCACAGAAGCAAGCAACTACACAAACTCAGACGCACACAGGCAAAGGCTTATGCACATACAAATAAACTTTATTATTATATTTTAAGAAAAGAAACGGGTTCAGAGATTAGCTCGAGGTGAAATTTTCATTTTAGATTAGGAGACTGTGGAAAGCTTGCCTGGTCATGGCCTACTAGCTAAGACTTGAGGAGAGGGAGTTGTGTGGGAAGGGTTCTCTCATTAGGAAGAAGACTGTGGGCTGGGAGTGAACTGGGCATGTCACACAGAAGCTGCTGTGTCAAGAGTAGAAGGGAAACCACTGGGAGGCTTTTGGACAGAGAAGAAGCTGGTCTGATACATTTATGTGGTTCCCTGGTCTGATACATTTATGTGATGCCCTGAAAACCGTATTGGGTAGGCCACTGGATGAGTAAGCCAGAGAAGTATGCTCAGAAATGAAACTATGAGACCCTGCACTTACACGGAGGAAGGTCTGGGATATAGTGCTGAAGGTGGCTGGCTTCTGGACCTAGGCCAGCTGTCTTAGGTATGGCTATGGTTTTTGGAAAGATGAGAGTATCCATTTGTTGCAGGAACTGTAGAAGGCCAGGTGGGACAAGAACAGAACTTATGTCCTTGGAAGATGTCAAATAGGCAGGCACAGATGTGAGCTGGGAGTCCTGGGCCAGAGATCCAGGGCTGGGAAGTATCTGACTGTGGATGGTGCTTGAAGCTGTGAGTTTGGTGAGGCCACAGTCTGTGCAGAGGCTTTCTAAAGAAGCAAGGAATATGGTGGCGATTTTCATCACTCAATGGATCCAGGGACCAAGGATTAGCCCTACCCTTCCTGATAACAATGCTCACAGATGTGGTACACCATGTGTTTGCTCTGTGCTCACACATGTTCACACACATGTTCTGTGTTGAGAAACCTTTGCATAAGACGCCTGGAGTAACAGACATGGCTACTGAGCTGTGGTTGCTGGTAGCTCTGTTGTCTCAAGAGCATCAGAGGTGAACACTTGTAACTTTGCTAGGCTTTCTTAGTTAGGATTATTTTAAGTTTACTTAATGGGTATGATGGCAACTGTGGAGTAAGGAGTGAAACTGGCTCAAAAGATGTGAATTTAAAAGGAGCTTGAGGTCTGGGGTTGTAGGTCAGTGGCGGAATATAAGACATTGCATTACATTGGGGATAAAAAGAGATTGATCAATAGGACTGACATTTGTGGAAGTCTGAGGGGAACCTGAATCATAGCATTTAGTAGATGGGAATGAACTATTTATGATGCTGTTGCTATGGATGCCGTTAGGGGCATTAGCTGTGCTTCAAGCTAGCTCAGAGGAGGTCAGAGAGGGTACCACAAAACAGTCATGGCTATCAAGTCCAATACTGGAGAGTTAGAGCCTGGGACATTCTGGGAGATATTTTTTTCTTCTAATGAAATAGTTTGAAATAAGACACAGTAGTAGGGATAGACGGGGAAGGGAGGCTAGACAGGTGGGTGGCCTGGGAAGAGCAGTTGGGGATCTCTAGAGGGAGAAGAGTGGGTGGGTGATGCTCCCAGGCATTCCTGACTCTAGGGGGAAGGATGTATTTATGAAATATTCTTTGTCCAGTTCTGAATTACAGGGATCAGTGTTTTATTGGTTGTTTTTGGTTTTCAAGACAGGGTTTCTCTATGTAGCTTTGGCTGTCCTGGAAGTCACCCTGTAGACCAAACTGGCCTTGAACTTATAGATCTGCCTGTCTCTGCCTCCCAAATGCTGGGATAAAAGGCATGTGCCACCACTGTCTGGCTCACAAAGGCCAATTTAAATATCAAAACCTTATTTCAAAATCCAAATAACTTTTAAAGTAGACACAATCTCAATTTCCCACATTACCAGTGTAATTCCTTTTTTTACTTGTTCTTTGATTTTCATGATTTTCTCTTTGTATTATTTTTTTTTAATTTTATGTATGTGAGTGTTTTGTCTGCGTGGATATATGTGCATTGTGTGCATGCCTGCTGCCCACAGAGGTCAGAAGAAGGTTTTGGATCCCCTGGAACTAGAGTTACACTTGAGAGCCACCATGTGGGTGCTGGAAACCAAAACCAAGTTTTCCATAAGAGCAGCAAATGCTCTTAACCACTGAGCTATGTCCCTGTCTGTGTCCGTGTCCGTATGTGTGTGTGTCTGTCTGTGTCTATATGTATGTATGCATGTGTGTGTGTGTGTCTATCTGTGTGTATCTGTGTGTGTGTATGATTTTTGTATTTCTTGGGACAGTGGCCTTGAGGCATGAAGGATAGAAATTTGGGGTTAGATTCCTTGGGCTTTGCCTCTGTAGGTTGTAAATACTTCCATCTCAGTCCACCATGTCTTCTGATTCAAAAGAATGGGGAAAGGTCAGGAGTGGGCCAGTCATGGCATCCCAAAGCTGGCAGGGTCTGCACTGAGCATCCCACGGGGAGAGTTCATCCCAGCTGTGCTTTACAGAGTCCATGGCTGGATGTGCTCACTGCTCGTCGGTTCATAGACCATCAGGGTCAGGGTGAACGTCCACGGAGGACCATAGCCACCAAAGCTGGACGTGGCTCAGTCCTCTGAGCACCCCAGTTCTGGCTCAGAAGGAGGCGCAGGGAATCAGTCTGATTTGTTGGCCGAATCAGCAGGTGGTTCAGGACTCTACCCATCAATAGCATCCGGCTACGGGCTCATTCGTACCATCTGCTACCACTAATGGTCTCAAGTCCCTCCTCCAGGAGCTCACTGACCTCATGGAAAGGATGTACCAGGATGCTCTTGGTAAAGACAGAAATAAATGTTGGTTGTTTTTCTGGAACTGTGGTCACATGGTTGACAGAAGTCATGGGAAGAAGTTTGATTTGGCTCACACAGTTGAGGGGATACAGTCCGTTGTGCAGGGAAGACAGGCAGCCAGGGAAGCTCCGTGCCCAGTGGTGAAAACGTGTGCCCAATTGTGAGAGCTTGTGCATGGTGGTGAGGGCTTGTGCATGGTGGTGAGAGCTTGTGCTCAGTGGTAAGAGCTTGTGCTCAGTGGTGAGGGCTTGTGCTCAATGGTGAGGGCTTGTGCTCGATGGTGAGAGCCTGTGCACATCTTTCTAGCTCAAGAAGCAAAGCTTAGATAAAAGTAGGTTCCGAGTTCAACAGTTCCCTTCCCTTGTTCAACAATCCACCCCTGCCAGCCATGTCTCCCACCCCAAAGGTTTCACAACCTCCCCAAACAGCACTGTTCTCAGGAGAATGTGGCTAGGGGACAGTCTGGTCATTCCTGACTCCAGAGGGAAGGACAACTTACAAAGTCTTGTGTGTATGTGTGTGTGTGTGTGTGTATGTGTGTGTATTGATTATAATTAGCATCAGTGGTTATCATTTTAAAATTCAAATTCTTATTCCAAAATCCAAATGCATTTTTAAGGTAGGCTTTAGGGTTTTATAAAAAGATTTATTTATATGAAACACTGCAGCTGTCTTTAGACACACCAGACAGAAGAGTGCATCAGATTTCATTACAGATGGTTGTGAGCCACAATGTGGTTGCTGGGAATTGAACTCAGGACCTCTGAAAGGGCAGTCAGTGCTCTTAACCACTGAGCCATCTCTCCAGCCCCAGGTTTTAGGTTTTTAAAGCAGCTTTTAGTTTACTAATTTCCAATATAATTCTATTGTACTGAACAGGCTTTAGATTTTGTTATTCATTGTCAAGCGTTTGCATGCACATGTGTGTGAAGGGGATTCATACAGAAACTTAAGTCGTGAGGCTGGAGATGGCTTGGTGGTTAAGAACACTTGCTGCTCTTCCCGAGGACTGAAGTTCCCAACACGTGCAGTAGGTGGCTCACAGCAGCCTGTAACTCCAGCTCCTGAAGATCCATCCAACACTCTCCTCTGGTTTCTGAGATCACCACGAATGCACGTGGCAGACATACACACAGACAAATATAGATATGCAAATGTACACATAAGGGATTAAAAACAAGCAAACCCCCACAGCCTTGATATTTGGGTTCATGGTGGCTTAAATGTGTGCCTTTTGGATTTTATAGGCGGCCCCTGAAGAAGATGAGAGGAAAAGGAGGCGGCGAGAAAGAAATAAAATTGCTGCTGCCAAGTGTCGAAACAAGAAAAAGGAGAAGACAGAGTGCCTGCAGAAAGTGAGTCCTGCCTGGTCCAGCCTGTCCTAGGGGATGGAAAGCCTTGTGGGTGGGGCAGAAATGCCAGCTGTAGGCAGAGGATGGAGCAAAGCTATTAGCATGGCAGAAGCGGCTCTGGAGATATATGTATCTACACACACACACACACACACACACACACACACACGCACATATTTATATACATACATACAAACATACATACATACATACATACATATGTGTATACATATATCCAGGGCCAGCAACAGCTTGCCATGAAACCTGGCACCCTAGTTTGATACCCAGAACCCACTGTGGAAGGAAAGAACTGATTTCTAAAAGTGACCTCTGACCTCCTCATGCATGCTGTGACA CAGACTAGTCAGTCCACAAACCCCCAGCAGTTTCGAGACTTTCGAGTCACACCAACATA GTTAAAGAGACTTTACTCACCGGTTTTACCAAATACAACAAAACTATAAAACCCTGCTA TTGCCTTTGGCTCTCAGATTTCTTTTCCATGTCTCCCAACTTCCGAGGCCTCTACAGGGTT CATACCACCTTCCACCTAGTTTGATCATCCCATCTTTGTGGTACGATGGTTCCTCTAGCA GGTCTCTCTCTCAGTTTGAGGAGCCCCAAGGTTCCCAGGTGGTCCCCCACCTCCCTGCTC CTTGGCTCCCTCCATTGATTGTCCTCTCTTGATTGTCCCTCAGGAGTCAGAGAAACTGGA GAGTGTGAATGCTGAGCTGAAGGCCCAGATTGAGGAGCTGAAGAATGAGAAACAGCAT TTGATATACATGCTCAACCTGCACCGGCCCACCTGCATCGTCCGGGCTCAGAATGGACG GACACCGGAAGACGAGAGGAACCTCTTTATCCAACAGATAAAAGAAGGAACATTGCAG AGCTAAGCAGAGGTGGCACGGAGGCAATTGGGGAGTTCTTACTGAATCCTCCTTTTCCA CCCCACACCCTGAAGCCATTGGAAAACTGGCTTCCTGTGCACTTCTAGAATCCCAGCAG CCAAGAGCCGTTGGGGCAGGAGGGCCTGTGGTGACCTACTGCATTGACCCACTCTGCCC CCGAGTGAACCGTGGAGCAGGCAGGAGCATCCTTTGTCTCACCAATTCCAGGATTTAGG CCTTATCATCCCGGCCAGTCTCAGATGACCTAGCTGGCCCCAGGCTGGGGTCCTATGCAAAGCAGGATCCCACTAATGGGATTCAGGCAGAAGTGTCTACCTTGATAGGTGGGGTGGG ACCACATCCTCCACTGTGGCTGACAACGCCCTTCCAAGGGAATATGGAATGAGAACATT CATTATTGAGGTTGTCCAATGGCCAGGGTATGCTTTCTAGAAAATATGCTGTTCTGTCCC AGAATGACTGTGCATAGGGTATCCGTTTCAGAGCCTGGTGTTGTGCTATTTAGATGTTTG TCTTGCACAACATTGGCATGATTTTTCCGGGAGTTTCATCAGATCTGATTTCTGAGAGTC TGGGGATCTGCCATGGTGGAAAGTGCCCCTCAAAAGCATTTGTGTGGCCACATGAACTG GCTGGCACCAGGGGAGTGAAACTGGCTGATGACCAGCTGAGCCACTTTGTGCCAACAG AGGATGGACGACACCTTTCCCTGTACCCACTGCAGAGGAAGAACCCTGGGCACAGCAG CTTTGTCCTTGGCTACAAACTGTTACAACGTCACACAATGAAGGCACAAAGTCCAACTT TCAAAGGGTGTAGGACTCCATACTCAGTGACAGGGCAGGAAGAGCCAAAGATAACCAC AGCCACAGCCTGTGGAGACCAGGGTTGGAAGCCAGGTGCAGGGCCAGGCATCTGCATT GTGGGATGTTAATGGCACTTTTGTCTTGTAGCTATTTTGAGATGTGGTCCAGAGCATTTC AGCTGGGAGATCTCCCTCTGGCCACCAGGACTCTGGCTACTGTTAAAATCCTGATGTTTC TGTGGAATCCTCAGTGTTTAATCCCACTCAATAGTATCATTACAGTTTTCTGTAAGAGAAAATATTACTTATTTATCCCAGTATTCCTAGCCTGTCAACATAATAAATATCGGAACAAAA CCTGGTAAA (SEQ ID NO: 21). In some embodiments, the ATF3 gene comprises a sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% sequence identity to SEQ ID NO: 21.

[0076] A transcript of ATF3 is provided herein (NCBI Ref: NM 007498.3, with all T’s replaced with U’s to represent mRNA sequence):CUGGGAUUGGUAACCUGGAGUUAAGCGGGCUCCCUGCCAACGCGAGGGCUUUAAAAGGGGUGAUGCAACGCGCUCCCAGCCACAGUCUCACUCAGCGAGACGCCGCGCACGGUGCUUCCCCAGUGGAGCCAAUCGGCUAACCCGCGCUCCGGCAGAGUCCUUGGCGCUCGCCCGCCGGCGGGACAGACCACCCGCCUCUGGCCGCUCUCUGGACCCUGGCCGCCCCGAGCGAAGACUGGAGCAAAAUGAUGCUUCAACAUCCAGGCCAGGUCUCUGCCUCAGAAGUCAGUGCGACCGCCAUUGUCCCCUGCCUCUCACCUCCUGGGUCACUGGUAUUUGAGGAUUUUGCUAACCUGACACCCUUUGUCAAGGAAGAGCUGAGAUUCGCCAUCCAGAAUAAACACCUCUGCCAUCGGAUGUCCUCUGCGCUGGAGUCAGUUACCGUCAACAACAGACCCCUGGAGAUGUCAGUCACCAAGUCUGAGGCGGCCCCUGAAGAAGAUGAGAGGAAAAGGAGGCGGCGAGAAAGAAAUAAAAUUGCUGCUGCCAAGUGUCGAAACAAGAAAAAGGA GAAGACAGAGUGCCUGCAGAAAGAGUCAGAGAAACUGGAGAGUGUGAAUGCUGAGC UGAAGGCCCAGAUUGAGGAGCUGAAGAAUGAGAAACAGCAUUUGAUAUACAUGCUC AACCUGCACCGGCCCACCUGCAUCGUCCGGGCUCAGAAUGGACGGACACCGGAAGAC GAGAGGAACCUCUUUAUCCAACAGAUAAAAGAAGGAACAUUGCAGAGCUAAGCAGAG GUGGCACGGAGGCAAUUGGGGAGUUCUUACUGAAUCCUCCUUUUCCACCCCACACCC UGAAGCCAUUGGAAAACUGGCUUCCUGUGCACUUCUAGAAUCCCAGCAGCCAAGAGC CGUUGGGGCAGGAGGGCCUGUGGUGACCUACUGCAUUGACCCACUCUGCCCCCGAGU GAACCGUGGAGCAGGCAGGAGCAUCCUUUGUCUCACCAAUUCCAGGAUUUAGGCCUU AUCAUCCCGGCCAGUCUCAGAUGACCUAGCUGGCCCCAGGCUGGGGUCCUAUGCAAA GCAGGAUCCCACUAAUGGGAUUCAGGCAGAAGUGUCUACCUUGAUAGGUGGGGUGGG ACCACAUCCUCCACUGUGGCUGACAACGCCCUUCCAAGGGAAUAUGGAAUGAGAACA UUCAUUAUUGAGGUUGUCCAAUGGCCAGGGUAUGCUUUCUAGAAAAUAUGCUGUUC UGUCCCAGAAUGACUGUGCAUAGGGUAUCCGUUUCAGAGCCUGGUGUUGUGCUAUUU AGAUGUUUGUCUUGCACAACAUUGGCAUGAUUUUUCCGGGAGUUUCAUCAGAUCUGA UUUCUGAGAGUCUGGGGAUCUGCCAUGGUGGAAAGUGCCCCUCAAAAGCAUUUGUGU GGCCACAUGAACUGGCUGGCACCAGGGGAGUGAAACUGGCUGAUGACCAGCUGAGCC ACUUUGUGCCAACAGAGGAUGGACGACACCUUUCCCUGUACCCACUGCAGAGGAAGA ACCCUGGGCACAGCAGCUUUGUCCUUGGCUACAAACUGUUACAACGUCACACAAUGA AGGCACAAAGUCCAACUUUCAAAGGGUGUAGGACUCCAUACUCAGUGACAGGGCAGG AAGAGCCAAAGAUAACCACAGCCACAGCCUGUGGAGACCAGGGUUGGAAGCCAGGUG CAGGGCCAGGCAUCUGCAUUGUGGGAUGUUAAUGGCACUUUUGUCUUGUAGCUAUUU UGAGAUGUGGUCCAGAGCAUUUCAGCUGGGAGAUCUCCCUCUGGCCACCAGGACUCUGGCUACUGUUAAAAUCCUGAUGUUUCUGUGGAAUCCUCAGUGUUUAAUCCCACUCAA UAGUAUCAUUACAGUUUUCUGUAAGAGAAAAUAUUACUUAUUUAUCCCAGUAUUCC UAGCCUGUCAACAUAAUAAAUAUCGGAACAAAACCUGGUAAAAAAA (SEQ ID NO: 22). In some embodiments, the ATF3 transcript (i.e., mRNA) comprises a sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% sequence identity to SEQ ID NO: 22.

[0077] The mouse ATF3 protein can comprise a sequence of (Uniprot ID: Q4FJW1): MMLQHPGQVSASEVSATAIVPCLSPPGSLVFEDFANLTPFVKEELRFAIQNKHLCHRMSSAL ESVTVNNRPLEMSVTKSEAAPEEDERKRRRRERNKIAAAKCRNKKKEKTECLQKESEKLES VNAELKAQIEELKNEKQHLIYMLNLHRPTCIVRAQNGRTPEDERNLFIQQIKEGTLQS (SEQ ID NO: 23). In some embodiments, the ATF3 protein comprises an amino acid sequence of at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% sequence identity to SEQ ID NO: 23.Methods of Treatment

[0078] Methods and compositions for treating a disease or condition is provided herein. In certain aspects, the method includesincreasing activity of oneormore of transcription factors (TFs). In certain aspects, the method includes decreasing activity of one or more of transcription factors (TFs). In certain aspects, the method includes decreasing the activity of Activating Transcription Factor 3 (ATF3) in the cells.

[0079] In some embodiments, the disease or condition to be treated is a metabolism-related disease or condition. In some embodiments the disease or condition is a kidney disorder, diabetes or a diabetes- related disorder, obesity or an obesity related disorder, a liver disease, a cardiovascular disease, dyslipidemia, hypertension, systemic inflammation, or a neurological disorder. In some embodiments, the liver disease is a non-alcoholic fatty liver disease (NAFLD). In some embodiments, the liver disease is metabolic dysfunction-associated steatohepatitis (MASH), in some embodiments the liver disease is primary sclerosing cholangitis (PSC). In some embodiments, the liver disease is primary biliary cholangitis (PBC). In some embodiments, the diabetes is Type II diabetes. In some embodiments, the kidney disorder is diabetic nephropathy. In some embodiments, the obesity is morbid obesity. In some embodiments, the condition is or is associated with lipedema. In some embodiments, the condition is a fatty tumor (e.g., lipoma), in some embodiments, the condition is or is associated with fat accumulation. In some embodiments, the cancer is colon cancer, breast cancer, or endometrial cancer. In some embodiments the neurological disorder is dementia, depression, or anxiety. In some embodiments, the disease or condition is associated with fibrosis.

