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

Attorney Docket Number: J0365.70001WO00METHODS AND COMPOSITIONS FOR TREATING METABOLIC DISEASES RELATED APPLICATIONS

[0001] This Application claims the benefit under 35 U. S. C. § 119(e) of U. S. Provisional Application No. 63 / 734393, filed on December 16, 2024, and U. S. Provisional Application No. 63 / 854863, filed on July 31, 2025, the entire contents of each of which are incorporated herein by reference.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (J036570001WO00-SEQ-ZJG.xml; Size: 15,126,710 bytes; and Date of Creation: December 15, 2025) are herein incorporated by reference in their entirety.BACKGROUND

[0003] Obesity is a significant global 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0004] FIGs. 1A-1F show blood markers of healthy control mice, diet induced obese (DIO) control mice, and mice administered 1 mg / kg, 5 mg / kg, or 10 mg / kg of an ATF4 siRNA for 12 weeks. Blood was evaluated at week 28 of the study (16 weeks after cessation of treatment). * indicates p < 0.05; **** indicates p < 0.0001.

[0005] FIG.2 shows weight (in grams) of healthy control mice, diet induced obese (DIO) control mice, and mice administered 1 mg / kg, 5 mg / kg, or 10 mg / kg of an ATF4 siRNA for 12 weeks. Data was collected for an additional 19 weeks after treatment was ceased after the 12 week dosing period (dotted line).

[0006] FIG.3 shows cumulative caloric intake (in kcal) of healthy control mice, diet induced obese (DIO) control mice, and mice administered 1 mg / kg, 5 mg / kg, or 10 mg / kg of an ATF4Attorney Docket Number: J0365.70001WO00siRNA for 12 weeks. Data was collected for an additional 19 weeks after treatment was ceased after the 12 week dosing period.SUMMARY

[0007] Provided herein is a method of treating a disease or condition in a subject in need thereof, comprising administering an effective amount of a therapeutic agent targeting an ATF4 pathway.

[0008] In some embodiments, the disease or condition is a metabolism-related disease or condition.

[0009] 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, skeletal muscle atrophy, sarcopenia, or a neurodegenerative disorder.

[0010] In some embodiments, the liver disease is a non-alcoholic fatty liver disease (NAFLD).

[0011] In some embodiments, the diabetes is Type II diabetes.

[0012] In some embodiments, the cancer comprises colon cancer, breast cancer, or endometrium cancer.

[0013] In some embodiments, the neurodegenerative disorder comprises dementia, depression, or anxiety.

[0014] In some embodiments, the therapeutic agent is capable of lowering an mRNA level or a protein level of an ATF4 gene.

[0015] In some embodiments, the therapeutic agent is capable of inhibiting DNA binding to an ATF4 protein.

[0016] In some embodiments, the therapeutic agent is an siRNA molecule.

[0017] In some embodiments, the siRNA molecule is an siRNA molecule targeting an mRNA of the ATF4 gene.

[0018] In some embodiments, the siRNA molecule targets a sequence with at least 85% sequence identity to any one sense strand sequence provided in Table 1.

[0019] In some embodiments, the siRNA molecule comprises a sense strand with at least 85% sequence identity to any one sense strand sequence provided in Table 1.

[0020] In some embodiments, the siRNA molecule comprises an antisense strand with at least 85% sequence identity to any one antisense strand sequence provided in Table 1.Attorney Docket Number: J0365.70001WO00

[0021] In some embodiments, the siRNA molecule comprises: (a) a sense strand with at least 85% sequence identity to any one sense strand sequence provided in Table 1; and (b) an antisense strand with at least 85% sequence identity to any one antisense strand sequence provided in Table 1.

[0022] In some embodiments, the siRNA molecule targets a sequence with at least 85% sequence identity to any one sense strand sequence provided in Table 2.

[0023] In some embodiments, the siRNA molecule comprises a sense strand with at least 85% sequence identity to any one of the sense strand sequences provided in Table 2.

[0024] In some embodiments, the siRNA molecule comprises an antisense strand with at least 85% sequence identity to any one of the antisense strand sequences provided in Table 2.

[0025] In some embodiments, the siRNA molecule comprises: (a) a sense strand with at least 85% sequence identity to any one sense strand sequence provided in Table 2; and (b) an antisense strand with at least 85% sequence identity to any one antisense strand sequence provided in Table 2.

[0026] In some embodiments, the therapeutic agent is an antisense oligonucleotide molecule.

[0027] In some embodiments, the antisense oligonucleotide molecule is an antisense oligonucleotide molecule targeting an mRNA of the ATF4 gene.

[0028] In some embodiments, the siRNA molecule comprises at least one modification.

[0029] In some embodiments, the antisense oligonucleotide molecule comprises at least one modification.

[0030] In some embodiments, 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.

[0031] In some embodiments, the siRNA comprises a sense strand with at least 85% sequence identity to any one sense strand sequence provided in Table 3.

[0032] In some embodiments, the siRNA comprises an antisense strand with at least 85% sequence identity to any one antisense strand sequence provided in Table 3.

[0033] In some embodiments, the siRNA comprises: (a) a modified sense strand with at least 85% sequence identity to any one sense strand sequence provided in Table 3; and (b) a modified antisense strand with at least 85% sequence identity to any one antisense strand provided in Table 3.

[0034] In some embodiments, the therapeutic agent is a small molecule.

[0035] In some embodiments, the