[0080] In some embodiments, the method disclosed herein increases metabolic processes. Nonlimiting examples of a metabolic process include glucose level regulation, lipid metabolism, insulin sensitivity, and beta oxidation. In certain embodiments, the method disclosed herein may result in at least 5%, at least 10%, at least 15%, atleast 20%, atleast 25%, at least 30%, at least 35%, atleast 40%, at least45%, atleast 50%, at least 55%, at least 60%, atleast 65%, atleast 70%, atleast 75%, at least 80%, or more increase in expression of a metabolism associated gene compared to control cells not subjected to the method. In some embodiments the metabolism associated gene is related to mitochondrial function or glucose metabolism. In certain embodiments, the method disclosed herein may resultin about 5%, about 10%, about 15%, about20%, about25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, increase in expression of a metabolism associated gene compared to control cells not subjected to the method. In certain embodiments, the method disclosed herein may result in about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, decrease in expression of a metabolism associated gene compared to control cells not subjected to the method. In some embodiments the metabolism associated gene is related to mitochondrial function or glucose metabolism. In some embodiments the metabolism associated gene is related to lipid metabolism. In some embodiments, the metabolism associated gene is MITF, PC, ACLY, PPARG, MT-ND1, SDHA, MT-ATP6, ACSL1, DGAT2, o LPINl . In some embodiments, the glucose metabolism gene comprises MITF, PC, ACLY, PPARG, MT-ND1, SDHA, or MT-ATP6. In some embodiments, the lipid metabolism gene comprises ACSL1, DGAT2, or LPINL

[0081] In some embodiments, the method disclosed herein may result in at least 50%, 100%, 150%, 200%, 250%, or 300% increase in MITF gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in about 50%-400% increase in MITF gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in at least 25%, 50%, 75%, or 100% increase in PC gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in about 25%- 200% increase in PC gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in at least 50%, 75%, 100%, or 150% increase in ACLY gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in about 50%-300% increase in ACLY gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may resultin atleast 25% or 50% increase in PPARG gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in about25%-100% increase in PPARG gene expression in liver cells ascompared to a control. In some embodiments, the method disclosed herein may result in at least 5% increase in MT-ND1 gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in about 5%-20% increase in MT-ND1 gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in at least 25%, 50% or 75% increase in SDHA gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in about 25% -200% increase in SDHA gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in at least 5% increase in MT-ATP6 gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in about 5%-20% increase in MT-ATP6 gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in at least 25%, 50%, or 75% increase m ACSLl gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in about 25%-l 50% increase in ACSL1 gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in at least 50%, 75%, or 100% increase in DGAT2 gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in about 50%-250% increase in DGAT2 gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in at least 25%, 50%, or 75% increase in LPIN1 gene expression in liver cells as compared to a control. In some embodiments, the method disclosed herein may result in about 25%-150% increase in LPIN1 gene expression in liver cells as compared to a control. The liver cells can be human liver cells.

[0082] In some embodiments, the method disclosed herein may result in at least 25% increase nACLY gene expression in adipose cells as compared to a control. In some embodiments, the method disclosed herein may result in about 25%-75% increase in ACLY gene expression in adipose cells as compared to a control. In some embodiments, the method disclosed herein may result in at least 25% increase in PPARG gene expression in adipose cells as compared to a control. In some embodiments, the method disclosed herein may result in about 25%-75% increase in PPARG gene expression in adipose cells as compared to a control. In some embodiments, the method disclosed herein may result in at least 5% increase in SDHA gene expression in adipose cells as compared to a control. In some embodiments, the method disclosed herein may resultin about 5% -50% increase in SDHA gene expression in adipose cells as compared to a control. In some embodiments, the method disclosed herein may result in at least 25% or 50% increase in DGAT2 gene expression in adipose cells as compared to a control. In some embodiments, the method disclosed herein may result in about 25%-l 00% increase in DGAT2 gene expression in adipose cells as compared to a control. In some embodiments, the method disclosed herein may result in at least 25% or 50% increase in ACSL1 gene expression in adipose cells ascompared to a control. In some embodiments, the method disclosed herein may result in about 25%- 150% increase in ACS / J gene expression in adipose cells as compared to a control. The adipose cells can be human adipose cells.

[0083] In certain embodiments, the method disclosed herein may result in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or more increase in mitochondrial function in cells as compared to control cells not subjected to the method. In certain embodiments, the method disclosed herein may result in about 5%, about 10%, about 15%, about 20%, about 25%, or more increase in mitochondrial function in cells as compared to control cells not subjected to the method. In some embodiments, mitochondrial functions can be determined by gene expression or protein expression levels of mitochondrial and Krebs cycle genes. Mitochondrial function can be measured by any suitable methods, such as measuringmembrane potential (i.e., TMRE membrane potential marker), superoxide production, calcium levels, mitochondrial permeability, ATP production, orNAD / NADH levels. In some embodiments, the mitochondria-related gene comprises MITF, PC, ACHY, PPARG, MT-ND1, SDH A, o MT-ATP6.

[0084] In certain embodiments, the method disclosed herein may result in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or more increase in mitochondrial membrane potential as compared to control cells not subjected to the method.

[0085] In certain embodiments, the method disclosed herein may result in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or more decrease in fibrosis as compared to a corresponding untreated control. In certain embodiments, the method disclosed herein may result in about 5%, about 10%, about 15%, about 20%, about 25%, or more decrease in fibrosis as compared to a corresponding untreated control. Fibrosis can be measured by any suitable known method. Fibrosis can be measured by quantifying collagen build up in a tissue sample via Masson’s trichrome staining. Fibrosis can be measured by any known fibrosis scoring method. Fibrosis can be measured by quantifying hydroxyproline levels in the liver.

[0086] In some embodiments, the method results in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or more decrease in body weight as compared to a corresponding untreated control. In certain embodiments, the method disclosed herein may result in about 5%, about 10%, about 15%, about 20%, about 25%, or more decrease in body weight as compared to a corresponding untreated control.

[0087] In some embodiments, the method results in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or more decrease in relative fat mass as compared to a corresponding untreated control. In certain embodiments, the method disclosed herein may result in about 5%, about 10%, about 15%, about 20%, about 25%, or more decrease in relative fat mass as compared to acorrespondinguntreated control. In some embodiments, the method results in atleast 5%, atleast 10%, at least 15%, at least 20%, at least 25%, or more increase in relative lean mass as compared to a correspondinguntreated control. In certain embodiments, the method disclosed herein may result in about 5%, about 10%, about 15%, about 20%, about 25%, or more increase in relative lean mass as compared to a corresponding untreated control.

[0088] In some embodiments, the method results in at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or more increase in insulin sensitivity as compared to a correspondinguntreated control. In certain embodiments, the method disclosed herein may result in about 5%, about 10%, about 15%, about 20%, about 25%, or more increase in insulin sensitivity as compared to a correspondinguntreated control. Insulin sensitivity can be measured by any known method. Insulin sensitivity can be measured by performing a glucose tolerance test and quantifying the area under the curve of glucose concentration over time. Insulin sensitivity can be measured by quantifying levels of fasting insulin.

[0089] In some embodiments, the cell is a non-human cell. In some embodiments, the cell is a eukaryotic cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is a mouse cell. In some embodiments, the cell is a non- human primate cell.

[0090] In certain embodiments, the cells may be differentiated cells, e.g., adipose cells, skin cells, lung cells (e.g., lung fibroblasts), liver cells (e.g., hepatocytes), muscle cells (e.g., cardiac muscle cells), pancreatic cells, immune cells, renal cells, liver cells, bone cells, brain cells (e.g., microglial cells, glial cells, astrocytes, neurons, etc.), eye cells (e.g., retinal cells, such as, retinal cell is a retinal ganglion cell, an amacrine cell, a horizontal cell, a bipolar cell, a photoreceptor cell, a Muller glial cell, a microglial cell, or a retinal pigmented epithelium cell), scalp cells (e.g., hair follicles), etc. In certain embodiments, the cells may be fibroblasts, e.g., skin fibroblasts, liver fibroblasts, lung fibroblasts, or skeletal muscle fibroblasts. In certain embodiments, the cells may be pancreatic islet cells. In certain embodiments, the cells may be T cells, B cells, macrophages, or dendritic cells. In certain embodiments, the cells may be bone marrow cells. In certain embodiments, the cells may be neural cells, glial cells, or astrocytes. In some embodiments, the cells are adipose cells. In some embodiments, the cells are liver cells.

[0091] The compositions or methods described herein can include decreasing the activity of ATF3 in the cells of the tissue involved in the condition, e.g., cells in skin, cells in liver, cells in adipose tissue, etc. In some embodiments, the method comprises decreasing the activity of ATF3 transiently. For example, decreasing the activity of ATF3 for a period of time that is less than one month, less than three weeks, less than two weeks, less than one week, less than 5 days, less than 3 days, less than aday, less than 18 hours, less than 12 hours, less than 8 hours, less than 5 hours, or lesser, e.g., at least 1 hour.

[0092] In certain embodiments, the method may include administering to a subject in need thereof a composition comprising an ATF3 inhibitor. In some embodiments, the composition comprises a polynucleic acid (e.g., in a CRISPR / Cas9 complex, an antisense oligonucleotide, or siRNA) for inhibiting expression of one or more of ATF3. In some embodiments, the polynucleic acid (e.g., siRNA) comprises one or more chemical modifications. In some embodiments, the one or more chemical modifications comprise a 2 ’-O-m ethylation of one or more bases. In some embodiments, the one or more chemical modifications comprise a 2 ’-fluorination of one or more bases. In some embodiments, the siRNA is conjugated to an agent such as a peptide. In some embodiments, the peptide is about 3, about 5, about ?, about 9, about 11, about 13, about 15, about 17, or about 19 amino acids in length. In some cases, the siRNA is conjugated to a GalNAc. In some cases, the siRNA is conjugated to a lipid.

[0093] In some embodiments, the composition comprises a protein that functions to decrease the activity of ATF3 or a polynucleic acid encoding the protein. In some embodiments, the protein is an antibody or a fragment thereof. In some embodiments, the protein is a peptide. In some embodiments, the protein is a CRSIPR protein. The CRISPR protein can be a Cas protein or variants. In some embodiments, the composition further comprises a guide polynucleotide such as a guide RNA. In some embodiments, the guide RNA comprises a spacer sequence that targets a sequence on ATF3 mRNA, such as a portion of the sequence of SEQ ID NO: 17.

[0094] In some embodiments, the ATF3 inhibitor is a small molecule.

[0095] The route for delivery may be selected based on the disease. For example, an adult subject may have an adipose or metabolic condition (e.g., lipoma, fat accumulation, overweight, obesity, diabetes), a liver condition (e.g., non-alcoholic fatty liver disease), or a brain condition (e.g., dementia, depression, anxiety).

[0096] The method provided herein can be performed in vivo, in situ, in vitro, ex vivo, or any combination thereof.Decreasing Activity of a TF

[0097] Provided herein is a method comprises decreasing the activity of ATF3 protein. In some instances, decreasing the activity of ATF3 protein comprises decreasing the mRNA level of ATF3 in a cell. In some instances, decreasing the activity of ATF3 protein comprises decreasing the protein level of ATF3 in a cell. In some instances, decreasingthe activity of ATF3 protein comprises inhibiting or reducing the ATF3 protein binding to DNA.

[0098] In some embodiments, the method is administered to a target cell. In some embodiments, the target cell is an adipocyte, such as a white adipocyte (fat cell). In some embodiments, the target cell is formed as a result of fat accumulation (e.g., excess fat accumulation).

[0099] In some embodiments, the target cell is a preadipocyte. A preadipocyte can differentiate into a mature adipose cell.

[0100] In some embodiments, the target cell or target cells are present subcutaneous fat. In some embodiments, the target cell or target cells are present abdominal fat. In some embodiments, the target cell or target cells are present in visceral fat. In some embodiments, the target cell or target cells are present in hepatic fat. In some embodiments, the target cell or target cells are located in a cavity of a subject’s body that contains adipocytes. In some embodiments, the cavity is a thoracic cavity, abdominal cavity, peritoneal cavity, pelvic cavity, or pericardial cavity.

[0101] Decreasing the activity of a polypeptide such as ATF3 may encompass one or both of: decreasing total level of the polypeptide in a cell and decreasing the effect of the polypeptide. Level of a polypeptide in a cell may be decreased by decreasing expression of the polypeptide from an endogenous gene, decreasing the level of the mRNA encoding the polypeptide, inhibiting translation of the mRNA, etc. Effect of a polypeptide in the cell may be decreased by expressing a mutated version of the polypeptide, introducing into the cell an inhibitor of the polypeptide (e.g., a small molecule), fusing the polypeptide to a domain that decreases its localization to the nucleus, fusing the polypeptide to a domain that decreases its stability, etc. Decreased effect of a TF may be assessed by assaying expression levels of one or more genes activated by the TFs.

[0102] In certain embodiments, decreasing the activity of ATF3 may encompass decreasing the activity by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, atleast 17%, atleast 18%, atleast 19%, atleast20%, at least25%, at least 30%, atleast 35%, at least 40%, atleast45%, atleast 50%, at least 55%, atleast 60%, atleast 65%, at least 70%, at least 75%, at least 80%, atleast 85%, atleast 90%, at least 95%, at least 100% or more as compared to a control cell. In certain embodiments, decreasing the activity of ATF3 may encompass decreasing the mRNA level of ATF3 in cells by at least 1%, at least 2%, at least 3%, atleast 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11 %, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, atleast 35%, atleast40%, at least45%, atleast 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100% or more as compared to a control cell. In some instances, the mRNAlevel of ATF3 is decreased in cells by at least 30%, at least 40%, or atleast 50% as compared to a control cell. In some instances,the mRNA level of ATF3 is decreased in cells by at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% as compared to a control cell. In some instances, the cells are liver cells or adipose cells. In some instances, the cells are human cells.

[0103] In certain embodiments, the method comprises decreasing the function of ATF3. Non-limiting examples of function can include mRNA level, protein level, mRNA level of any suitable downstream targets, protein level of any suitable downstream targets, level of transcription, level of translation, level of any suitable positive feedback loop, level of any suitable negative feedback loop, or activity of downstream signaling pathways.

[0104] In certain embodiments, the method comprises decreasing the activity of ATF3, wherein decreasing the activity of ATF3 comprises decreasing the mRNA level of ATF3. In some embodiments, the method comprises inhibiting DNA binding to ATF3 protein.

[0105] In certain embodiments, decreasing the activity of ATF3 in a cell may encompass decreasing the activity of ATF3in a cell treated with by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more as compared to a control cell.

[0106] Level of a protein in a cell can be decreased by any suitable means, such as, by decreasing transcription of the endogenous gene encoding the protein, by introducing a polynucleic acid into the cells that specifically degrades mRNA encodingthe protein, by introducing into the cells a polynucleic acid that interferes with translation of the mRNA encoding the protein, and the like.

[0107] In certain embodiments, decreasing the level of ATF3 may include decreasing the expression level of ATF3 by, e.g., decreasing transcription of the endogenous A TF3 gene encoding the ATF3 protein.

[0108] In certain embodiments, decreasing transcription of the gene encodingthe protein may include introducing into the cell a Cas / guide RNA that suppresses expression of the protein. In certain embodiments, the guide RNA may bind to a region in the promoter of the gene encodingthe protein or in the coding region.

[0109] In certain embodiments, the Cas protein may be conjugated to a transcriptional repressor. In certain embodiments, the transcriptional repressor may be KRAB, Sin3a, LSD1, SUV39H1, G9A (EHMT2), DNMT1, DNMT3A-DNMT3L, DNMT3B, KOX, TGF-b eta-inducible early gene (TIEG), v-erbA, SID, MBD2, MBD3, Rb, or MeCP.

[0110] In certain embodiments, decreasing level of ATF3 may include contactingthe cells with one or more antisense oligonucleotides. By “antisense oligonucleotides” or “antisense compound” is meant an RNA or DNA molecule that binds to another RNA or DNA (target RNA, DNA). For example, if it is an RNA oligonucleotide it binds to another RNA target by means of RNA-RNA interactions andalters the activity of the target RNA. An antisense oligonucleotide can lead to degradation of the target RNA or inhibit its translation or both. Such molecules include, for example, siRNA, antisense RNA or DNA molecules, interference RNA (RNAi), micro RNA (miRNA), decoy RNA molecules, that hybridize to at least a portion of the target polynucleic acid. As such, these compounds may be introduced in the form of single-stranded, double-stranded, partially single-stranded, or circular oligomeric compounds.[OHl] In certain embodiments, the method comprises contacting the cells with an siRNA. In some embodiments, the siRNA comprises a sense strand sequence with at least 60%, atleast 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 1. In certain embodiments, the method comprises contactingthe cells with an siRNA. In some embodiments, the siRNA comprises a sense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 3. In some embodiments, the siRNA comprises a sense strand sequence with atleast 60%, atleast 70%, atleast 80%, at least 90%, atleast 95%, at least 99% or 100% identity to SEQ ID NO: 5. In some embodiments, the siRNA comprises a sense strand sequence with atleast 60%, at least 70%, at least 80%, atleast 90%, atleast 95%, at least 99% or 100% identity to SEQ ID NO: 7. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 2. In some embodiments, the siRNA comprises an antisense strand sequence with atleast 60%, atleast 70%, atleast 80%, atleast 90%, atleast 95%, atleast 99% or 100% identity to SEQ ID NO: 4. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 6. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 8.

[0112] In some embodiments, the siRNA specifically binds a target sequence, wherein the target sequence has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to a sequence as setforth in SEQ ID NO: 3 on the gene ATF3. In some embodiments, the siRNA specifically binds a target sequence, wherein the target sequence has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to a sequence as set forth in SEQ ID NO: 5 on the gene ATF3. In some embodiments, the siRNA specifically binds a target sequence, wherein the target sequence has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to a sequence as set forth in SEQ ID NO: 7 on the gene ^TFJ. In some embodiments, the siRNA specifically binds a target sequence of GCAAAGUGCCGAAACAAGA (SEQ ID NO: 24) on the gene ATF3. In some embodiments, thesiRNA specifically binds a target sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 24 on the gene ATF3. In some embodiments, the siRNA specifically binds a target sequence from position 1 to 200, from position 100 to 300, from position 200 to 600, from position 300 to 500, from position 400 to 600, from position 500 to 700, from position 600 to 800, or from position 700 to 900 of SEQ ID NOs: 17 or 22. In some embodiments the length of the target sequence is about 15 nucleotides, about 16 nucleotides, about 17 nucleotides, about 18 nucleotides, about 19 nucleotides, about 20 nucleotides, about 21 nucleotides, about 22 nucleotides, about 23 nucleotides, about 24 nucleotides, about 25 nucleotides, about 26 nucleotides, about 27 nucleotides, about 28 nucleotides, about 29 nucleotides, about 30 nucleotides, about 31 nucleotides, about 32 nucleotides, about 33 nucleotides, about 34 nucleotides, about 35 nucleotides, about 40 nucleotides, nucleotides, about 45 nucleotides, about 50 nucleotides, about 55 nucleotides, or about 60 nucleotides.

[0113] In some embodiments, the method comprises contacting the cells with an siRNA targeting ATF3 (e.g., anmRNAof^TFJ gene). In some embodiments, the siRNAcomprises an antisense strand comprising a region of complementarity of at least 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , or more) nucleosides to an ATF3 RNA (e.g., mRNA) sequence set forth in any one of SEQ ID NOs: 2148, 17, and 22, and a sense strand thatis atleast substantially complementary to the antisense strand. In some embodiments, the sense strand is 15 -35 (e.g., 15, 16. 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) nucleosides in length, and / or the antisense strand is 15-35 (e.g., 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) nucleosides in length, wherein the antisense strand and the sense strand hybridize to form a duplex region of 15-30 (e.g., 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) base pairs in length. In some embodiments, the duplex region is 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25 nucleobases in length.

[0114] In some embodiments, an siRNA used in a method described herein comprises an antisense strand comprising a region of complementarity of at least 8 nucleobases to an ATF3 RNA sequence as set forth in SEQ ID NO: 24, or to the sense strand sequence of any one of the siRNAs listed in Tables 1-6, or 16. In some embodiments, the antisense strand comprises a region of complementary 15-21 (e.g., 15, 16, 17, 18, 19, 20, or 21) nucleobases to an ATF3 RNA sequence as set forth in SEQ ID NO:24, or to the sense strand sequence of any one of the siRNAs listed in Tables 1-6, or 16. In some embodiments, the antisense strand comprises at least 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23) consecutive nucleobases of the antisense strand of any one of the siRNAs listed in Tables 1 -6, or 16. In some embodiments, the antisense strand comprises the nucleobase sequences of the antisense strand of any one of the siRNAs listed in Tables 1 -6, or 16. In someembodiments, the siRNAs comprises a sense strand comprising at least 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23) consecutive nucleobases of the sense strand of any one of 1he siRNAs listed in Tables 1 -6, or 16, optionally wherein the sense strand comprises the nucleobase sequences of the sense strand of any one of the siRNAs listed in Tables 1-6, or 16.

[0115] In some embodiments, an siRNA used in a method described herein comprises an antisense strand comprising at least 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23) consecutive nucleobases of any one of SEQ ID NOs: 58, 66, 68, 274, 356, 358, 370, 378, 380, 386, 392, 408, 414, 416, 444, 446, 478, 486, 488, 694, 776, 778, 790, 798, 800, 806, 812, 828, 834, 836, 864. In some embodiments, the antisense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 58, 66, 68, 274, 356, 358, 370, 378, 380, 386, 392, 408, 414, 416, 444, 446, 478, 486, 488, 694, 776, 778, 790, 798, 800, 806, 812, 828, 834, 836, 864. In some embodiments, alternatively or in combination, the siRNA comprises a sense strand comprising least 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23) consecutive nucleobases of any one of SEQ ID NOs: 57, 65, 67, 273, 355, 357, 369, 377, 379, 385, 391, 407, 413, 415, 444, 445, 478, 485, 487, 693, 775, 777, 789, 797, 799, 805, 811, 827, 833, 835, 863 . In some embodiments, the sense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 57, 65, 67, 273, 355, 357, 369, 377, 379, 385, 391, 407, 413, 415, 444, 445, 478, 485, 487, 693, 775, 777, 789, 797, 799, 805, 811, 827, 833, 835, 863.

[0116] In some embodiments, an siRNA used in a method described herein comprises an antisense strand comprising 15-23 consecutive nucleobases of any one of SEQ IDNOs: 274, 356, 378, 392, 414, 444, 694, 776, 798, 812, 834, 864, and comprises a sense strand comprising 15-21 nucleobases of any one of SEQ ID NOs: 273, 355, 377, 391, 413, 443, 693, 775, 797, 811, 833, and 863.

[0117] In some embodiments, an siRNA used in a method described herein the nucleobase sequences of any one of siRNA-23, siRNA-27, siRNA-28, siRNA-131, siRNA-172, siRNA-173, siRNA-179, siRNA-183, siRNA-184, siRNA-187, siRNA-190, siRNA-198, siRNA-201, siRNA-202, siRNA- 216, siRNA-233, siRNA-237, siRNA-238, siRNA-341, siRNA-382, siRNA-383, siRNA-389, siRNA-393, siRNA-394, siRNA-397, siRNA-400, siRNA-408, siRNA-411, siRNA-412, and siRNA-426. In some embodiments, the siRNA comprises the nucleobase sequences of any one of siRNA-131, siRNA-172, siRNA-183, siRNA-190, siRNA-201, siRNA-216, siRNA-341, siRNA-382, siRNA-393, siRNA-400, siRNA-411, and siRNA-426.

[0118] In some embodiments, any one of the siRNAs used in a method described herein comprises one or more modified nucleosides. In some embodiments, each nucleoside of the antisense strand is a modified nucleoside and each nucleoside of the sense strand is a modified nucleoside. In some embodiments, the one or more modified nucleosides are 2’ modified nucleosides. In some embodiments, the 2 ’-modified nucleoside is selected from 2’-deoxyribonucleoside (DNA), 2’-fluoro(2’-F), 2’-O-methyl (2’-O-Me), 2’-O-methoxyethyl (2 ’-MOE), 2’-O-aminopropyl (2’-O-AP), 2’-O- dimethylaminoethyl (2’-O-DMAOE), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-O- dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-O-N-methylacetamido (2’-0-NMA) modified nucleoside and combinations thereof.

[0119] In some embodiments, in an siRNA used in a method described herein, each nucleoside of the antisense strand is selected from a 2’-F modified nucleoside and a 2’-O-Me modified nucleoside, and each nucleoside of the sense strand is a 2’ -modified nucleoside selected from a 2’-F modified nucleoside and a 2’-O-Me modified nucleoside.

[0120] In some embodiments, in an siRNA used in a method described herein, the nucleosides at one or more positions 9, 10, and 11 (counting 5 ’to3’) of the sense strand are 2’-F modified nucleosides. In some embodiments, the nucleosides atpositions 9, 10, and 11 (counting 5’ to 3’) of the sense strand are 2’-F modified nucleosides. In some embodiments, the nucleoside at position 7 (counting 5’ to 3’) of the sense strand is a 2’-F modified nucleoside. In some embodiments, nucleosides at one or more positions 2, 6, 7, 8, 9, 14 or 16 (countings’ to 3’) of the antisense strand are 2 ’-F modified nucleosides. In some embodiments, wherein the nucleosides atpositions 2 and 14 of the antisense strand are 2’ -F modified nucleosides. In some embodiments, the antisense strand further comprises one or more of 2’- deoxyribonucleosides (DNA). In some embodiments, wherein the nucleoside at one of both of positions 5 and 7 (counting 5’ to 3’) of the antisense strand is a DNA.

[0121] In some embodiments, in an siRNA used in a method described herein, the siRNA comprises one or more modified intemucleoside linkages. In some embodiments, the siRNA comprises one or more phosphorothioate internucleosidelinkages in atleast one strand. In some embodiments, the sense strand comprises two phosphorothioate internucleoside linkages. In some embodiments, the two phosphorothioate internucleoside linkages are the first two internucleoside linkages in the sense strand from 5’ to 3’. In some embodiments, alternatively or in combination, the antisense strand comprises four phosphorothioate intemucleoside linkages, wherein the four phosphorothioate intemucleoside linkages are the first two intemucleoside linkages and the last two intemucleoside linkages in the antisense strand from 5’ to 3’.

[0122] In some embodiments, in an siRNA used in a method described herein, the nucleosides at positions 9, 10, and 11 (counting 5’to3’) of the sense strand are 2’-F modified nucleosides, the nucleosides at one or more of positions 2, 6, 7, 8, 9, 14 or 16 (counting 5’ to 3’) of the antisense strand are 2 ’ -F modified nucleosides, the first two intemucleoside linkages in the sense strand from 5 ’ to 3 ’ are phosphorothioate intemucleoside linkages, and the first two intemucleoside linkages and the last two internucleosidelinkages in the antisense strand from 5’ to 3’ are phosphorothioate intemucleoside linkages.

[0123] In some embodiments, the siRNA is selected from any one of the siRNAs listed in Tables 4-6. In some embodiments, the siRNA is selected from: siRNA-443, siRNA-447, siRNA-448, siRNA-551, siRNA-592, siRNA-593, siRNA-599, siRNA-603, siRNA-604, siRNA-607, siRNA-610, siRNA-618, siRNA-621, siRNA-622, and siRNA-636. In some embodiments, the siRNA is selected from: siRNA- 551, siRNA-592, siRNA-603, siRNA-610, siRNA-621, and siRNA-636.

[0124] In some embodiments, any one of the siRNAs used in a method described herein may be conjugated (e.g., covalently linked) to a targeting agent. In some embodiments, the targeting agent is N-acetylgalactosamine(GalNAc). In some embodiments, GalNAc is covalently linked to the siRNA. In some embodiments, the therapeutic agent is an siRNA and the GalNAc is covalently linked to the 3’ end of the sense strand of the siRNA. In some embodiments, the GalNAc comprises a structure of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d).

[0125] In some embodiments, an siRNA used in a method described herein is selected from the siRNAs listed in Table 16. In some embodiments, the siRNA is selected from: siRNA-1057, siRNA- 1058, siRNA-1059, siRNA-1060, siRNA-1061, siRNA-1062, siRNA-1063, siRNA-1064, siRNA- 1065, siRNA-1066, siRNA-1067, siRNA-1069, siRNA-1070, siRNA-1071, and siRNA-1072. In some embodiments, the siRNA is selected from siRNA-1060, siRNA-1061, siRNA-1064, siRNA-1067, siRNA- 1070, and siRNA- 1072.

[0126] In certain embodiments, the method comprises decreasing the activity of ATF3 by administering one or more inhibitors, such as, antibody or a small molecule that inhibits protein activity. In some embodiments, the inhibitor comprises an antisense oligonucleotide. In some embodiments, the antisense oligonucleotide targets an ATF3 mRNA.

[0127] In certain embodiments, an RNA-guided transcriptional repressor of ATF3 may be introduced in the cells as a guide RNA and transcriptional repressor or as one or more polynucleic acids encoding the guide RNA and transcriptional repressor.Methods of Production

[0128] A composition disclosed herein can be produced by various methods in any quantity. For example, a composition disclosed herein can be produced in an amount of about 0.5 microgram, 1 microgram, about 1 milligram, about 1 gram, about 1 kilogram, or more. Non -limiting examples of production methods include in vitro transcription methods, polymerase chain transcription (PCT), recombinant overexpression (e.g., in A. coli, R. sulfidophilum, or other in vitro systems), transfer RNA (tRNA) scaffold methods, enzymatic methods, chemical methods, solid-phase oligonucleotide synthesis, solid-phase chemical synthesis, ribozyme cleavage methods, T4 ligation methods, position- selective labeling of RNA (PLOR), T7 RNA polymerase in vitro methods, T3 RNA polymerase invitro methods, SP6 RNA polymerase in vitro methods, phosphoramidite chemistry, cell-free polynucleic acid expression methods, or a combination thereof. Non-limiting examples of purification methods include precipitation and solvent extraction, ultracentrifugation, polyacrylamide gel electrophoresis (PAGE), liquid chromatography (e.g., reversed-phase ion-pairing HPLC (RP-IP- HPLC), ion-exchange HPLC (IE-HPLC), ion-exchange fast-performance liquid chromatography (IE- FPLC), affinity chromatography (e.g., systematic evolution of ligands by exponential enrichment (SELEX), and size-exclusion chromatography (SEC)), or a combination thereof. Purification methods can be used to achieve varying degrees of purity of a composition disclosed herein, e.g., at least 80% purity, at least 85% purity, at least 90% purity, atleast 91% purity, at least 92% purity, at least 93% purity, at least 94% purity, at least 95% purity, atleast 96% purity, at least 97% purity, at least 98% purity, at least 99% purity, or at least 99.99%. Methodsfor the preparation of compositions comprising the compositions described herein include formulating the compositions with one or more inert, pharmaceutically -acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include, for example, solutions in which a composition is dissolved, emulsions comprising a composition, or a solution containing liposomes, micelles, nanoparticles, vesicles, microvesicles, or nanovesicles comprising a composition as disclosed herein. Semi-solid compositions include, for example, gels, suspensions, lotions, and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.

[0129] A polynucleotide described herein can be assembled by a variety of methods, e.g., by automated solid-phase synthesis. A polynucleotide can be constructed using standard solid -phase DNA / RNA synthesis. A polynucleotide can also be constructed using a synthetic procedure. A polynucleotide can be synthesized manually or in a fully automated fashion. A polynucleotide can be a recombinant polynucleic acid. In some cases, a synthetic procedure may comprise 5'-hydroxyl oligonucleotides that can be initially transformed into corresponding 5 '-H-phosph onate mono esters, subsequently oxidized in the presence of imidazole to activated 5 '-phosphorimidazolidates, and finally reacted with pyrophosphate on a solid support. This procedure may include a purification step after the synthesis such as PAGE, HPLC, MS, or any combination thereof. Polynucleotides can be purchased commercially.A. Chemical Synthesis

[0130] Where a polypeptide is chemically synthesized, the synthesis may proceed via liquid-phase or solid-phase. Solid-phase peptide synthesis (SPPS) allows the incorporation of unnatural amino acids and / or peptide / protein backbone modification. Various forms of SPPS, such as Fmoc and Boc, are available for synthesizing polypeptides of the present disclosure. Details of the chemical synthesis are known in the art (e.g., Ganesan A. 2006 Mini Rev. Med. Chem. 6:3 -10; and Camarero J. A. et al., 2005 Protein Pept Lett. 12:723-8).B. Recombinant Production

[0131] Where a polypeptide is produced using recombinant techniques, the polypeptide may be produced as an intracellular protein or as a secreted protein, using any suitable construct and any suitable host cell, which can be a prokaryotic or eukaryotic cell, such as a bacterial (e.g., E. coif) or a yeast host cell, respectively. In some embodiments, eukaryotic cells that are used as host cells for production of the polypeptides include insect cells, mammalian cells, and / or plant cells. In some embodiments, mammalian host cells are used and may include human cells (e.g., HeLa, 293, H9,NSO, and Jurkat cells); mouse cells (e.g., NIH3T3, L cells, and C127 cells); primate cells (e.g., Cos 1, Cos 7 and CV1) and hamster cells (e.g., Chinese hamster ovary (CHO) cells). In specific embodiments, the polypeptide disclosed herein are produced in CHO cells.

[0132] In some embodiments, the host cells can be from a transgenic animal, e.g., mammary epithelial cell.

[0133] A variety of host-vector systems suitable for the expression of a polypeptide may be employed accordingto standard procedures known in the art. See, e.g., Sambrooket al., 1989 Current Protocols in MolecularBiology Cold Spring Harbor Press, New York; and Au sub el et al. 1995 CurrentProtocols in MolecularBiology, Eds. Wiley and Sons. Methods for introduction of genetic material into host cells include, for example, transformation, electroporation, conjugation, calcium phosphate methods and the like. The method for transfer can be selected so as to provide for stable expression of the introduced polypeptide-encoding polynucleic acid. The polypeptide-encoding polynucleic acid can be provided as an inheritable episomal element (e.g., a plasmid) or can be genomically integrated and expressed under the control of an inducible promoter, for example. A variety of appropriate vectors for use in production of a polypeptide of interest are commercially available.

[0134] Vectors can provide for extrachromosomal maintenance in a host cell or can provide for integration into the host cell genome. The expression vector provides transcriptional and translational regulatory sequences and may provide for inducible or constitutive expression where the coding regionis operably -linked under the transcriptional control of the transcriptional initiation region, and a transcriptional and translational termination region. The transcriptional and translational regulatory sequences can include, but are not limited to, promoter sequences, ribosomal binding sites, transcriptional start and stop sequences, translational start and stop sequences, and enhancer or activator sequences. Promoters can be either constitutive or inducible, and can be a strong constitutive promoter (e.g., T7). A promoter disclosed herein can be a mammalian promoter or derived from a mammalian promoter. A promoter disclosed herein can be a human promoter or derived from a human promoter.

[0135] The promoter can be a promoter as found in a naturally -occurring genome. In some embodiments, a promoter is not found in a naturally -occurring genome. In some embodiments, the promoter is an engineered promoter. The promoter can be a minimal promoter.

[0136] Also provided herein are polynucleic acids encoding the polypeptides disclosed and / or guide RNA disclosed herein and / or Cas9 protein disclosed herein. In some embodiments, a polynucleic acid encoding the polypeptides disclosed herein is operably linked to a promoter sequence that confers expression of the polypeptide. In some embodiments, the sequence of the polynucleic acid is codon optimized for expression of the polypeptide in a human cell. In some embodiments, the polynucleic acid is a deoxyribonucleic acid (DNA). In some embodiments, the polynucleic acid is a ribonucleic acid (RNA). Also provided herein is a vector comprising the polynucleic acid encoding the polypeptides for binding a target polynucleic acid as described herein. In some embodiments, the vector is a viral vector.

[0137] A variety of enzymes can catalyze insertion of foreign DNA into a host genome. Non -limiting examples of gene editing tools and techniques include CRISPR, TALEN, zinc finger nuclease (ZFN), meganuclease, Mega-TAL, and transposon-based systems.

[0138] In some embodiments, a host cell comprising the polynucleic acid or the vector encoding the polypeptides disclosed herein is provided. In some embodiments, a host cell comprising the polypeptides disclosed herein is provided. In some embodiments, a host cell that expresses the polypeptide is also disclosed.

[0139] In some embodiments, described herein are host cells comprising the vectors described herein. The cell can be, but is not limited to, a eukaryotic cell, a bacterial cell, an insect cell, or a human cell. Suitable eukaryotic cells include, but are not limited to, HepG2 cells, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells, adipose cells and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells.Delivery

[0140] Compositions comprising any polynucleic acid, cell, polypeptide, gene, gene product, or transcription factor describedherein can be delivered by any suitable means. Compositions comprising polynucleic acids (e.g., one or more siRNAs or in a CRISPR / Cas9 complex) for inhibiting expression of a TF can be delivered by any suitable means, including, for example, by injection, infection, transfection, and vesicle or lipid nanoparticle mediated delivery. In some embodiments, the TF is ATF3.

[0141] In certain embodiments, introducing a protein, polynucleic acid, or a small molecule for increasing or decreasing expression of a protein as disclosed herein can include administering a composition comprising the protein, polynucleic acid, or a small molecule to a human subject intradermally, e.g., by a superficial injection or topically, e.g., in a topical formulation.Vectors

[0142] described herein, in certain embodiments, is a vector comprising one or more of the polynucleic acid molecules as described herein.

[0143] Further provided herein are vectors comprising the polypeptide sequences described herein. In some embodiments, the vectors comprise polynucleic acid sequences encoding the polypeptide sequences, described herein. In some embodiments, the vectors comprise the nucleotide sequences described herein. The vectors include, but are not limited to, a virus, plasmid, cosmid, lambda phage or a yeast artificial chromosome (YAC).

[0144] Numerous vector systems can be employed. For example, one class of vectors utilizes DNA elements which are derived from animal viruses such as, for example, bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retroviruses (Rous Sarcoma Virus, MMTV or MOMLV) or SV40 virus. Another class of vectors utilizes RNA elements derived from RNA viruses such as Semliki Forest virus, Eastern Equine Encephalitis virus and Flaviviruses.

[0145] Additionally, cells which have stably integrated the DNA into their chromosomes may be selected by introducing one or more markers which allow f or the selection of transfected host cells. The marker may provide, for example, prototropy to an auxotrophic host, biocide resistance (e.g, antibiotics), or resistance to heavy metals such as copper, or the like. The selectable marker gene can be either directly linked to the DNA sequences to be expressed, or introduced into the same cell by cotransformation. Additional elements may also be needed for optimal synthesis of mRNA. These elements may include splice signals, as well as transcriptional promoters, enhancers, and termination signals.

[0146] Once the expression vector or DNA sequence containing the constructs has been prepared for expression, the expression vectors may be transfected or introduced into an appropriate host cell. Various techniques may be employed to achieve this, such as, for example, protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene gun, lipid based transfection or other conventional techniques. In the case of protoplast fusion, the cells are grown in media and screened for the appropriate activity.

[0147] Methods and conditions for culturing the resulting transfected cells and for recovering the antibody molecule produced are known to those skilled in the art, and may be varied or optimized depending upon the specific expression vector and mammalian host cell employed, based upon the present description.

[0148] In some embodiments, an mRNA or a vector encoding the proteins disclosed herein may be injected, transfected, or introduced via viral infection into a cell, where the cell is ex vivo or in vivo. Any vector systems may be used including, but not limited to, plasmid vectors, retroviral vectors, lentiviral vectors, adenovirus vectors, poxvirus vectors; herpes simplex virus vectors and adeno- associated virus vectors, etc. Non-viral vector delivery systems include DNA plasmids, naked polynucleic acid, and polynucleic acid complexed with a delivery vehicle such as a liposome or poloxamer. Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes after delivery to the cell. Vectors suitable for introduction of polynucleotides as described herein include described herein include non -integrating lentivirus vectors (IDLV).

[0149] Non-viral vector delivery systems include electroporation, lipofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipidmucleicacid conjugates, naked DNA, artificial virions, and agent-enhanced uptake of DNA.

[0150] Cells may be isolated and subjected to the methods disclosed herein ex vivo for reintroduction into the subject.

[0151] In applications where transient expression of the polypeptide of the present disclosure is desired, adenoviral based systems may be used. Adeno -associated virus (“AAV”) vectors can also be used to transduce cells with polynucleic acids encoding the polypeptide of the present disclosure, e.g, in the in vitro production of polynucleic acids and peptides, and for in vivo and ex vivo gene therapy procedures. In some embodiments, recombinant adeno-associated virus vectors (rAAV) such as replication-deficientrecombinant adenoviral vectors may be used for introduction of polynucleic acids encoding the polypeptides disclosed herein.

[0152] In some embodiments, polynucleic acids disclosedhereincan be deliveredusing a gene therapy vector with a high degree of specificity to a particular tissue type or cell type. A viral vector is typically modified to have specificity for a given cell type by including a sequence encoding a ligand expressedas a fusion protein with a viral coat protein on the viruses’ outer surface. The ligand is chosen to have affinity for a receptor known to be present on the cell type of interest.

[0153] In some embodiments, gene therapy vectors can be delivered in vivo by administration to an individual patient. In some embodiments, administration involves systemic administration (e.g., intravenous, intraperitoneal, intramuscular, subdermal, or intracranial infusion), direct injection (e.g, intrathecal), or topical application, as described below. Alternatively, vectors can be delivered to cells ex vivo, such as cells explanted from an individual patient followed by reimplantation of the cells into a patient.

[0154] In some embodiments, the compositions provided herein are administered to an individual as a method of treating a disease or disorder. In some embodiments, the individual has a genetic disease, such as any of the diseases described herein. In some embodiments, the individual is at risk of having a disease, such as any of the diseases described herein. In some embodiments, the individual is at increased risk of having a disease or disorder caused by insufficient amount of a protein or insufficient activity of a protein. If an individual is “at an increased risk” of having a disease or disorder caused insufficient amount of a protein or insufficient activity of a protein, the method involves preventative or prophylactic treatment. For example, an individual may be at an increased risk of having such a disease or disorder because of family history of the disease. Typically, individuals at an increased risk of having such a disease or disorder benefit from prophylactic treatment (e.g., by preventing or delaying the onset or progression of the disease or disorder). In some embodiments, a fetus is treated in utero, e.g., by administering the compositions as described herein to the fetus directly or indirectly (e.g., via the mother).

[0155] Suitable routes for administration of the compositions as described herein may vary depending on cell type to which delivery of the compositions is desired. The compositions as described herein may be administered to patients parenterally, for example, by intrathecal injection, intracerebroventricular injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection. The compositions as described herein may be administered to patients orally.

[0156] In some embodiments, the compositions as described herein are administered with one or more agents capable of promoting penetration of the subject the compositions as described herein across the blood-brain barrier by any method known in the art.

[0157] In some embodiments, the compositions as described herein can be administered using a nebulizer, inhaler, nasal spray, auto -injector, micro needle array, or eye drop.Lipid Nanoparticles

[0158] In some embodiments, a delivery vector can be a non -viral vector. A delivery vector can be a lipid-based vector, for example, a proteo-lipid vehicle (PLV), a lipid nanoparticle (LNP), or a liposome. A lipid-based vector can comprise an electroneutral lipid . A lipid-based vector can comprise an ionizable lipid. A lipid-based vector can comprise a cationic lipid. In some embodiments, the lipid- based vector is a PEG-modified lipid. A lipid-based vector can comprise, for example, l,2-dioleoyl-3- dimethylammonium -propane (DODAP), l,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1,2- dioleoyl-sn-glycero-3 -phosphoethanolamine (DOPE), Cholesterol, 1,2 -dimyristoyl -rac-glycero-3- methoxypoly ethylene glycol (DMG-PEG), or any combination thereof. In some embodiments, the pH of the nanoparticle is from about 5 to about 8, about 5.5 to about 7.5, about 6 to about ?, about 6 to 6.5. In some embodiments, the pH of the nanoparticle is about 6. In some embodiments, the lipid nanoparticle encapsulates a polynucleotide. In some embodiments, the polynucleotide comprises an siRNA disclosed herein. In some embodiments, the polynucleotide comprises an antisense oligonucleotide disclosed herein.

[0159] In some embodiments, the lipid-based vector is formulated to have a molar ratio of about 20- 60% cationic lipid: 5-25% non-cationic lipid: 25-55% sterol; and 0.5-15% PEG-modified lipid.

[0160] In some embodiments, the lipid-based vector is a cationic lipid nanoparticle. The cationic lipid nanoparticle comprises a cationic lipid, a PEG-modified lipid, a sterol and a non -cationic lipid. In some embodiments, the cationic lipid is selected from the group consisting of 2,2-dilinoleyl-4- dimethylaminoethyl-[l,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-l-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319). In some embodiments, the cationic lipid nanoparticle has a molar ratio of about 20-60% cationic lipid: about 5-25% non-cationic lipid: about 25-55% sterol; and about 0.5-15% PEG-modified lipid. In some embodiments, the cationic lipid nanoparticle comprises a molar ratio of about 50% cationic lipid, about 1.5% PEG-modified lipid, about 38.5% cholesterol and about 10% non-cationic lipid. In some embodiments, the cationic lipid nanoparticle comprises a molar ratio of about 55% cationic lipid, about 2.5% PEG lipid, about 32.5% cholesterol and about 10% non-cationic lipid. In some embodiments, the cationic lipid is an ionizable cationic lipid and the non-cationic lipid is a neutral lipid, and the sterol is a cholesterol. In some embodiments, the cationic lipid nanoparticle has a molar ratio of 50:38.5 :10: 1.5 of cationic lipid: cholesterol: PEG2000-DMG:DSPC.

[0161] Additional lipid nanoparticle (LNP) compositions and components can be found in published US Patents US9687550, US10844002B2, or US Patent Publications US20230097090A1, which are incorporated by reference herein in their entirety.

[0162] In some embodiments, the lipid nanoparticle comprises a targeting agent. In some embodiments, the targeting agent comprises an adipose targeting peptide agent. In some embodiments, the adipose targeting agent comprises an adipose targeting. In some embodiments, the adipose targeting peptide has at least 80%, at least 85%, at least 90%, at least 95% sequence identity to SEQ ID NO: 11.

[0163] In some embodiments, disclosed herein are nanoparticles comprise the adipose targeting peptides, wherein the adipose targeting peptides have at least one positive charged amino acid on the C-terminus of the adipose targeting peptide. The at least one positive charged amino acid can be on the N-terminus of the adipose targeting peptide. In some embodiments, the positive charged amino acid comprises arginine, lysine, or histidine. In some embodiments, the positive charged amino acid comprises arginine.

[0164] In some embodiments, the molar ratio of the peptide to the polynucleotide targeting ATF3 disclosed herein is at least 5 :1, at least 10:1, at least 15 :1, at least20:l, at least 25: 1, at least 30: 1, at least 35 :1, at least 40:1, at least 45:1, or at least 50: 1. In some embodiments, the molar ratio of the peptide to the polynucleotide is from about 20: 1 to about 80:1. In some embodiments, the molar ratio of the peptide to the polynucleotide is from about 30:1 to about 70:1. In some embodiments, the molar ratio of the peptide to the polynucleotide is from about 40: 1 to about 60:1. In some embodiments, the molar ratio of the peptide to the polynucleotide is from about40:l to about 70:1 . In some embodiments, the molar ratio of the peptide to the polynucleotide is from about20: l to about40: l, about25 :l to about 40: 1, about 30:1 to about 40:1, about 35: 1 to about 40: 1, about 40:1 to about 45:1, about 40:1 to about 50: 1, about 40:1 to about 55 :1, about 40: 1 to about 60: 1, about 40: 1 to about 65: 1, about 40:1 to about 70: 1, about 40:1 to about 75 :1, about 40: 1 to about 80: 1, about 40:1 to about 85:1, about 40:1 to about 90: 1, about 40: 1 to about 95 :l, or about 40:1 to about 100:1. In some embodiments, the molar ratio of the peptide to the polynucleotide is about 20:1, about 25 :1, about 30:1, about 35 :1, about 40:1, about45: l, about 50: l, about 55 :l, about 60:1, about 65: l, about 70:l, about 75 :l, about 80: l, about 85 : 1, about 90:1, about 95 :1, or about 100: 1. In some embodiments, the molar ratio of the peptide to the polynucleotide is about 40: 1. In some embodiments, the molar ratio of the peptide to the polynucleotide is about 45 : 1 . In some embodiments, the molar ratio of the peptide to the polynucleotide is about 50: 1.

[0165] In some embodiments, the adipose targeting peptide has a sequence of SEQ ID NO: 11. In some embodiments, the molar ratio of the peptide to the siRNA is at least 5: 1, at least 10: 1, at least15 : 1, at least 20: 1, at least 25 :1, at least 30: 1, at least 35 :1, at least 40: 1, at least 45 :1, or at least 50:1. In some embodiments, the molar ratio of the peptide to the siRNA is from about 20: 1 to about 80:1. In some embodiments, the molar ratio of the peptide to the siRNA is from about 30:1 to about 70:1. In some embodiments, the molar ratio of the peptide to the siRNA is from about 40:1 to about 60:1. In some embodiments, the molar ratio of the peptide to the siRNA is from about 40:1 to about 70:1. In some embodiments, the molar ratio of the peptide to the siRNA is from about 20 : 1 to about 40 : 1 , about 25 : 1 to about 40: 1, about 30:1 to about 40: 1, about 35: 1 to about 40:1, about 40:1 to about 45 :1, about 40: 1 to about 50: 1, about 40:1 to about 55: 1, about 40: 1 to about 60:1, about 40:1 to about 65 :1, about 40: 1 to about 70: 1, about 40:1 to about 75 :1, about 40:1 to about 80: 1, about 40:1 to about 85 :1, about 40: 1 to about 90: 1, about 40: 1 to about 95 :1, or about 40:1 to about 100: 1. In some embodiments, the molar ratio of the peptide to the siRNA is about 20:1, about 25 :1, about 30: 1, about 35 :1, about 40:1, about45: l, about 50: l, about 55 :l, about 60:1, about 65: l, about 70:l, about 75 :l, about 80: l, about 85 : 1, about 90:1, about 95 :1, or about 100: 1. In some embodiments, the molar ratio of the peptide to the siRNA is about 40: 1. In some embodiments, the molar ratio of the peptide to the siRNA is about 45 : 1. In some embodiments, the molar ratio of the peptide to the siRNA is about 50: 1.

[0166] In some embodiments, the targeting agent comprises a liver cell targeting agent. In some embodiments, the liver cell targeting agent comprises a GalNAc.

[0167] In some embodiments, the LNP formulation comprises a pH value thatis less than 10, lessthan 9, less than 8, or less than 7. In some embodiments, the pH value is from about 9 to about 5, from about 8.5 to about 5.5, from about 8 to about 5, from about 7.5 to about 5, from about 7 to about 5, or from about 6.5 to about 5.5. In some embodiments, the pH value is about 7, about 6.5, about 6, about 5.5, or about 5. In some embodiments, the pH valueis about 7. In some embodiments, the pH value is about 6. In some embodiments, the pH value is about 5.Compositions

[0168] In some embodiments, the polypeptides, the polynucleic acids, small molecules described herein may be present in a composition comprising an acceptable excipient. In some embodiments, the polypeptides and / or the polynucleic acids are present in a therapeutically effective amount in the composition. A therapeutically effective amount can be determined based on an observed effectiveness of the composition. A therapeutically effective amount can be determined using assays that measure the desired effect in a cell. The compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic and prophylactic methods and uses described herein.

[0169] The compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.

[0170] Suitably acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, nuclease inhibitors, protease inhibitors, a suitable vehicle such as physiological saline solution or citrate buffered saline.

[0171] Certain aspects of the present disclosure relate to compositions and formulations (e.g., compositions and formulations) comprising any of the recombinant polynucleic acids (e.g., a recombinant viral genome such as herpes virus genome) and / or viruses (e.g., rAAV virus, a herpes virus comprising a recombinant genome described herein (such as a herpes simplex virus comprising a recombinant herpes simplex virus genome), and an excipient or carrier (e.g., a suitably acceptable excipient or carrier). In some embodiments, the composition or formulation is a cosmetic composition or formulation (e.g., a skin care product) for example in the form of a liquid formulation such as, serum, astringent, or a fluid such as a cream or a lotion.

[0172] In some embodiments, the composition provided herein comprises an inhibitor of a transcription factor involved in the ATF3 pathway, including but not limited to ATF3. In some embodiments, the inhibitor is a small molecule.

[0173] In some embodiments, the inhibitor comprises an siRNA, CRISPR system, a repression plasmid, an antisense oligonucleotide, or a polynucleic acid encoding the CRISPR system, the antisense oligonucleotide, or the siRNA.

[0174] Provided herein is a composition comprising an siRNA targeting an ATF3 pathway. In some embodiments, the siRNA comprises (a) a sense strand having a sequence with at least at least 60%, at least 70%, at least 80%, atleast 90%, atleast 95%, atleast 99% or 100% sequence identity to any one sense strand sequence presentedin Tables 1-6 or 16 and (b) an antisense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% sequence identity to any one antisense strand sequence presented in Tables 1-6 or 16. In some embodiments, the siRNA comprises (a) a sense strand having a sequence with at least at least 60%, at least 70%, at least 80%, atleast 90%, atleast 95%, atleast 99% or 100% sequence identity to any one sense strand sequence presented in Table 1 and (b) an antisense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% sequence identity to any one antisense strand sequence presented in Table 1. In some embodiments, the siRNA comprises (a) a sense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% sequence identity to any one sense strand sequence presented in Table 2 and (b) an antisense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% sequence identity to any one antisense strand sequence presented in Table 2. In some embodiments, the siRNA comprises (a) a sense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, atleast 95%, atleast 99% or 100% sequence identity to any one sense strand sequencepresented in Table 3 and (b) an antisense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, atleast 95%, atleast 99% or 100% sequence identity to any one antisense strand sequence presented in Table 3. In some embodiments, the siRNA comprises(a) a sense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% sequence identity to any one sense strand sequence presented in Table 4 and (b) an antisense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% sequence identity to any one antisense strand sequence presentedin Table 4. In some embodiments, the siRNA comprises (a) a sense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% sequence identity to any one sense strand sequencepresented in Table 5 and (b) an antisense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% sequence identity to any one antisense strand sequence presented in Table 5. In some embodiments, the siRNA comprises (a) a sense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% sequence identity to any one sense strand sequence presented in Table 6 and (b) an antisense strand having a sequence with at least at least 60%, at least 70%, at least 80%, atleast 90%, atleast 95%, atleast 99% or 100% sequence identity to any one antisense strand sequence presentedin Table 6. In some embodiments, the siRNA comprises (a) a sense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, atleast 99% or 100% sequence identity to any one sense strand sequencepresented in Table 16 and (b) an antisense strand having a sequence with at least at least 60%, at least 70%, at least 80%, at least 90%, atleast 95%, atleast 99% or 100% sequence identity to any one antisense strand sequence presented in Table 16.

[0175] In some embodiments, the siRNA comprises an antisense strand comprising a region of complementarity of atleast 8 (e.g., atleast 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more) nucleosides to an 477’ 3 RNA (e.g., mRNA) sequence set forth in any one of SEQ ID NOs: 2148, 17, and 22, and a sense strand that is at least substantially complementary to the antisense strand. In some embodiments, the sense strand is 15-35 (e.g., 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) nucleosides in length, and / or the antisense strand is 15 -35 (e.g., 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) nucleosides in length, wherein the antisense strand and the sense strand hybridize to form a duplex region of 15-30 (e.g, 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) base pairs in length. In some embodiments, the duplex region is 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25 nucleobases in length.

[0176] In some embodiments, the siRNA comprises an antisense strand comprising a region of complementarity of at least 8 nucleobases to an ATF3 RNA sequence as set forth in SEQ ID NO: 24, or to the sense strand sequence of any one of the siRNAs listed in Tables 1 -6, or 16. In some embodiments, the antisense strand comprises a region of complementary 15-21 (e.g., 15, 16, 17, 18,19, 20, or 21) nucleobases to an 477’3 RNA sequence as set forth in SEQ ID NO: 24, or to the sense strand sequence of any one of the siRNAs listed in Tables 1-6, or 16. In some embodiments, the antisense strand comprises atleast 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23) consecutive nucleobases of the antisense strand of any one of the siRNAs listed in Tables 1-6, or 16. In some embodiments, the antisense strand comprises the nucleobase sequences of the antisense strand of any one of the siRNAs listed in Tables 1 -6, or 16. In some embodiments, the siRNA comprises a sense strand comprising at least 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23) consecutive nucleobases of the sense strand of any one of the siRNAs listed in Tables 1-6, or 16. In some embodiments, the sense strand comprises the nucleobase sequences of the sense strand of any one of the siRNAs listed in Tables 1-6, or 16.

[0177] In some embodiments, the siRNA comprises an antisense strand comprising at least 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23) consecutive nucleobases of any one of SEQ ID NOs: 58, 66, 68, 274, 356, 358, 370, 378, 380, 386, 392, 408, 414, 416, 444, 446, 478, 486, 488, 694, 776, 778, 790, 798, 800, 806, 812, 828, 834, 836, 864. In some embodiments, the antisense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 58, 66, 68, 274, 356, 358, 370, 378, 380, 386, 392, 408, 414, 416, 444, 446, 478, 486, 488, 694, 776, 778, 790, 798, 800, 806, 812, 828, 834, 836, 864. In some embodiments, alternatively or in combination, the siRNA comprises a sense strand comprising least 8 (e.g., at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23) consecutive nucleobases of any one of SEQ ID NOs: 57, 65, 67, 273, 355, 357, 369, 377, 379, 385, 391, 407, 413, 415, 444, 445, 478, 485, 487, 693, 775, 777, 789, 797, 799, 805, 811, 827, 833, 835, 863. In some embodiments, the sense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 57, 65, 67, 273, 355, 357, 369, 377, 379, 385, 391, 407, 413, 415, 444, 445, 478, 485, 487, 693, 775, 777, 789, 797, 799, 805, 811, 827, 833, 835, 863.

[0178] In some embodiments, the siRNA comprises an antisense strand comprising 15 -23 consecutive nucleobases of any one of SEQ ID NOs: 274, 356, 378, 392, 414, 444, 694, 776, 798, 812, 834, 864, and comprises a sense strand comprising 15 -21 nucleobases of any one of SEQ ID NOs: 273, 355, 377, 391, 413, 443, 693, 775, 797, 811, 833, and 863.

[0179] In some embodiments, the siRNA comprises the nucleobase sequences of any one of siRNA-23, siRNA-27, siRNA-28, siRNA-131, siRNA-172, siRNA-173, siRNA-179, siRNA-183, siRNA- 184, siRNA-187, siRNA-190, siRNA-198, siRNA-201, siRNA-202, siRNA-216, siRNA-233,siRNA-237, siRNA-238, siRNA-341, siRNA-382, siRNA-383, siRNA-389, siRNA-393, siRNA- 394, siRNA-397, siRNA-400, siRNA-408, siRNA-411, siRNA-412, and siRNA-426. In some embodiments, the siRNA comprises the nucleobase sequences of any one of siRNA-131, siRNA-172, siRNA-183, siRNA-190, siRNA-201, siRNA-216, siRNA-341, siRNA-382, siRNA-393, siRNA-400, siRNA-411, and siRNA-426. In some embodiments the siRNA comprises the nucleobase sequence of siRNA-23. In some embodiments the siRNA comprises the nucleobase sequence of siRNA-27. In some embodiments, siRNA-28. In some embodiments, siRNA-131. In some embodiments, siRNA- 172. In some embodiments, siRNA- 173. In some embodiments, siRNA- 179. In some embodiments, siRNA-183. In some embodiments, siRNA-184. In some embodiments, siRNA-187. In some embodiments, siRNA-190. In some embodiments, siRNA-198. In some embodiments, siRNA-201. In some embodiments, siRNA-202. In some embodiments, siRNA-216. In some embodiments, siRNA- 217. In some embodiments, siRNA-233. In some embodiments, siRNA-237. In some embodiments, siRNA-238. In some embodiments, siRNA-341. In some embodiments, siRNA-382. In some embodiments, siRNA-383. In some embodiments, siRNA-389. In some embodiments, siRNA-393. In some embodiments, siRNA-394. In some embodiments, siRNA-397. In some embodiments, siRNA- 400. In some embodiments, siRNA-408. In some embodiments, siRNA-411. In some embodiments, siRNA-412. In some embodiments, and siRNA-426.

[0180] In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 273 and an antisense strand having a sequence of SEQ ID NO: 274. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 355 and an antisense strand having a sequence of SEQ ID NO: 356. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 377 and an antisense strand having a sequence of SEQ ID NO: 378. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 391 and an antisense strand having a sequence of SEQ ID NO: 392. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 413 and an antisense strand having a sequence of SEQ ID NO: 414. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 415 and an antisense strand having a sequence of SEQ ID NO: 416. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 443 and an antisense strand having a sequence of SEQ ID NO: 444. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 445 and an antisense strand having a sequence of SEQ ID NO: 446. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 693 and an antisense strand having a sequence of SEQ ID NO: 694. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 775 and an antisense strand having a sequence of SEQ ID NO: 776. In some embodiments, the siRNA comprisesa sense strand having a sequence of SEQ ID NO: 797 and an antisense strand having a sequence of SEQ ID NO: 798. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 811 and an antisense strand having a sequence of SEQ ID NO: 812. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 833 and an antisense strand having a sequence of SEQ ID NO: 834. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 863 and an antisense strand having a sequence of SEQ ID NO: 864.

[0181] In some embodiments, the siRNA comprises a sense strand comprising the nucleobase sequence of any one sense strand sequence presentedin column 2 of Tables 2-6, or 16 and an antisense sense strand comprising the nucleobase sequence of the corresponding antisense strand sequence presented column 4 of Table 2-6 or 16.

[0182] In some embodiments, the siRNA comprises one or more modified nucleosides. In some embodiments, each nucleoside of the antisense strand is a modified nucleoside and each nucleoside of the sense strand is a modified nucleoside. In some embodiments, the one or more modified nucleosides are 2’ modified nucleosides. In some embodiments, the 2’ -modified nucleoside is selected from 2’- deoxyribonucleoside (DNA), 2 ’ -fluoro (2 ’ -F), 2 ’ -O-methyl (2 ’ -O-Me), 2 ’ -O-methoxy ethyl (2’ -MOE), 2’-O-aminopropyl (2’-O-AP), 2’-O-dimethylaminoethyl (2’-O-DMAOE), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-O-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-O-N-methylacetamido (2’-0-NMA) modified nucleoside and combinations thereof. In some embodiments, the 2 ’-modified nucleoside comprises 2’-deoxyribonucleoside (DNA). In some embodiments, the 2 ’-modified nucleoside comprises 2’-fluoro (2’-F). In some embodiments, the 2 ’-modified nucleoside comprises 2’-O-methyl (2’-O-Me). In some embodiments, the 2’-modified nucleoside comprises 2’-O- methoxy ethyl (2’-MOE). In some embodiments, the 2 ’-modified nucleoside comprises 2’-O- aminopropyl (2’-O-AP). In some embodiments, the 2’-modified nucleoside comprises 2’-O- dimethylaminoethyl (2’-O-DMAOE). In some embodiments, the 2’-modified nucleoside comprises 2’-O-dimethylaminopropyl (2’-O-DMAP). In some embodiments, the 2’-modified nucleoside comprises 2’-O-dimethylaminoethyloxyethyl (2’-O-DMAEOE). In some embodiments, the 2’- modified nucleoside comprises or 2’-O-N-methylacetamido (2’-0-NMA) modified nucleoside.

[0183] In some embodiments, in an siRNA described herein, each nucleoside of the antisense strand is selected from a 2’-F modified nucleoside and a 2 ’-O-Me modified nucleoside, and each nucleoside of the sense strand is a 2’-modified nucleoside selected from a 2’-F modified nucleoside and a 2’-O- Me modified nucleoside.

[0184] In some embodiments, in an siRNA described herein, the nucleosides at one or more positions 9, 10, and 11 (counting 5’to3’) of the sense strand are 2’-F modified nucleosides. In someembodiments, the nucleosides at positions 9, 10, and 11 (counting 5’ to 3’) of the sense strand are 2’- F modified nucleosides. In some embodiments, the nucleoside at position 7 (counting 5’ to 3’) of the sense strand is a2’-F modified nucleoside. In some embodiments, nucleosides atone ormore positions 2, 6, 7, 8, 9, 14 or 16 (counting s’ to 3’) of the antisense strand are2’-F modified nucleosides. In some embodiments, wherein the nucleosides at positions 2 and 14 of the antisense strand are 2’ -F modified nucleosides. In some embodiments, the antisense strand further comprises one or more of 2’ - deoxyribonucleosides (DNA). In some embodiments, wherein the nucleoside at one of both of positions 5 and 7 (counting 5’ to 3’) of the antisense strand is a DNA.

[0185] In some embodiments, in an siRNA described herein, the siRNA comprises one or more modified intemucleoside linkages. In some embodiments, the siRNA comprises one or more phosphorothioate intemucleoside linkages in at least one strand. In some embodiments, the sense strand comprises two phosphorothioate intemucleoside linkages. In some embodiments, the two phosphorothioate intemucleoside linkages are the first two intemucleoside linkages in the sense strand from 5’ to 3’. In some embodiments, alternatively or in combination, the antisense strand comprises four phosphorothioate intemucleoside linkages, wherein the four phosphorothioate intemucleoside linkages are the first two intemucleoside linkages and the last two intemucleoside linkages in the antisense strand from 5’ to 3’.

[0186] In some embodiments, in an siRNA described herein, the nucleosides at positions 9, 10, and 11 (counting 5 ’to3’) of the sense strand are 2’-F modified nucleosides, the nucleosides at one or more of positions 2, 6, 7, 8, 9, 14 or 16 (counting 5’ to 3’) of the antisense strand are 2’-F modified nucleosides, the first two intemucleoside linkages in the sense strand from 5’ to 3’ are phosphorothioate intemucleoside linkages, and the first two intemucleoside linkages and the last two intemucleoside linkages in the antisense strand from 5’ to 3 ’phosphorothioate intemucleoside linkages.

[0187] In some embodiments, the siRNA comprises a sense strand comprising the sequence of any one sense strand sequence presented in column 2 of Tables 4-6 and an antisense sense strand comprising the sequence of the corresponding antisense strand sequence presented column 4 of Table 4-6. In some embodiments, the siRNA is configured to interact with an RNA-induced silencing complex (RISC).

[0188] In some embodiments, the siRNA is selected from any one of the siRNAs listed in Tables 4-6. In some embodiments, the siRNA is selected from siRNA-443. In some embodiments, the siRNA is siRNA-447. In some embodiments, the siRNA is siRNA-448. In some embodiments, the siRNA is siRNA-551 . In some embodiments, the siRNA is siRNA-592. In some embodiments, the siRNA is siRNA-593. In some embodiments, the siRNA is siRNA-599. In some embodiments, the siRNA issiRNA-603. In some embodiments, the siRNA is siRNA-604. In some embodiments, the siRNA is siRNA-607. In some embodiments, the siRNA is siRNA-610. In some embodiments, the siRNA is siRNA-618. In some embodiments, the siRNA is siRNA-621 . In some embodiments, the siRNA is siRNA-622. In some embodiments, the siRNA is and siRNA-636. In some embodiments. In some embodiments, the siRNA is the siRNA is selected from: siRNA-551. In some embodiments, the siRNA is siRNA-592. In some embodiments, the siRNA is siRNA-603. In some embodiments, the siRNA is siRNA-610. In some embodiments, the siRNA is siRNA-621. In some embodiments, the siRNA is siRNA-636.

[0189] In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 1113 and an antisense strand having a sequence of SEQ ID NO: 1114. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 1195 and an antisense strand having a sequence of SEQ ID NO: 1196. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 1197and an antisense strand having a sequence of SEQ ID NO: 1198. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 1209 and an antisense strand having a sequence of SEQ ID NO: 1210. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 1217 and an antisense strand having a sequence of SEQ ID NO: 1218. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 1231 and an antisense strand having a sequence of SEQ ID NO: 1232. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 1253 and an antisense strand having a sequence of SEQ ID NO: 1254. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 1283 and an antisense strand having a sequence of SEQ ID NO: 1284.

[0190] In some embodiments, any one of the siRNAs described herein may be conjugated (e.g., covalently linked) to a targeting agent. In some embodiments, the targeting agent is N- acetylgalactosamine (GalNAc). In some embodiments, GalNAc is covalently linked to the siRNA. In some embodiments, the therapeutic agent is an siRNA and the GalNAc is covalently linked to the 3’ end of the sense strand of the siRNA. In some embodiments, the GalNAc comprises a structure of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d).

[0191] In some embodiments, the siRNA is selected from the siRNAs listed in Table 16. In some embodiments, the siRNA is siRNA-1057. In some embodiments, the siRNA is siRNA-1058. In some embodiments, the siRNA is siRNA- 1059. In some embodiments, the siRNA is siRNA- 1060. In some embodiments, the siRNA is siRNA- 1061. In some embodiments, the siRNA is siRNA- 1062. In some embodiments, the siRNA is siRNA- 1063. In some embodiments, the siRNA is siRNA- 1064. In some embodiments, the siRNA is siRNA-1065. In some embodiments, the siRNA is siRNA- 1066. In someembodiments, the siRNA is siRNA-1067. In some embodiments, the siRNA is siRNA-1069. In some embodiments, the siRNA is siRNA- 1070. In some embodiments, the siRNA is siRNA- 1071. In some embodiments, the siRNA is siRNA-1072.

[0192] In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 2132 and an antisense strand having a sequence of SEQ ID NO: 1114. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 2133 and an antisense strand having a sequence of SEQ ID NO: 1196. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 2134 and an antisense strand having a sequence of SEQ ID NO: 1198. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 2135 and an antisense strand having a sequence of SEQ ID NO: 1210. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 2136 and an antisense strand having a sequence of SEQ ID NO: 1218. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 2139 and an antisense strand having a sequence of SEQ ID NO: 1232. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 2142 and an antisense strand having a sequence of SEQ ID NO: 1254. In some embodiments, the siRNA comprises a sense strand having a sequence of SEQ ID NO: 2144 and an antisense strand having a sequence of SEQ ID NO: 1284.

[0193] In some embodiments, the siRNA comprises one or more chemical modifications. In some embodiments, the one or more chemical modifications comprise a 2 ’-O-methylation of one or more bases. In some embodiments, the one or more chemical modifications comprise a 2’ -fluorination of one or more bases. In some embodiments, the siRNA comprises a 5’ uridine residue (U) on the antisense strand. In some embodiments, the siRNA comprises a 3 ’ adenosine residue (A) on the sense strand. In some embodiments, the siRNA comprises a sense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one sense strand sequence provided in Table 2. In some embodiments, the siRNA comprises a sense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one sense strand sequence provided in Table 3. In some embodiments, the siRNA comprises a sense strand sequence with atleast 60%, at least 70%, at least 80%, atleast 90%, at least 95%, atleast 99% or 100% identity to any one sense strand sequence provided in Table 4. In some embodiments, the siRNA comprises a sense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one sense strand sequence provided in Table 5. In some embodiments, the siRNA comprises a sense strand sequence with atleast60%, atleast 70%, at least 80%, atleast 90%, at least 95%, at least 99% or 100% identity to any one sense strand sequence provided in Table 6. In some embodiments, the siRNA comprises an antisense strand sequence withat least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one antisense strand sequence provided in Table 2. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one antisense strand sequence provided in Table 3. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one antisense strand sequence provided in Table 4. In some embodiments, the siRNA comprises an antisense strand sequence with atleast 60%, at least 70%, atleast 80%, atleast 90%, atleast 95%, atleast 99% or 100% identity to any one antisense strand sequence provided in Table 5. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one antisense strand sequence provided in Table 6.

[0194] In some embodiments, the siRNA is conjugated to an agent such as a peptide. In some embodiments, the peptide is about 3, about 5, about 7, about 9, about 11, about 13, about 15, about 17, or about 19 amino acids in length. In some embodiments, the inhibitor comprises a targeting agent. In some embodiments, the targeting agent is a peptide. In some embodiments, the peptide comprises an amino acid sequence with at least 80%, 85%, 90%, or 95% sequence identity to SEQ ID NO: 11 . In some embodiments, the peptide has a sequence of SEQ ID NO: 11 . In some embodiments, the peptide is covalently linked to the inhibitor. In some embodiments, the inhibitor is an siRNA and the peptide is covalently linked to the 3 ’ end of the sense strand of the siRNA. In some embodiments, the targeting agent is N-acetylglucosamine (GalNAc). In some embodiments, the GalNAc is covalently linked to the inhibitor. In some embodiments, the inhibitor is an siRNA and the GalNAc is covalently linked to the 3 ’ end of the sense strand of the siRNA. In some embodiments, the GalNAc is a GalNAc L96 (also referred to as “GalNAc-5”, e.g., in Table 16). The GalNAc L96 can have a structure of Formula (I-a) as shown below:Formula (I-a)

[0195] In some embodiments, the GalNAc is a GalNAc amino C7. The GalNAc amino C7 can have a structure of Formula (I-b) as shown below:Formula (I-b)

[0196] In some embodiments, the GalNAc is a GalNAc-serinol. The GalNAc-serinol can have a structure of Formula (I-c) as shown below:Formula (I-c)

[0197] In some embodiments, the GalNAc is a GalNAc-1. The GalNAc-1 can have a structure of Formula (I-d) as shown below:Formula(I-d)

[0198] The GalNAc disclosed herein can be conjugated to any one of the siRNA disclosed herein. In some embodiments, the GalNAc modified siRNA comprises a sense strand with at least 80%, 85%, 90%, or 95% sequence identity to any one sense strand provided in Table 16. In some embodiments, the GalNAc modified siRNA comprises an antisense strand with at least 80%, 85%, 90%, or 95% sequence identity to any one antisense strand provided in Table 16.

[0199] In some embodiments, the siRNA is conjugated to a lipid moiety. The lipid moiety can be conjugated at an internal nucleotide on the sense strand. The lipid moiety can be conjugated at an internal nucleotide on the antisense strand. The lipid moiety can be conjugated at the 5’ end or 3’ end of the sense strand. The lipid moiety can be conjugated at the 5’ end or 3’ end of the antisense strand. The lipid moiety can be conjugated at, from 5’ to 3’ end, position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 of the sense strand. The lipid moiety can be conjugated at, from 5’ to 3’ end, position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 of the antisense strand. In some cases, the lipid moiety is conjugated at, from 5’ to 3’ end, position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the sense strand. In some cases, the lipid moiety is conjugated at, from 5’ to 3’ end, position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the antisense strand. In some cases, the lipid moiety is conjugated at, from 3’ to 5’ end, position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the sense strand. In some cases, the lipid moiety is conjugated at, from 3 ’ to 5’ end, position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the antisense strand. In some cases, the lipid moiety is conjugated at, from 5’ to 3 ’ end, position 1 , 2, 3, 4, or 5 of the sense strand. In some cases, the lipid moiety is conjugated at, from 5’ to 3’ end, position 1, 2, 3, 4, or 5 of the antisense strand. In some cases, the lipid moiety is conjugated at, from 3’ to 5’ end, position 1, 2, 3, 4, or 5 of the sense strand. In some cases, the lipid moiety is conjugated at, from 3’ to 5’ end, position 1, 2, 3, 4, or 5 of the antisense strand.

[0200] The lipid moiety can be conjugated on the ribose sugar of a nucleotide or nucleotide base analog in the RNA. The lipid moiety can be conjugated to the ribose sugar by 2 ’-O-modifi cation. In some embodiments, the nucleotide or nucleotidebase analogis selected from the group consisting of adenine (A), guanine (G), cytosine (C), thymine (T) and uracil (U). In some cases, the siRNA comprises one lipid moiety. In some cases, the siRNA comprises two lipid moieties. In some cases, the siRNA comprises three lipid moieties.

[0201] In some embodiments, the lipid moiety -conjugated siRNA comprises a structure of 2’-O- docosanoxyl (C22) nucleotide base-3 ’-phosphate (Formula Il-a):wherein B is a nucleotide base or a nucleotide base analog, optionally wherein B is selected from the group consisting of adenine, guanine, cytosine, thymine and uracil (Formula Il-a).

[0202] In some embodiments, the lipid moiety -conjugated siRNA comprises a structure of 2’-O- hexadecyl (C16) nucleotide base-3 ’-phosphate (Formula Il-b):wherein B is a nucleotide base or a nucleotide base analog, optionally wherein B is selected from the group consisting of adenine, guanine, cytosine, thymine and uracil (Formula Il-b).

[0203] In some embodiments, the lipid moiety is conjugated at a 3’ end terminal nucleotide on the sense strand. In some cases, the lipid moiety is conjugated at a 3’ end terminal nucleotide on the antisense strand. In some cases, the lipid moiety is conjugated at a 5’ end terminal nucleotide on 1he sense strand. In some cases, the lipid moiety is conjugated at a 5’ end terminal nucleotide on the antisense strand. In some embodiments, the lipid moiety comprises a C22 lipid monomer. In some embodiments, the lipid moiety comprises a Cl 6 lipid monomer.

[0204] In some embodiments, the siRNA comprises a sense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 1. In certain embodiments, the method comprises contacting the cells with an siRNA. In some embodiments, the siRNA comprises a sense strand sequence with at least 60%, atleast 70%, at least 80%, atleast 90%, atleast 95%, atleast 99% or 100% identity to SEQ ID NO: 3. In some embodiments,the siRNA comprises a sense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 5. In some embodiments, the siRNA comprises a sense strand sequence with atleast 60%, atleast 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 7. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 2. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 4. In some embodiments, the siRNA comprises an antisense strand sequence with atleast 60%, atleast 70%, atleast 80%, atleast 90%, atleast 95%, atleast 99% or 100% identity to SEQ ID NO: 6. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 8.

[0205] In some embodiments, the siRNA comprises a sense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one sense strand provided in Table 2. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one antisense strand provided in Table 2. In some cases, the siRNA comprises a sense sequence having one, two, three, or four mismatches as compared to any one sense strand provided in Table 2. In some cases, the siRNA comprises an antisense sequence having one, two, three, or four mismatches as compared to any one antisense strand provided in Table 2. In some cases, the siRNA comprises a sense sequence having atmost one, two, three, or four mismatches as compared to any one sense strand provided in Table 2. In some cases, the siRNA comprises an antisense sequence having at most one, two, three, or four mismatches as compared to any one antisense strand provided in Table 2.

[0206] In some embodiments, the siRNA specifically binds a target sequence with at least 60%, at least 70%, at least 80%, atleast 90%, atleast 95%, at least 99% or 100% identity to SEQ ID NO: 1 on the gene ATF3. In some embodiments, the siRNA specifically binds a target sequence with at least 60%, at least 70%, at least 80%, atleast 90%, atleast 95%, at least 99% or 100% identity to SEQ ID NO: 3 on the gene ATF3. In some embodiments, the siRNA specifically binds a target sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 5 on the gene ATF3. In some embodiments, the siRNA specifically binds a target sequence with atleast 60%, atleast 70%, atleast 80%, atleast 90%, atleast 95%, atleast 99% or 100% identity to SEQ ID NO: 7 on the gene ATF3. In some embodiments, the siRNA specifically binds a target sequence of GCAAAGUGCCGAAACAAGA (SEQ ID NO: 24) on the gene ATF3. In some embodiments, the siRNA specifically binds a target sequence with at least 60%, at least 70%, at least80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 24 on the gene ^TFJ. In some embodiments, the siRNA specifically binds a target sequence from position 1 to 200, from position 100 to 300, from position 200 to 600, from position 300 to 500, from position 400 to 600, from position 500 to 700, from position 600 to 800, or from position 700 to 900 of SEQ ID NOs: 17 or 22. In some embodiments the length of the target sequence is about 15 nucleotides, about 16 nucleotides, about 17 nucleotides, about 18 nucleotides, about 19 nucleotides, about 20 nucleotides, about 21 nucleotides, about 22 nucleotides, about 23 nucleotides, about 24 nucleotides, about 25 nucleotides, about 26 nucleotides, about 27 nucleotides, about 28 nucleotides, about 29 nucleotides, about 30 nucleotides, about 31 nucleotides, about 32 nucleotides, about 33 nucleotides, about 34 nucleotides, about 35 nucleotides, about 40 nucleotides, nucleotides, about 45 nucleotides, about 50 nucleotides, about 55 nucleotides, or about 60 nucleotides.

[0207] In some embodiments, the inhibitor is an antisense oligonucleotide. In some embodiments, the siRNA or the antisense oligonucleotide comprises at least one modification. In some embodiments, the modification is a 2’-OMethyl modification. In some embodiments, the modification is a 2’ fluoro modification. In some embodiments, the modification is a phosphorothioate backbone. In some embodiments, the modification is a deoxynucleoside. In some embodiments, the siRNA comprises a sense strand sequence with atleast 60%, at least 70%, at least 80%, atleast 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 12. In certain embodiments, the method comprises contacting the cells with an siRNA. In some embodiments, the siRNA comprises a sense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 14. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, atleast 90%, atleast 95%, at least 99% or 100% identity to SEQ ID NO: 13. In some embodiments, the siRNA comprises an antisense strand sequence with atleast 60%, at least 70%, at least 80%, at least 90%, atleast 95%, at least 99% or 100% identity to SEQ ID NO: 15.

[0208] In some embodiments, the siRNA comprises a sense strand with atleast 60%, atleast 70%, at least 80%, at least 90%, atleast 95%, at least 99% or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 273, 355, 377, 391, 413, and443. In some embodiments, the siRNA comprises an antisense strand with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 274, 356, 378, 392, 414, and 444. In some embodiments, the siRNA comprises a sense strand with at least 60%, at least 70%, at least 80%, atleast 90%, atleast 95%, at least 99% or 100% identity to SEQ ID NO: 273 and an antisense strand with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 274. In some embodiments, the siRNA comprisesa sense strand with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 355 and an antisense strand with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 356. In some embodiments, the siRNA comprises a sense strand with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 377 and an antisense strand with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 378. In some embodiments, the siRNA comprises a sense strand with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 391 and an antisense strand with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 392. In some embodiments, the siRNA comprises a sense strand with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO : 413 and an antisense strand with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 414. In some embodiments, the siRNA comprises a sense strand with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 443 and an antisense strand with atleast 60%, atleast 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 444. In some embodiments, the siRNA comprises a sense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one sense strand sequence provided in Table 2. In some embodiments, the siRNA comprises a sense strand sequence with atleast 60%, at least 70%, atleast 80%, at least 90%, at least 95%, atleast 99% or 100% identity to any one sense strand sequenceprovided in Table 3. In some embodiments, the siRNA comprises a sense strand sequence with atleast 60%, atleast 70%, atleast 80%, atleast 90%, atleast 95%, atleast 99% or 100% identity to any one sense strand sequence provided in Table 4. In some embodiments, the siRNA comprises a sense strand sequence with atleast 60%, atleast 70%, atleast 80%, at least 90%, atleast 95%, at least 99% or 100% identity to any one sense strand sequence provided in Table 5. In some embodiments, the siRNA comprises a sense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one sense strand sequence provided in Table 6. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one antisense strand sequence provided in Table 2. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, atleast 90%, at least 95%, at least 99% or 100% identity to any one antisense strand sequence provided in Table 3. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one antisense strandsequence provided in Table 4. In some embodiments, the siRNA comprises an antisense strand sequence with atleast 60%, at least 70%, atleast 80%, atleast 90%, atleast 95%, atleast 99% or 100% identity to any one antisense strand sequence provided in Table 5. In some embodiments, the siRNA comprises an antisense strand sequence with at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, at least 99% or 100% identity to any one antisense strand sequence provided in Table 6. In some cases, the siRNA comprises a sense sequence having one, two, three, or four mismatches as compared to any one sense strand provided in Table 3. In some cases, the siRNA comprises an antisense sequence having one, two, three, or fourmismatches as comparedto any one antisense strand provided in Table 3. In some cases, the siRNA comprises a sense sequence having one, two, three, or four mismatches as compared to any one sense strand provided in Table 4. In some cases, the siRNA comprises an antisense sequence having one, two, three, or four mismatches as compared to any one antisense strand provided in Table 4. In some cases, the siRNA comprises a sense sequence having one, two, three, or four mismatches as compared to any one sense strand provided in Table 5. In some cases, the siRNA comprises an antisense sequence having one, two, three, or four mismatches as compared to any one antisense strand provided in Table 5. In some cases, the siRNA comprises a sense sequence having one, two, three, or four mismatches as compared to any one sense strand provided in Table 6. In some cases, the siRNA comprises an antisense sequence having one, two, three, or four mismatches as compared to any one antisense strand provided in Table 6. In some cases, the siRNA comprises a sense sequence having atmost one, two, three, or four mismatches as compared to any one sense strand provided in Table 3. In some cases, the siRNA comprises an antisense sequence having at most one, two, three, or four mismatches as comparedto any one antisense strand provided in Table 3. In some cases, the siRNA comprises a sense sequence having at most one, two, three, or four mismatches as comparedto any one sense strand provided in Table 4. In some cases, the siRNA comprises an antisense sequence having at most one, two, three, or four mismatches as compared to any one antisense strand provided in Table 4. In some cases, the siRNA comprises a sense sequence having atmost one, two, three, or four mismatches as comparedto any one sense strand provided in Table 5. In some cases, the siRNA comprises an antisense sequence having at most one, two, three, or four mismatches as comparedto any one antisense strand provided in Table 5. In some cases, the siRNA comprises a sense sequence having atmost one, two, three, or fourmismatches as compared to any one sense strand provided in Table 6. In some cases, the siRNA comprises an antisense sequence having at most one, two, three, or four mismatches as compared to any one antisense strand provided in Table 6.Pharmaceutical Compositions

[0209] Any of the compositions provided herein may be administered to an individual. “Individual” may be used interchangeably with “subject” or “patient.” An individual may be a mammal, for example a human or animal such as a non-human primate, a rodent, a rabbit, a rat, a mouse, a horse, a donkey, a goat, a cat, a dog, a cow, a pig, or a sheep. In some embodiments, the individual is a human. In some embodiments, the individual is a fetus, an embryo, or a child. In other embodiments, the individual may be another eukaryotic organism, such as a plant. In some embodiments, the compositions provided herein are administered to a cell ex vivo.

[0210] A pharmaceutical composition of the disclosure can comprise a therapeutic complex of the present disclosure. A pharmaceutical composition can be a combination of any therapeutic complexes described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the therapeutic complex to an organism.

[0211] Pharmaceutical formulations for administration can include aqueous solutions of the active composition in water soluble form. Suspensions of the active composition can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compositions to allow for the preparation of highly concentrated solutions. The active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0212] The pharmaceutical compositions can include at least one pharmaceutically -acceptable carrier, diluent, or excipient and compositions described herein as free -base or pharmaceutically-acceptable salt form.

[0213] Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include binding agents, disintegrating agents, anti -adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, spheronization agents, and any combination thereof.

[0214] A therapeutic complex described herein can be conveniently formulated into pharmaceutical compositions composed of one or more pharmaceutically-acceptable carriers. See e.g., Remington’s Pharmaceutical Sciences, latest edition, by E.W. Martin Mack Pub. Co., Easton, PA, incorporated by reference in its entirety, which discloses typical carriers and conventional methods of preparingpharmaceutical compositions. Such carriers can be carriers for administration of compositions to humans and non-humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. Pharmaceutical compositions can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, and anesthetics.

[0215] Non-limiting examples of pharmaceutically -acceptable carriers include saline, Ringer’s solution, and dextrose solution. In some embodiments, the pH of the solution can be from about 5 to about 8, and can be from about ? to about 7.5. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic complex. The matrices can be in the form of shaped articles, for example, films, liposomes, microparticles, or microcapsules.

[0216] Non-limiting examples of pharmaceutically active agents suitable for combination with compositions of the disclosure include anti -inf ectives, i.e., aminoglycosides, antiviral agents, antimicrobials, anti-cholinergics / anti-spasmotics, antidiabetic agents, antihypertensive agents, anti- neoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations.

[0217] In some embodiments, the pharmaceutical composition provided herein comprises a therapeutically effective amount of a therapeutic complex herein in admixture with a pharmaceutically -acceptable carrier and / or excipient, for example, saline, phosphate buffered saline, phosphate and amino acids, polymers, polyols, sugar, buffers, preservatives, and other proteins. Illustrative agents include octylphenoxy poly ethoxy ethanol compounds, polyethylene gly col monostearate compounds, polyoxyethylene sorbitan fatty acid esters, sucrose, fructose, dextrose, maltose, glucose, mannitol, dextran, sorbitol, inositol, galactitol, xylitol, lactose, trehalose, bovine or human serum albumin, citrate, acetate, Ringer’s and Hank’s solutions, cysteine, arginine, carnitine, alanine, glycine, lysine, valine, leucine, polyvinylpyrrolidone, polyethylene, and glycol.

[0218] In some embodiments, a pharmaceutical formulation disclosed herein can comprise: (i) a therapeutic complex disclosed herein; (ii) a buffer; (iii) a non -ionic detergent; (iv) a tonicity agent; and (v) a stabilizer. In some embodiments, the pharmaceutical formulation disclosed herein is a stable liquid pharmaceutical formulation.

[0219] In some embodiments, a pharmaceutical formulation disclosed herein is a liquid formulation that can comprise about 5 mg / mL to about 150 mg / mL of the therapeutic complex, about 7.5 mg / mL to about 140 mg / mL of the therapeutic complex, about 10 mg / mL to about 130 mg / mL of the therapeutic complex, about 10 mg / mL to about 100 mg / mL of the therapeutic complex, about 20 mg / mL to about 80 mg / mL of the therapeutic complex, or about 30 mg / mL to about 70 mg / mL of the therapeutic complex. For example, a formulation of the present disclosure can comprise about 5mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, or about 150 mg / mL of a therapeutic complex described herein.

[0220] In some embodiments, a pharmaceutical formulation disclosed herein can comprise a buffer. In some embodiments, the buffer serves to maintain a stable pH and to help stabilize a therapeutic complex disclosed herein. In some embodiments, the buffer or buffer system comprises at least one buffer that has a buffering range that overlaps fully or in part the range of pH 5.5 -7.4. In some embodiments, the buffer has a pKa of about 6.2±0.5. In some embodiments, the buffer comprises a sodium phosphate buffer. In some embodiments, the sodium phosphate is present at a concentration of about 5 mM to about 15 mM, about 6 mM to about 14 mM, about 7 mM to about 13 mM, about 8 mM to about 12 mM, about 9 mM to about 11 mM, or about 10 mM. In certain embodiments, the buffer system comprises sodium phosphate at 10 mM, at a pH of 6.2±0.3 or 6.1±0.3.

[0221] The pH of the disclosed composition can range from about 3 to about 12. The pH of the composition can be, for example, from about 3 to about 4, from about 4 to about 5, from about 5 to about 6, from about 6 to about 7, from about 7 to about 8, from about 8 to about 9, from about 9 to about 10, from about 10 to about 11 , or from about 11 to about 12 pHunits. The pH of the composition can be, for example, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 pH units. The pH of the composition can be, for example, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 or at least 12 pH units. The pH of the composition can be, for example, atmost 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11 , or at most 12 pH units. A pharmaceutical f ormulation disclosed herein can have a pH of from about 5.5 to about 6.5. For example, a formulation of the present disclosure can have apH of about5.5, about5.6, about5.7, about5.8, about5.9, about6.0, about6.1, about6.2, about 6.3, about 6.4, or about 6.5. In some embodiments, the pH is 6.2±0.3, 6.2±0.2, 6.2±0. 1, about 6.2, or 6.2.

[0222] If the pH is outside the range desired by the formulator, the pH can be adjusted by using sufficient pharmaceutically -acceptable acids and bases.

[0223] In some embodiments, a pharmaceutical formulation disclosed herein can comprise a non -ionic detergent. In some embodiments, the non-ionic detergent is a nonionic polymer containing a polyoxyethylene moiety. In some embodiments, the non-ionic detergent is any one or more of polysorbate 20, poloxamer 188 or polyethylene glycol 3350. In some embodiments, the non-ionic detergent is polysorbate 20. In some embodiments, the non-ionic detergent is polysorbate 80. In some embodiments, a pharmaceutical formulation disclosed herein can contain about 0.01% to about 1%non-ionic detergent. For example, a formulation of the present disclosure can comprise about 0.0085%, about0.01%, about0.02%, about0.03%, about0.04%, about0.05%, about0.06%, about0.07%, about 0.08%, about 0.09%, about 0.1%, aboutO. l 1%, about 0.12%, about0.13%, about 0.14%, about 0.15%, about 0.16%, aboutO. l 7%, aboutO. l 8%, aboutO. l 9%, about 0.20%, about 0.21%, about 0.22%, about 0.23%, about 0.24%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1 .1%, about 1.15%, about 1 .2%, about 1 .25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, or about 2% polysorbate 20, polysorbate 80 or poloxamer 188.

[0224] In some embodiments, a pharmaceutical formulation disclosed herein can comprise a tonicity agent. In some embodiments, the tonicity agent is sodium chloride or potassium chloride. In some embodiments, the tonicity agent is sodium chloride. In some embodiments, the sodium chloride is present at a concentration of about 5 mMto about 100 mM, about 10 mM to about 50 mM, or about 40 mM.

[0225] In some embodiments, a pharmaceutical formulation disclosedherein can comprise a stabilizer. In some embodiments, the stabilizer is a thermal stabilizer that can stabilize a therapeutic complex disclosed herein under conditions of thermal stress. In some embodiments, the stabilizer maintains greater than about 93% of the therapeutic complex in a native conformation when the solution containing the therapeutic complex and the thermal stabilizer is kept at about 45 °C for up to about 28 days. In some embodiments, the stabilizer prevents aggregation of the therapeutic complex and less than 4% of the therapeutic complex is aggregated when the solution containingthe therapeutic complex and the thermal stabilizer is kept at about 45 °C for up to about 28 days. In some embodiments, the stabilizer maintains greater than about 96% of the therapeutic complex in a native conformation when the solution containingthe therapeutic complex and the thermal stabilizer is kept at about 37 °C for up to about28 days. In some embodiments, the stabilizer prevents aggregation of the therapeutic complex and less than about 2% of the therapeutic complex is aggregated when the solution containing the therapeutic complex and the thermal stabilizer is kept at about 37 °C for up to about 28 days.

[0226] In some embodiments, the thermal stabilizer is a sugar or sugar alcohol, for example, sucrose, sorbitol, glycerol, trehalose, or mannitol, or any combination thereof. In some embodiments, the stabilizer is a sugar. In some embodiments, the sugar is sucrose, mannitol or trehalose. In some embodiments, the stabilizer is sucrose. In some embodiments, a pharmaceutical formulation or ophthalmic formulation disclosed herein can comprise about 1 % to about 20% sugar or sugar alcohol, about 2% to about 18% sugar or sugar alcohol, about 3% to about 15% sugar or sugar alcohol, about 4% to about 10% sugar or sugar alcohol, or about 5% sugar or sugar alcohol. For example, apharmaceutical formulation or ophthalmic formulation of the present disclosure can comprise about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, or about 14% sugar or sugar alcohol (e.g., sucrose, trehalose ormannitol). In some embodiments, the stabilizer is at a concentration of from about 1% w / v to about 20% w / v. In some embodiments, the stabilizer is sucrose at a concentration of from about 1 % w / v to about 15% w / v, or from about 1% w / v to about 10% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 5% w / v or about 5% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 7.5% w / v or about 7.5% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 10% w / v or about 10% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 12.5% w / v or about 12.5% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 15% w / v or about 15% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 20% w / v or about 20% w / v.

[0227] A therapeutic complex of the disclosure can be, for example, an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the therapeutic complexto act rapidly. Non-limiting examples ofimmediate release formulations include readily dissolvable formulations. A controlled release formulation canbe a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements, or has been formulated to effect release of an active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.

[0228] In some embodiments, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a therapeutic complex’ s action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more therapeutic complexes, for example, for about 4, about 8, about 12, about 16, or about 24 hours.

[0229] A controlled release formulation canbe a sustained release form. A sustained release form can be formulated to sustain, for example, the therapeutic complex’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any therapeutic complex described herein (e.g., provide a physiologically -effective blood profile) over about4, about 8, about 12, about 16, or about 24 hours.

[0230] Provided herein is a pharmaceutical composition comprising any one of the compositions disclosed herein and a pharmaceutically acceptable excipient. Provided herein is a pharmaceuticalcomposition comprising any one of the nanoparticle compositions disclosed herein and a pharmaceutically acceptable excipient.

[0231] Also provided herein is the use of any one of the pharmaceutical compositions disclosed herein for the treatment of a disease or condition. In some embodiments, the pharmaceutical composition comprises (a) any one of the therapeutic agents disclosed herein and (b) a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises (a) any one of the nanoparticle compositions disclosed herein and (b) a pharmaceutically acceptable excipient.

[0232] Also provided herein is a method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject any one of the pharmaceutical compositions disclosed herein.

[0233] In some embodiments, the disease or condition is a metabolism -related disease or condition. In some embodiments, the disease or condition is a kidney disorder, a diabetes or a diabetes -related disorder, a cancer, an obesity or an obesity -related disorder, a liver disease, a cardiovascular disease (CVD), dyslipidemia, hypertension, systemic inflammation, or a neurodegenerative disorder. In some embodiments, the disease or condition is a kidney disorder. In some embodiments, the disease or condition is a diabetes or diabetes related disorder. In some embodiments, the disease or condition is a cancer. In some embodiments, the disease or condition is an obesity or obesity -related disorder. In some embodiments, the disease or condition is a liver disease. In some embodiments, the disease or condition is a cardiovascular disease. In some embodiments, the disease or condition is dyslipidemia. In some embodiments, the disease or condition is hypertension. In some embodiments, the disease or condition is systemic inflammation. In some embodiments, the disease or condition is a neurodegenerative disorder. In some embodiments, the liver disease is a non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH), primary sclerosing cholangitis (PSC), or primary biliary cholangitis (PBS). In some embodiments, the liver disease is a NAFLD. In some embodiments, the liver disease is a MASH. In some embodiments, the liver disease is a PSC. In someembodiments, the liver disease is a PBS. In some embodiments, the diabetes is Type II diabetes. In some embodiments, the disease or condition is associated with fibrosis. In some embodiments, the cancer comprises colon cancer, breast cancer, or endometrium cancer. In some embodiments, the cancer comprises colon cancer. In some embodiments, the cancer comprises breast cancer. In some embodiments, the cancer comprises endometrium cancer.EXAMPLESExample 1. Targeting ATF3 Alters Metabolic Gene Expression

[0234] In order to determine the effectiveness of targeting ATF3 to modulate metabolic gene expression, siRNAs targeting ATF3 were tested in HepG2 human liver cells. Cells were treated with lOOpL of a mastermix generated by mixing 20pL of 20pM siRNA targeting ATF3 (SEQ ID NOs: 1 and 2) or nontargeting siRNA control (SEQ ID NOs: 19 and 20), lOpLof ThermoFisherlipofectamine RNAi max, and 80pL of opti-MEM media. Media was changed daily. After culturing for three days, RNA was extracted from the cells. Following synthesis of cDNA using SuperScript IV Reverse Transcriptase, qPCR was performed to measure expression of genes related to mitochondria and glucose metabolism (MITF, PC, ACLY, PPARG, MT-ND1, SDHA, MT-ATP6) and lipid metabolism (ACSL1, DGAT2, LPINP). The control gene for qPCR was actin (ACTB). Analysis was performed comparing Cts of a gene of interest (i.e., ACLY and the control gene (ACTB) to calculate a delta Ct for each sample. Then, delta Cts of the cells treated with ATF3 siRNA were compared to cells treated with non-targeting control siRNA, which does not bind any targets in the genome. Statistical analysis consisted of one-sided t-tests comparing the delta Ct values for a given gene in the control versus the cells treated with d 77’3 siRNA. As shown in FIG. 1, treatment with siRNA targeting ATF3 effectively downregulated ^47F3 expression and resulted in increased percent change in expression (relative to non-targeting siRNA treated controls) of many of the metabolism-related genes tested. This demonstrates that targeting ATF3 can enhance metabolic gene expression.

[0235] Similarly, effects of targeting ATF3 in adipose cells, which are the primary drivers of obesity, were tested. Primary murine and human preadipocytes were obtained from ATCC (mouse), ZenBio (human), or Lonza (human). Preadipocytes were differentiated into mature adipose cells and treated with 3 pL of ThermoFisher lipofectamine RNAi max, 0.5 pL of lOpmol siRNA targeting ATF3 (SEQ ID NOs: 5 and 6 for mouse, SEQ ID NOs: 1 and 2 for human) or a non -targeting siRNA control (SEQ ID NO: 19 and20) and lOOpLofOpti-MEMmedia. After culturing for three days, RNA was extracted. Following synthesis of cDNA using SuperScript IV Reverse Transcriptase, qPCR was performed to measure expression of mitochondria / Krebs cycle metabolism ACLY, PPARG, SDHA and lipid metabolism (ACSL1, and DGAT2). The control gene for qPCR was actin (ACTB . Analysis was performed comparing Cts of a gene of interest (i.e., ACLY) and the control gene (ACTB) to calculate a delta Ct for each sample. Then, delta Cts of the cells treated with ATF3 siRNA were compared to cells treated with non-targeting control siRNA, which does not bind any targets in the genome. Statistical analysis consisted of one-sided t-tests comparing the delta Ct values for a given gene in the control versus the cells treated with ATF3 siRNA. Shown in FIG. 2, treatment with siRNA targeting ATF3 effectively downregulated ATF3 expression and resulted in increased percent change in expression (relative to non -targeting siRNAtreated controls) of many of the metabolism-related genes tested. This demonstrates that targeting ATF3 in adipose cells can alter metabolic gene expression.

[0236] Table 1. siRNAs Targeting ATF3Example 2. Design and Synthesis of siRNAs Targeting ATF3

[0237] Additional siRNA duplexes were designed and tested to identify duplexes capable of targeting human ATF3. A total of 210 human A TF3 siRNA duplexes were synthesized at 0.2umol scale with 2’- OMe and 2’-F chemical modifications. siRNA sequences, including unmodified sequences, are detailed in Tables 2-6. Single strands (sense and antisense) of the siRNA duplexes were synthesized according to phosphoramidite chemistry on a Dr. Oligo 192 synthesizer (BioAutomation). Commercially available controlled pore glass solid supports were usedfor the synthesis. Commercially available 2’-O-methyl and 2’-F-modified RNA phosphoramidites with standard protecting groups were obtained. For the syntheses, all phosphoramidites were used at a concentration of 0.1 M in CH3CN except for 2 ’-O-methyl -uridine, which were used at 0.1 M concentration in 10% DMF (v / v). A coupling time of 7 minutes was used for all phosphoramidite couplings. The activator was 0.5 M 5- ethyl-thio-tetrazole in acetonitrile (CAN). For the PO-oxidation, 50 mM iodine in water / pyridine (10:90 v / v) was used. For the PS-oxidation O. lM DDTT in pyridine was used. After completion of synthesis, the support was transferred to a 1.5 mL tube. The oligonucleotide was cleaved from the support with simultaneous deprotection of base and phosphate groups with 1 mL of an ammonium hydroxide / methylamine (AMA) solution for 3 hours at room temperature. Then the AMA solution containing oligonucleotides was filtered into a 15 mL tube and diluted to 4 mL with DI water for purification. The crudeoligo samples were purifiedbyHPLC on aTSK-Gel SuperQ-5PW (20) column (15 x2.5 cm). The buffers used were 20 mM phosphate in 10% CH3CN, pH 8.5 (buffer A) and 20 mM phosphate, 1.0 MNaBr in 10% CH3CN, pH 8.5 (buffer B). The flow rate was 2 mL / min. Wavelengths of 280 nm were monitored. The fractions containing the full-length oligonucleotides were pooled together. The purified oligonucleotides were desalted on a desalting column with Sephadex G-25 column. The purified single strands were analyzed for concentration, characterized by LCMS for mass identity and UPLC for UV-purity. For double stranded duplexes annealing, equal amounts, by OD, of two RNA strands were mixed together. The mixtures were frozen at -80° C. and dried under vacuum on a speed vac. Integrity of the duplex was confirmed by UPLC analysis and characterized by LCMS. A control siRNA was also developed with a sense strand sequence of UAACGACGCGACGACGUAAUA (SEQ ID NO: 2125) and an antisense strand sequence of UAUUACGUCGUCGCGUCGUUAUU (SEQ ID NO: 2126).Table 2. Unmodified siRNA SequencesTable 3. Modified siRNA Sequences With 3’ A on Sense Strand and 5’U on Antisense StrandTable 4. Chemically Modified siRNA Sequences (mN = 2’-O-Me; fN = 2’-F nucleoside; dN = deoxy nucleoside; * = phosphorothioate linkage)Table 5. Chemically Modified siRNA Sequences (mN = 2’-O-Me; fN = 2’-F nucleoside; dN = deoxy nucleoside; * = phosphorothioate linkage)IllTable 6. Chemically Modified siRNA Sequences (mN = 2’-O-Me; fN = 2’-F nucleoside; dN = deoxy nucleoside; = phosphorothioate linkage)Example 3. Testing of siRNA Activity Targeting Human ATF3

[0238] In order to determine the ability of designed siRNA constructs to effectively target human ATF3, the siRNAs described in Table 4 were tested in vitro. Following synthesis, an in vitro screen was conducted in either the human cell line of HEK293T or in Hep G2. Briefly, cells were transfected with siRNA to a final concentration ranging between 0.16nMand 100 nM of the siRNA duplexes.Forty-eight hours following transfection, RNA was extracted from the cells. Following synthesis of cDNA using SuperScript IV Reverse Transcriptase, qPCR was performed to measure the relative expression of ATF3. The data were normalized to GAPDH, and the data obtained are presented as the mean relative knockdown of triplet wells. p-values presented are relative to GAPDH control.

[0239] Table 7 depicts results measuring percent change in expression of ATF3 at concentrations of InM or lOnMin HEK293T cells. Table 8 depicts results measuring log2-fold change (Log2FC) of ATF3 expression at concentrations of InM or lOnM in HEK293T cells. Table 9 depicts results measuring percent of ATF3 mRNA remaining after siRNA transfection in HEK293T cells.Table 7. Percent Change in Expression of ATF3Table 8. Log2FC of ATF3 ExpressionTable 9. Percent of ATF3 mRNA remaining

[0240] Top performing siRNAs from the results obtained in Tables 7-9 were further verified by repeating the experiments in both HepG2 cells (Hep) and HEK293T (HEK) cells. Table 10 depicts results measuring percent change in expression of ATF3 at concentrations of InM or lOnMin either HepG2 cells or HEK293T cells. Table 11 depicts results measuring log2 -fold change (Log2FC) of ATF3 expression at concentrations of InM or lOnMin either HepG2 cells orHEK293T cells. Table 12 depicts results measuring percent of ATF3 mRNA remaining after siRNA transfection in either HepG2 cells or HEK293T cells.Table 10. Percent Change in ATF3 ExpressionTable 11. Log2FC of ATF3 ExpressionTable 12. Percent ATF3 mRNA Remaining

[0241] Top performing siRNAs from the results obtained in Tables 10-12 were further verified by performing a dose response curve experiment in HEK293T cells. Table 13A depicts results measuring percent change in expression of ATF3 at indicated concentrations in HEK293T cells, with p-values, IC50 and R2values shown in Table 13B. Table 14A depicts results measuring log2FC of ATF3 expression at indicated concentrations in HEK293T cells, with p-values, IC50 and R2values shown in Table 14B. Table 15A depicts results measuring percent of ATF3 mRNA remaining after siRNA transfection at indicated concentrations in HEK293T cells, with p-values, IC50 and R2values shown in Table 15B.Table 13A. Percent Change in ATF3 ExpressionTable 13B. p-value, IC50, and R2for Percent Change in ATF3 ExpressionTable 14A. Log2FC in ATF3 ExpressionTable 14B. p-value, IC50, and R2for Log2FC in ATF3 ExpressionTable 15A. Percent ATF3 mRNA RemainingTable 15B. p-value, IC50, and R2for Percent ATF3 mRNA RemainingWSGR Docket No.: 63320-704.601Example 4. Lipid- and Carbohydrate-based siRNA Modifications

[0242] siRNA duplexes were designed and synthesized to incorporate additional moieties that can direct the delivery of the siRNAs. siRNAs comprising 2’-OMe and 2’-F modifications were synthesized to incorporate a GalNAc-5 moiety derived from GalNAc (L96) (Formula I-a) at the 3’ end of the sense strand. The GalNAc moiety used is shown in FIG. 3 A. Exemplary sequences are detailed in Table 16.Table 16. GalNAc Modified siRNAs167

[0243] Other modifications can also be introduced. GalNAc or lipid moieties can be introduced into the siRNA sequences at an internal nucleotide position or at a terminal position on 3 ’ -end or 5 ’ -end of the sense strand within the siRNA duplex. Possible GalNAc moieties are depicted in FIGs. 3A- 3D. Lipid moieties suitable to be introduce to an internal nucleotide position can include (i) a 2’-O- docosanoxyl (C22) nucleotide base-3 ’-phosphate (Formula Il-a) shown in FIG. 4A or a 2’-O- hexadecyl (C16) nucleotide base-3 ’-phosphate (Formula Il-b) shown in FIG. 4B. Lipid moieties suitable to be introduced at a terminal position include a C22 lipid monomers shown in FIG. 4C or Cl 6 lipid monomers introduced into terminal position shown in FIG. 4D.Example 5. Knockdown of ATF3 in Human Liver Organoids

[0244] The efficacy of siRNAs to knock down ATF3 in human liver organoids was also assessed. Commercially available human liver organoids were used, which were generated from primary human hepatocytes. Organoids were then treated with varying concentrations of six exemplary siRNAs selected from Table 2. siRNAs were modified and conjugated to GalNAc, which allows for free uptake into the organoids. The expression of ATF3 was measured by qPCR on days 3 and 6 post-treatment with siRNA. The results of this experiment are shown in Table 17. These data demonstrate that the designed siRNAs can effectively decrease expression of ATF3, with knockdown being observed for as long as 6 days.Table 17. ATF3 Knockdown in Liver OrganoidsExample 6. Effects of ATF3 Knockdown in vivo

[0245] The efficacy of siRNAs to knock down ATF3 in vivo was assessed using a mouse model.Mice were injected subcutaneously with ATF3 siRNA designed to target murine ATF3, a non-targeting control siRNA, or PBS. Mice were dosed with siRNA either weekly, every two weeks, or every four weeks. siRNA was delivered using a commercially available lipid nanoparticle or via conjugation of GalNAc or lipids onto the siRNA.

[0246] To test the effects of ATF3 knockdown on a mouse model of type 2 diabetes, diet induced obese (DIO) mice (mice fed with a 60% fat diet) were treated with siRNA in the commercially available LNP as described above. As shown in FIG. 5A, obese mice treated with ATF3 siRNA demonstrated reduced body weight. A glucose tolerance test was performed wherein mice were orally administered glucose and the systemic concentration of glucose was measured at regular intervals over 120 minutes. Glucose tolerance was determined by calculating the area under the curve of the concentration of glucose through the testing period. As shown in FIG. 5B, ATF3 siRNA treatment resulted in improvement in glucose metabolism demonstrated by a decrease in AUC relative to obese mice treated with non-targeting controls. Similarly, concentration of insulin was decreased in the ATF3 siRNA treated groups (FIG. 5C). Taken together, this demonstrates that ATF3 siRNAs are capable of improving metabolic outcomes related to type 2 diabetes.

[0247] The effect of ATF3 knockdown on a mouse model of metabolic dysfunction-associated steatohepatitis (MASH) was also tested. In this experiment, DIO mice were treated with ATF3 siRNA conjugated to a lipid for delivery. Then, mice were assessed for body composition of lean and fat mass using a dual energy X-ray absorptiometry (DEXA) scan. As shown in FIGs. 6A and 6B, DIO mice treated with ATF3 siRNA demonstrated an increase in relative lean mass and decrease in fat mass compared to control treated DIO mice.

[0248] To investigate the effect of ATF3 knockdown on high fat diet-induced liver fibrosis, aged DIO mice were treated with ATF3 siRNA delivered using a commercially available LNP. Liver histology was performed using Masson’s trichrome strain to quantify collagen buildup. As shown in FIG. l^ATFS siRNA treated mice demonstrated a decrease in collagen staining. Livers were also scored by a pathologist for a MASH score and for overall fibrosis. As shown in FIGs. 7B and 7C, MASH activity was significantly decreased in the ATF3 siRNA treated group.

[0249] In a mouse model of liver fibrosis, mice were treated with a diet containing 3,5 - diethoxy carbonyl-1, 4-dihydrocollidine (DDC). DDC diet induces cholestatic disease, a condition characterized by impaired bile flow. This mouse model can model liver fibrosis diseases like MASH, primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC). DDC mice were treated with GalNAc conjugated ATF3 siRNA or lipid conjugated ATF3 siRNA. To assess levels of fibrosis, the concentration of hydroxyproline (HYP) was measured in the liver. As shown in FIG. 8, concentration of HYP was decreased in DDC mice receiving the conjugated ATF3 siRNAs. Theseresults demonstrate that siRNAs targeting ATF3 can improve fibrosis, collagen buildup, and other symptoms of metabolic diseases.NUMBERED EMBODIMENTS

[0250] Embodiment 1. A method of treating a disease or condition in a subject in need thereof, comprising administering an effective amount of a therapeutic agent targeting ATF3 pathway.

[0251] Embodiment 2. The method of embodiment 1, wherein the disease or condition is a metabolism-related disease or condition.

[0252] Embodiment s . The method of embodiment 1, wherein the disease or condition is a kidney disorder, a diabetes or a diabetes-related disorder, a cancer, an obesity or an obesity-related disorder, a liver disease, a cardiovascular disease (CVD), dyslipidemia, hypertension, systemic inflammation, or a neurodegenerative disorder.

[0253] Embodiment 4. The method of embodiment 3, wherein the liver disease is a non-alcoholic fatty liver disease (NAFLD).

[0254] Embodiment 5. The method of embodiment 3, wherein the diabetes is Type II diabetes.

[0255] Embodiment 6. The method of embodiment 3, wherein the cancer comprises colon cancer, breast cancer, or endometrium cancer.

[0256] Embodiment 7. The method of embodiment 3, wherein the neurodegenerative disorder comprises dementia, depression, or anxiety.

[0257] Embodiment 8. The method of any one of embodiments 1 -7, wherein the therapeutic agent is capable of lowering an mRNA level of ATF3 or a protein level of ATF3.

[0258] Embodiment 9. The method of any one of embodiments 1 -8, wherein the therapeutic agent is capable of inhibiting DNA binding to ATF3 protein.

[0259] Embodiment 10. The method of any one of embodiments 1 -9, wherein the therapeutic agent is an siRNA molecule.

[0260] Embodiment 11. The method of embodiment 10, wherein the siRNA molecule is an siRNA molecule targeting an mRNA of ATF3 gene.

[0261] Embodiment 12. The method of embodiment 11, wherein the siRNA molecule targeting ATF3 targets a sequence with atleast 85% sequence identity to any one of SEQ ID NOs: 24, 3, 5, or 7 on the mRNA of ATF3 gene.

[0262] Embodiment 13. The method of embodiment 11 or 12, wherein the siRNA molecule comprises a sense strand with at least 85% sequence identity to SEQ ID NO: 1.

[0263] Embodiment 14. The method of embodiment 11 or 12, wherein the siRNA molecule comprises a sense strand with at least 85% sequence identity to SEQ ID NO: 3.

[0264] Embodiment 15. The method of embodiment 11 or 12, wherein the siRNA molecule comprises a sense strand with at least 85% sequence identity to SEQ ID NO: 5.

[0265] Embodiment 16. The method of embodiment 11 or 12, wherein the siRNA molecule comprises a sense strand with at least 85% sequence identity to SEQ ID NO: 7.

[0266] Embodiment 17. The method of any one of embodiments 11 -16, wherein the siRNA molecule comprises an antisense strand with at least 85% sequence identity to SEQ ID NO: 2.

[0267] Embodiment 18. The method of any one of embodiments 11 -16, wherein the siRNA molecule comprises an antisense strand with at least 85% sequence identity to SEQ ID NO: 4.

[0268] Embodiment 19. The method of any one of embodiments 11 -16, wherein the siRNA molecule comprises an antisense strand with at least 85% sequence identity to SEQ ID NO: 6.

[0269] Embodiment 20. The method of any one of embodiments 11 -16, wherein the siRNA molecule comprises an antisense strand with at least 85% sequence identity to SEQ ID NO: 8.

[0270] Embodiment 21 . The method of any one of embodiments 11 -20, wherein the siRNA molecule comprises a sense strand of having a sequence of SEQ ID NO: 1, and an anti-sense strand of SEQ ID NO: 2.

[0271] Embodiment 22. The method of any one of embodiments 11 -20, wherein the siRNA molecule comprises a sense strand of SEQ ID NO: 3, and an anti-sense strand of SEQ ID NO: 4.

[0272] Embodiment 23. The method of any one of embodiments 11-20, wherein the siRNA molecule comprises a sense strand of SEQ ID NO: 5, and an anti-sense strand of SEQ ID NO: 6.

[0273] Embodiment 24. The method of any one of embodiments 11 -20, wherein the siRNA molecule comprises a sense strand of SEQ ID NO: 7, and an anti-sense strand of SEQ ID NO: 8.

[0274] Embodiment 25. The method of embodiment 11 or 12, wherein the siRNA molecule comprises: (a) an unmodified sense strand with at least 85% sequence identity to any one sense strand provided in Table 2; and (b) an unmodified antisense strand with at least 85% sequence identity to any one antisense strand provided in Table 2.

[0275] Embodiment 26. The method of any one of embodiments 1 -9, wherein the therapeutic agent is an antisense oligonucleotide molecule.

[0276] Embodiment 27. The method of embodiment 26, wherein the antisense oligonucleotide molecule is an antisense oligonucleotide molecule targeting an mRNA of ATF3 gene.

[0277] Embodiment 28. The method of any one of embodiments 10-24, wherein the siRNA molecule comprises at least one modification.

[0278] Embodiment 29. The method of embodiment 26 or 27, wherein the antisense oligonucleotide molecule comprises at least one modification.

[0279] Embodiment 30. The method of embodiment 28 or 29, wherein the siRNA or the antisense oligonucleotide molecule comprises a modification selected from the group consisting of 2’ - OMethyl, 2’-fluoro, a deoxynucleoside, and phosphorothioate backbone.

[0280] Embodiment 31. The method of embodiment 28 or 30, wherein the siRNA comprises a sense strand with at least 85% sequence identity to SEQ ID NO: 12.

[0281] Embodiment 32. The method of embodiment 28 or 30, wherein the siRNA comprises a sense strand with at least 85% sequence identity to SEQ ID NO: 14.

[0282] Embodiment 33. The method of any one of embodiments 28, 30-32, wherein the siRNA comprises an antisense strand with at least 85% sequence identity to SEQ ID NO: 13.

[0283] Embodiment 34. The method of any one of embodiments 28, 30-32, wherein the siRNA comprises an antisense strand with at least 85% sequence identity to SEQ ID NO: 15.

[0284] Embodiment 35. The method of any one of embodiments 28-34, wherein the siRNA comprises the sense strand of SEQ ID NO: 12, and an antisense strand of SEQ ID NO: 13.

[0285] Embodiment 36. The method of any one of embodiments 28-34, wherein the siRNA comprises the sense strand of SEQ ID NO: 14, and the antisense strand of SEQ ID NO: 15.

[0286] Embodiment 37. The method of embodiment 28, wherein the siRNA comprises:(a) a modified sense strand with at least 85% sequence identity to any one sense strand provided in Tables 3-6; (b) a modified antisense strand with at least 85% sequence identity to any one antisense strand provided in Tables 3-6.

[0287] Embodiment 38. The method of any one of embodiments 1-9, wherein the therapeutic agent is a small molecule.

[0288] Embodiment 39. The method of any one of embodiments 1 -38, wherein the subject is a human.

[0289] Embodiment 40. The method of any one of embodiments 1 -39, wherein the therapeutic agent specifically targets liver cells, kidney cells, muscle cells, or adipose cells.

[0290] Embodiment 41. The method of embodiment 40, wherein the therapeutic agent comprises a targeting agent.

[0291] Embodiment 42. The method of embodiment 41, wherein the targeting agent is a peptide.

[0292] Embodiment 43. The method of embodiment 42, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 11.

[0293] Embodiment 44. The method of embodiment 42 or 43, wherein the peptide is covalently linked to the therapeutic agent.

[0294] Embodiment 45. The method of embodiment 44, wherein the therapeutic agent is an siRNA and the peptide is covalently linked to the 3’ end of the sense strand of the siRNA.

[0295] Embodiment 46. The method of embodiment 41, wherein the targeting agent is N- acetylgalactosamine (GalNAc).

[0296] Embodiment 47. The method of embodiment 46, wherein the GalNAc is covalently linked to the therapeutic agent.

[0297] Embodiment 48. The method of embodiment 47, wherein the therapeutic agent is an siRNA and the GalNAc is covalently linked to the 3’ end of the sense strand of the siRNA.

[0298] Embodiment 49. The method of embodiment 48, wherein the siRNA comprises: (a) a modified sense strand with at least 85% sequence identity to any one sense strand provided in Table 16; and (b) a modified antisense strand with at least 85% sequence identity to any one antisense strand provided in Table 16.

[0299] Embodiment 50. The method of any one of embodiments 1 -49, wherein the therapeutic agent is an siRNA and the siRNA is conjugated to a lipid.

[0300] Embodiment 51. The method of embodiment 50, wherein the lipid is conjugated to an internal nucleotide of a sense strand or an antisense strand of the siRNA.

[0301] Embodiment 52. The method of embodiment 51, wherein the lipid -conjugated internal nucleotide comprises a 2’-O-docosanoxyl (C22) nucleotide base-3 ’-phosphate.

[0302] Embodiment 53. The method of embodiment 51, wherein the lipid -conjugated internal nucleotide comprises a 2’-O-hexadecyl (Cl 6) nucleotide base-3 ’-phosphate.

[0303] Embodiment 54. The method of embodiment 52 or 53, wherein the nucleotide base is selected from the group consisting of adenine, guanine, cytosine, thymine, uracil and analogs thereof.

[0304] Embodiment 55. The method of embodiment 50, wherein the lipid is conjugated to a terminus of a sense strand or an antisense strand of the siRNA.

[0305] Embodiment 56. The method of embodiment 55, wherein the lipid comprises a C22 lipid monomer or a Cl 6 lipid monomer.

[0306] Embodiment 57. The method of any one of embodiments 1 -56, wherein the method results in an increase in expression of a metabolism related gene in the cell as compared to a corresponding untreated control.

[0307] Embodiment 58. The method of embodiment 57, wherein the metabolism related gene is selected from the group consisting of MITF, PC, ACLY, PPARG, MT-ND1, SDHA, MT-ATP6, ACSL1, DGAT2, and LPIN1.

[0308] Embodiment 59. A pharmaceutical composition, comprising a therapeutic agent targeting ATF3 pathway.

[0309] Embodiment 60. The pharmaceutical composition of embodiment 59, wherein the therapeutic agent is capable of lowering an mRNA level of ATF3 or a protein level of ATF3.

[0310] Embodiment 61. The pharmaceutical composition of embodiment 59 or 60, wherein the therapeutic agent is capable of inhibiting DNA binding to ATF3 protein.

[0311] Embodiment 62. The pharmaceutical composition of any one of embodiments 59-61, wherein the therapeutic agent is an siRNA molecule.

[0312] Embodiment 63. The pharmaceutical composition of embodiment 62, wherein the siRNA molecule is an siRNA molecule targeting an mRNA of ATF3 gene.

[0313] Embodiment 64. The pharmaceutical composition of embodiment 63, wherein the siRNA molecule targeting ATF3 targets a sequence with at least 85% sequence identity to any one of SEQ ID NOs: 24, 3, 5, or 7 on the mRNA of ATF3 gene.

[0314] Embodiment 65. The pharmaceutical composition of embodiment 62 or 63, wherein the siRNA molecule comprises a sense strand with at least 85% sequence identity to SEQ ID NO: 1.

[0315] Embodiment 66. The pharmaceutical composition of embodiment 62 or 63, wherein the siRNA molecule comprises a sense strand with at least 85% sequence identity to SEQ ID NO: 3.

[0316] Embodiment 67. The pharmaceutical composition of embodiment 62 or 63, wherein the siRNA molecule comprises a sense strand with at least 85% sequence identity to SEQ ID NO: 5.

[0317] Embodiment 68. The pharmaceutical composition of embodiment 62 or 63, wherein the siRNA molecule comprises a sense strand with at least 85% sequence identity to SEQ ID NO: 7.

[0318] Embodiment 69. The pharmaceutical composition of any one of embodiments 62-68, wherein the siRNA molecule comprises an antisense strand with at least 85% sequence identity to SEQ ID NO: 2.

[0319] Embodiment 70. The pharmaceutical composition of any one of embodiments 62-68, wherein the siRNA molecule comprises an antisense strand with at least 85% sequence identity to SEQ ID NO: 4.

[0320] Embodiment 71. The pharmaceutical composition of any one of embodiments 62-68, wherein the siRNA molecule comprises an antisense strand with at least 85% sequence identity to SEQ ID NO: 6.

[0321] Embodiment 72. The pharmaceutical composition of any one of embodiments 62-68, wherein the siRNA molecule comprises an antisense strand with at least 85% sequence identity to SEQ ID NO: 8.

[0322] Embodiment 73. The pharmaceutical composition of any one of embodiments 62-72, wherein the siRNA molecule comprises a sense strand of SEQ ID NO: 1, and an anti-sense strand of SEQ ID NO: 2.

[0323] Embodiment 74. The pharmaceutical composition of any one of embodiments 62-72, wherein the siRNA molecule comprises a sense strand of SEQ ID NO: 3, and an anti -sense strand of SEQ ID NO: 4.

[0324] Embodiment 75. The pharmaceutical composition of any one of embodiments 62-72, wherein the siRNA molecule comprises a sense strand of SEQ ID NO: 5, and an anti -sense strand of SEQ ID NO: 6.

[0325] Embodiment 76. The pharmaceutical composition of any one of embodiments 62-72, wherein the siRNA molecule comprises a sense strand of SEQ ID NO: 7, and an anti -sense strand of SEQ ID NO: 8.

[0326] Embodiment 77. The pharmaceutical composition of embodiment 62 or 63, wherein the siRNA molecule comprises: (a) an unmodified sense strand with at least 85% sequence identity to any one sense strand provided in Table 2; and (b) an unmodified antisense strand with at least 85% sequence identity to any one antisense strand provided in Table 2.

[0327] Embodiment 78. The pharmaceutical composition of any one of embodiments 59-61, wherein the therapeutic agent is an antisense oligonucleotide molecule.

[0328] Embodiment 79. The pharmaceutical composition of embodiment 78, wherein the antisense oligonucleotide molecule is an antisense oligonucleotide molecule targeting an mRNA of ATF3 gene.

[0329] Embodiment 80. The pharmaceutical composition of any one of embodiments 62-76, wherein the siRNA molecule comprises at least one modification.

[0330] Embodiment 81. The pharmaceutical composition of any one of embodiments 78 or 79, wherein the antisense oligonucleotide molecule comprises at least one modification.

[0331] Embodiment 82. The pharmaceutical composition of embodiment 80 or 81, wherein the siRNA or the antisense oligonucleotide molecule comprises a modification selected from the group consisting of 2’ -OMethyl, 2’-fluoro, a deoxynucleoside, and phosphorothioate backbone.

[0332] Embodiment 83. The pharmaceutical composition of embodiment 80 or 82, wherein the siRNA comprises a sense strand with at least 85% sequence identity of SEQ ID NO: 12.

[0333] Embodiment 84. The pharmaceutical composition of embodiment 80 or 82, wherein the siRNA comprises a sense strand with at least 85% sequence identity to SEQ ID NO: 14.

[0334] Embodiment 85. The pharmaceutical composition of any one of embodiments 80-84, wherein the siRNA comprises an antisense strand with at least 85% sequence identity to SEQ ID NO: 13.

[0335] Embodiment 86. The pharmaceutical composition of any one of embodiments 80-84, wherein the siRNA comprises an antisense strand with at least 85% sequence identity of SEQ ID NO: 15.

[0336] Embodiment 87. The pharmaceutical composition of any one of embodiments 80-84, wherein the siRNA comprises the sense strand to SEQ ID NO: 12, and an antisense strand to SEQ ID NO: 13.

[0337] Embodiment 88. The pharmaceutical composition of any one of embodiments 80-84, wherein the siRNA comprises the sense strand of SEQ ID NO: 14, and the antisense strand of SEQ ID NO: 15.

[0338] Embodiment 89. The pharmaceutical composition of embodiment 80 or 82, wherein the siRNA comprises: (a)a modified sense strand with at least 85% sequence identity to any one sense strand provided in Tables 3 -6; (b) a modified antisense strand with at least 85% sequence identity to any one antisense strand provided in Tables 3 -6.

[0339] Embodiment 90. The pharmaceutical composition of any one of embodiments 59-61, wherein the therapeutic agent is a small molecule.

[0340] Embodiment 91. The pharmaceutical composition of any one of embodiments 59-90, wherein the therapeutic agent comprises a targeting agent.

[0341] Embodiment 92. The pharmaceutical composition of embodiment 91, wherein the targeting agent is a peptide.

[0342] Embodiment 93. The pharmaceutical composition of embodiment 92, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 11 .

[0343] Embodiment 94. The pharmaceutical composition of embodiment 92 or 93, wherein the peptide is covalently linked to the therapeutic agent.

[0344] Embodiment 95. The pharmaceutical composition of embodiment 94, wherein the therapeutic agent is an siRNA and the peptide is covalently linked to the 3 ’ end of the sense strand of the siRNA.

[0345] Embodiment 96. The pharmaceutical composition of embodiment 91, wherein the targeting agent is N-acetylgalactosamine (GalNAc).

[0346] Embodiment 97. The pharmaceutical composition of embodiment 96, wherein the GalNAc is covalently linked to the therapeutic agent.

[0347] Embodiment 98. The pharmaceutical composition of embodiment 97, wherein the therapeutic agent is an siRNA and the GalNAc is covalently linked to the 3’ end of the sense strand of the siRNA.

[0348] Embodiment 99. The pharmaceutical composition of embodiment 98, wherein the siRNA comprises: (a) a modified sense strand with at least 85% sequence identity to any one sense strand provided in Table 16; and (b) a modified antisense strand with at least 85% sequence identity to any one antisense strand provided in Table 16.

[0349] Embodiment 100. The pharmaceutical composition of any one of embodiments 59-99, wherein the therapeutic agent is an siRNA and the siRNA is conjugated to a lipid.

[0350] Embodiment 101. The pharmaceutical composition of embodiment 100, wherein the lipid is conjugated to an internal nucleotide of a sense strand or an antisense strand of the siRNA.

[0351] Embodiment 102. The pharmaceutical composition of embodiment 101, wherein the lipid - conjugated internal nucleotide comprises a 2’-O-docosanoxyl (C22) nucleotide base-3 ’-phosphate.

[0352] Embodiment 103. The pharmaceutical composition of embodiment 101, wherein the lipid - conjugated internal nucleotide comprises a 2’ -O-h exadecyl (Cl 6) nucleotide base-3 ’-phosphate.

[0353] Embodiment 104. The pharmaceutical composition of embodiment 102 or 103, wherein the nucleotide base is selected from the group consisting of adenine, guanine, cytosine, thymine, uracil and analogs thereof.

[0354] Embodiment 105. The pharmaceutical composition of embodiment 100, wherein the lipid is conjugated to a terminus of a sense strand or an antisense strand of the siRNA.

[0355] Embodiment 106. The pharmaceutical composition of embodiment 105, wherein the lipid comprises a C22 lipid monomer or a Cl 6 lipid monomer.

[0356] Embodiment 107. A nanoparticle composition comprising the pharmaceutical composition of any one of embodiments 59-106.

[0357] Embodiment 108. The nanoparticle composition of embodiment 107, wherein the pharmaceutical composition comprises an adipose targeting peptide having a sequence set forth in SEQ ID NO: 11.

[0358] Embodiment 109. The nanoparticle composition of embodiment 108, wherein the adipose targeting peptide is modified to bind to the therapeutic agent.

[0359] Embodiment 110. The nanoparticle composition of embodiment 108, wherein the adipose targeting peptide is modified such that at least one positive charged amino acid is added to C- terminus of the adipose targeting peptide.

[0360] Embodiment 111. The nanoparticle composition of embodiment 110, wherein the at least one positive charged amino acid comprises arginine, lysine, or histidine.

[0361] Embodiment 112. The nanoparticle composition of embodiment 111, wherein the positive charged amino acid is arginine.

[0362] Embodiment 113. The nanoparticle composition of any one of embodiments 107-112, wherein the therapeutic agent is siRNA.

[0363] Embodiment 114. The nanoparticle composition of any one of embodiments 108-113, wherein a ratio of the peptide to the siRNA is at least 10:1, 20:1, 30:1, or 40:1.

[0364] Embodiment 115. The nanoparticle composition of any one of embodiments 107-114, wherein the pH of the nanoparticle composition is from about 5.5 to about 7.5.

[0365] Embodiment 116. The nanoparticle composition of embodiment 115, wherein the pH is from about 6 to about 6.5.

[0366] Embodiment 117. The nanoparticle composition of embodiment 116, wherein the pH is about 6.

Claims

CLAIMSWhat is claimed is:1 . A composition comprising an siRNA targeting an ATF3 pathway, wherein the siRNA comprises(a) a sense strand having a sequence with at least 80% sequence identity to any one sense strand sequence presented in Tables 1-6 or 16;(b) an antisense strand having a sequence with at least 80% sequence identity to any one antisense strand sequence presented in Tables 1-6 or 16.

2. The composition of claim 1, wherein the siRNA comprises an antisense strand comprising a region of complementarity of at least 8 nucleosides to an ATF3 RNA sequence set forth in any one of SEQ ID NOs: 2148, 17, and 22, and a sense strand that is at least substantially complementary to the antisense strand.

3. The composition of claim 1 or 2, wherein the sense strand is 15-35 nucleosides in length, and / or the antisense strand is 15-35 nucleosides in length.

4. The composition of any one of claims 1-3, wherein the antisense strand and the sense strand hybridize to form a duplex region of 15-25 base pairs in length.

5. The composition of any one of claims 1 -4, wherein the antisense strand comprises a region of complementarity of at least 8 nucleobases to(a) an ATF3 RNA sequence as set forth in SEQ ID NO: 24, or(b) to the sense strand sequence of any one sense strand sequence presented in Tables 1- 6, or 16.

6. The composition of any one of claims 1-5, wherein the antisense strand comprises a region of complementary 15-21 nucleobases to(a) an ATF3 RNA sequence as set forth in SEQ ID NO: 24, or(b) to the sense strand sequence of any one sense strand sequence presented in Tables 1- 6, or 16.

7. The composition of any one of claims 1-6, wherein the antisense strand comprises at least 8 consecutive nucleobases of the antisense strand of any one of the antisense strand sequence presented in Tables 1-6, or 16.

8. The composition of any one of claims 1-7, wherein the antisense strand comprises the nucleobase sequences of any one antisense strand sequence presented in Tables 1-6, or 16.

9. The composition of any one of claims 1-8, wherein the sense strand comprises at least 8 consecutive nucleobases of any one sense strand sequence presented in Tables 1-6, or 16.

10. The composition of any one of claims 1-9, wherein the sense strand comprises the nucleobase sequence of any one sense strand sequence presented in Tables 1-6, or 16.11 . The composition of any one of claims 1-10, wherein the antisense strand comprises at least 8 consecutive nucleobases of any one of SEQ ID NOs: 58, 66, 68, 274, 356, 358, 370, 378, 380, 386, 392, 408, 414, 416, 444, 446, 478, 486, 488, 694, 776, 778, 790, 798, 800, 806, 812, 828, 834, 836, 864.

12. The composition of any one of claims 1-11, wherein the antisense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 58, 66, 68, 274, 356, 358, 370, 378, 380, 386, 392, 408, 414, 416, 444, 446, 478, 486, 488, 694, 776, 778, 790, 798, 800, 806, 812, 828, 834, 836, 864.

13. The composition of any one of claims 1-12, wherein the sense strand comprises least 8 consecutive nucleobases of any one of SEQ ID NOs: 57, 65, 67, 273, 355, 357, 369, 377, 379, 385, 391, 407, 413, 415, 443, 445, 477, 485, 487, 693, 775, 777, 789, 797, 799, 805, 811, 827, 833, 835, 863.

14. The composition of any one of claims 1-13, wherein the sense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 57, 65, 67, 273, 355, 357, 369, 377, 379, 385, 391, 407, 413, 415, 443, 445, 477, 485, 487, 693, 775, 777, 789, 797, 799, 805, 811, 827, 833, 835, 863.

15. The composition of any one of claims 1-14, wherein(a) the antisense strand comprises 15-23 consecutive nucleobases of any one of SEQ ID NOs: 274, 356, 378, 392, 414, 444, 446, 694, 776, 798, 812, 834, 864, and(b) the sense strand comprises 15-21 nucleobases of any one of SEQ ID NOs: 273, 355, 377, 391, 413, 443, 445, 693, 775, 797, 811, 833, and 863.

16. The composition of any one of claims 1-15, wherein the siRNA comprises the nucleobase sequence of any one of siRNA-23, siRNA-27, siRNA-28, siRNA-131, siRNA-172, siRNA-173, siRNA-179, siRNA-183, siRNA-184, siRNA-187, siRNA-190, siRNA-198, siRNA-201, siRNA-202, siRNA-216, siRNA-217, siRNA-233, siRNA-237, siRNA-238, siRNA-341, siRNA-382, siRNA-383, siRNA-389, siRNA-393, siRNA-394, siRNA-397, siRNA-400, siRNA-408, siRNA-411, siRNA-412, and siRNA-426.

17. The composition of any one of claims 1-16, wherein the siRNA comprises the nucleobase sequence of any one of siRNA-131, siRNA-172, siRNA-183, siRNA-190, siRNA-201, siRNA-202, siRNA-216, siRNA-217, siRNA-341, siRNA-382, siRNA-393, siRNA-400, siRNA-411, and siRNA-426.

18. The composition of any one of claims 1 -16, wherein the siRNA comprises(a) a sense strand having a sequence of SEQ ID NO: 273 and an antisense strand having a sequence of SEQ ID NO: 274;(b) a sense strand having a sequence of SEQ ID NO: 355 and an antisense strand having a sequence of SEQ ID NO: 356;(c) a sense strand having a sequence of SEQ ID NO: 377 and an antisense strand having a sequence of SEQ ID NO: 378;(d) a sense strand having a sequence of SEQ ID NO: 391 and an antisense strand having a sequence of SEQ ID NO: 392;(e) a sense strand having a sequence of SEQ ID NO: 413 and an antisense strand having a sequence of SEQ ID NO: 414;(f) a sense strand having a sequence of SEQ ID NO: 415 and an antisense strand having a sequence of SEQ ID NO: 416;(g) a sense strand having a sequence of SEQ ID NO: 443 and an antisense strand having a sequence of SEQ ID NO: 444;(h) a sense strand having a sequence of SEQ ID NO: 445 and an antisense strand having a sequence of SEQ ID NO: 446;(i) a sense strand having a sequence of SEQ ID NO: 693 and an antisense strand having a sequence of SEQ ID NO: 694;(j) a sense strand having a sequence of SEQ ID NO: 775 and an antisense strand having a sequence of SEQ ID NO: 776;(k) a sense strand having a sequence of SEQ ID NO: 797 and an antisense strand having a sequence of SEQ ID NO: 798;(l) a sense strand having a sequence of SEQ ID NO: 811 and an antisense strand having a sequence of SEQ ID NO: 812;(m) a sense strand having a sequence of SEQ ID NO: 833 and an antisense strand having a sequence of SEQ ID NO: 834; or(n) a sense strand having a sequence of SEQ ID NO: 863 and an antisense strand having a sequence of SEQ ID NO: 864.

19. The composition of any one of claims 1 -18, wherein the siRNA comprises a sense strand comprising the nucleobase sequence of any one sense strand sequence presented in column 2 of Tables 2-6 or 16 and an antisense sense strand comprising the nucleobase sequence of the corresponding antisense strand sequence presented in column 4 of Table 2-6 or 16.

20. The composition of any one of claims 1 -19, wherein the siRNA is configured to interact with an RNA-induced silencing complex (RISC).

21. The composition of any one of claims 1-20, wherein the siRNA comprises one or more modified nucleosides.

22. The composition of any one of claims 1 -21, wherein each nucleoside of the antisense strand is a modified nucleoside and each nucleoside of the sense strand is a modified nucleoside.

23. The composition of claim 21 or 22, wherein the one or more modified nucleosides are 2’ modified nucleosides.

24. The composition of claim 23, wherein the 2’-modified nucleoside is selected from 2’- deoxy ribonucleoside (DNA), 2’-fluoro (2’-F), 2’-O-methyl (2’-O-Me), 2’-O-methoxyethyl (2’-MOE), 2’-O-aminopropyl (2’-O-AP), 2’-O-dimethylaminoethyl (2’-O-DMAOE), 2’-O- dimethylaminopropyl (2’-O-DMAP), 2’-O-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-O-N-methylacetamido (2’-0-NMA) modified nucleoside and combinations thereof.

25. The composition of any one of claims 22-24, wherein each nucleoside of the antisense strand is selected from a 2’-F modified nucleoside and a 2’-O-Me modified nucleoside, and each nucleoside of the sense strand is a 2’ -modified nucleoside selected from a 2’-F modified nucleoside and a 2’-O-Me modified nucleoside.

26. The composition of any one of claims 21-25, wherein the nucleosides at one or more positions 9, 10, and 11 (counting 5’ to 3’) of the sense strand are 2’-F modified nucleosides.

27. The composition of any one of claims 21-26, wherein the nucleosides at positions 9, 10, and 11 (counting 5’ to 3 ’) of the sense strand are 2’-F modified nucleosides.

28. The composition of any one of claims 21-26, wherein the nucleoside at position 7 (counting 5’ to 3 ’) of the sense strand is a 2’-F modified nucleoside.

29. The composition of any one of claims 21-28, wherein the nucleosides at one or more positions 2, 6, 7, 8, 9, 14 and 16 (counting 5 ’ to 3 ’) of the antisense strand are 2’-F modified nucleosides, optionally wherein the nucleosides at positions 2 and 14 of the antisense strand are 2’-F modified nucleosides.

30. The composition of any one of claims 1 -29, wherein the antisense strand further comprises one or more of 2’ -deoxyribonucleosides (DNA), optionally wherein the nucleoside at one of both of positions 5 and 7 (counting 5’ to 3’) of the antisense strand is a DNA.31 . The composition of any one of claims 1 -30, wherein the siRNA comprises one or more modified internucleoside linkages.

32. The composition of any one of claims 1 -31, wherein the siRNA comprises one or more phosphorothioate internucleoside linkages in at least one strand.

33. The composition of any one of claims 1 -32, wherein the sense strand comprises two phosphorothioate internucleoside linkages.

34. The composition of claim 33, wherein the two phosphorothioate internucleoside linkages are the first two internucleoside linkages in the sense strand from 5’ to 3’.

35. The composition of any one of claims 1 -34, wherein the antisense strand comprises four phosphorothioate internucleoside linkages.

36. The composition of claim 35, wherein the four phosphorothioate intemucleoside linkages are the first two internucleoside linkages and the last two intemucleoside linkages in the antisense strand from 5’ to 3’.

37. The composition of any one of claims 32-36, wherein the nucleosides at positions 9, 10, and 11 (counting 5 ’to 3’) of the sense strand are 2’-F modified nucleosides, the nucleosides at one or more of positions 2, 6, 7, 8, 9, 14 and 16 (counting 5 ’ to 3 ’) of the antisense strand are 2’-F modified nucleosides, the first two intemucleoside linkages in the sense strand from 5’ to 3’ are phosphorothioate intemucleoside linkages, and the first two intemucleoside linkages and the last two intemucleoside linkages in the antisense strand from 5’ to 3 ’are phosphorothioate intemucleoside linkages.

38. The composition of any one of claims 1 -37, wherein the siRNA comprises a sense strand comprising the sequence of any one sense strand sequence presented in column 2 of Tables 4-6 and an antisense sense strand comprising the sequence of the corresponding antisense strand sequence presented column 4 of Table 4-6.

39. The composition of any one of claims 1-38, wherein the siRNA is selected from: siRNA-443, siRNA-447, siRNA-448, siRNA-551, siRNA-592, siRNA-593, siRNA-599, siRNA-603, siRNA-604, siRNA-607, siRNA-610, siRNA-618, siRNA-621, siRNA-622, and siRNA-636.

40. The composition of claim 39, wherein the siRNA is selected from: siRNA-551, siRNA-592, siRNA-593, siRNA-599, siRNA-603, siRNA-610, siRNA-621, and siRNA-636.

41. The composition of any one of claims 1 -40, wherein the siRNA comprises(a) a sense strand having a sequence of SEQ ID NO: 1113 and an antisense strand having a sequence of SEQ ID NO: 1114;(b) a sense strand having a sequence of SEQ ID NO: 1195 and an antisense strand having a sequence of SEQ ID NO: 1196;(c) a sense strand having a sequence of SEQ ID NO: 1197and an antisense strand having a sequence of SEQ ID NO: 1198;(d) a sense strand having a sequence of SEQ ID NO: 1209 and an antisense strand having a sequence of SEQ ID NO: 1210;(e) a sense strand having a sequence of SEQ ID NO: 1217 and an antisense strand having a sequence of SEQ ID NO: 1218;(f) a sense strand having a sequence of SEQ ID NO: 1231 and an antisense strand having a sequence of SEQ ID NO: 1232;(g) a sense strand having a sequence of SEQ ID NO: 1253 and an antisense strand having a sequence of SEQ ID NO: 1254; or(h) a sense strand having a sequence of SEQ ID NO: 1283 and an antisense strand having a sequence of SEQ ID NO: 1284.

42. The composition of any one of claims 1 -41, wherein the composition further comprises a targeting agent.

43. The composition of claim 42, wherein the targeting agent is a peptide.

44. The composition of claim 43, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 11.

45. The composition of claim 43 or 44, wherein the peptide is covalently linked to the siRNA.

46. The composition of claim 45, wherein the peptide is covalently linked to the 3’ end of the sense strand of the siRNA.

47. The composition of claim 42, wherein the targeting agent is a N-acetylgalactosamine (GalNAc).

48. The composition of claim 47, wherein the GalNAc is covalently linked to the siRNA.

49. The composition of claim 48, wherein the GalNAc is covalently linked to the 3’ end of the sense strand of the siRNA.

50. The composition of any one of claims 47-49, wherein the GalNAc comprises a structure of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d).51 . The composition of any one of claims 47-50, wherein the siRNA is selected from the siRNAs listed in Table 16.

52. The composition of any one of claims 47-51, wherein the siRNA is selected from: siRNA- 1057, siRNA-1058, siRNA-1059, siRNA-1060, siRNA-1061, siRNA-1062, siRNA-1063, siRNA-1064, siRNA-1065, siRNA-1066, siRNA-1067, siRNA-1069, siRNA-1070, siRNA- 1071, and siRNA-1072.

53. The composition of claim 52, wherein the siRNA is selected from siRNA-1060, siRNA-1061, siRNA-1062, siRNA-1063, siRNA-1064, siRNA-1067, siRNA-1070, and siRNA-1072.

54. The composition of any one of claims 47-53, wherein the siRNA comprises(a) a sense strand having a sequence of SEQ ID NO: 2132 and an antisense strand having a sequence of SEQ ID NO: 1114;(b) a sense strand having a sequence of SEQ ID NO: 2133 and an antisense strand having a sequence of SEQ ID NO: 1196;(c) a sense strand having a sequence of SEQ ID NO: 2134 and an antisense strand having a sequence of SEQ ID NO: 1198;(d) a sense strand having a sequence of SEQ ID NO: 2135 and an antisense strand having a sequence of SEQ ID NO: 1210;(e) a sense strand having a sequence of SEQ ID NO: 2136 and an antisense strand having a sequence of SEQ ID NO: 1218;(f) a sense strand having a sequence of SEQ ID NO: 2139 and an antisense strand having a sequence of SEQ ID NO: 1232;(g) a sense strand having a sequence of SEQ ID NO: 2142 and an antisense strand having a sequence of SEQ ID NO: 1254;(h) a sense strand having a sequence of SEQ ID NO: 2144 and an antisense strand having a sequence of SEQ ID NO: 1284.

55. The composition of any one of claims 1 -54, wherein the siRNA is conjugated to a lipid.

56. The composition of claim 55, wherein the lipid is conjugated to an internal nucleotide of a sense strand or an antisense strand of the siRNA.

57. The composition of claim 56, wherein the lipid-conjugated internal nucleotide comprises a 2’-O-docosanoxyl (C22) nucleotide base-3 ’-phosphate.

58. The composition of claim 56, wherein the lipid-conjugated internal nucleotide comprises a 2’-O-hexadecyl (C16) nucleotide base-3 ’-phosphate.

59. The composition of claim 57 or 58, wherein the nucleotide base is selected from the group consisting of adenine, guanine, cytosine, thymine, uracil and analogs thereof.

60. The composition of claim 55, wherein the lipid is conjugated to a terminus of a sense strand or an antisense strand of the siRNA.61 . The composition of claim 60, wherein the lipid comprises a C22 lipid monomer or a Cl 6 lipid monomer.

62. A nanoparticle composition comprising the siRNA of any one of claims 1 -61 .

63. The nanoparticle composition of claim 62, wherein the nanoparticle composition comprises an adipose targeting peptide having a sequence set forth in SEQ ID NO: 11 .

64. The nanoparticle composition of claim 63, wherein the adipose targeting peptide is modified to bind to the therapeutic agent.

65. The nanoparticle composition of claim 62 or 63, wherein the adipose targeting peptide is modified such that at least one positive charged amino acid is added to C -terminus of the adipose targeting peptide.

66. The nanoparticle composition of claim 65, wherein the at least one positive charged amino acid comprises arginine, lysine, or histidine.

67. The nanoparticle of claim 66, wherein the positive charged amino acid is arginine.

68. The nanoparticle composition of any one of claims 63-67, wherein a ratio of the adipose targeting peptide to the siRNA is at least 10:1, 20: 1, 30:1, or 40: 1.

69. The nanoparticle composition of any one of claims 62-68, wherein the pH of the nanoparticle composition is from about 5.5 to about 7.5.

70. The nanoparticle composition of any one of claims 62-69, wherein the pH is from about 6 to about 6.5.

71. The nanoparticle composition of any one of claims 62-70, wherein the pH of the nanoparticle composition is about 6.

72. A pharmaceutical composition comprising (a) the composition of any one of claims 1 -61 or the nanoparticle composition of any one of claims 62-71 ; and (b) a pharmaceutically acceptable excipient.

73. A method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 72.

74. The method of claim 73, wherein the subject is a human.

75. The method of claim 73 or 74, wherein the disease or condition is a metabolism -related disease or condition.

76. The method of any one of claim 73-75, wherein the disease or condition is a kidney disorder, a diabetes or a diabetes-related disorder, a cancer, an obesity or an obesity -related disorder, a liver disease, a cardiovascular disease (CVD), dyslipidemia, hypertension, systemic inflammation, or a neurodegenerative disorder.

77. The method of claim 76, wherein the liver disease is a non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH), primary sclerosing cholangitis (PSC), or primary biliary cholangitis (PBC).

78. The method of claim 76, wherein the diabetes is Type II diabetes.

79. The method of any one of claims 73-78, wherein the disease or condition is associated with fibrosis.

80. The method of claim 76, wherein the cancer comprises colon cancer, breast cancer, or endometrium cancer.

81. The method of claim 76, wherein the neurodegenerative disorder comprises dementia, depression, or anxiety.

82. The method of any one of claims 73-81, wherein the method results in a lowering of an mRNA level of ATF3 or a protein level of ATF3.

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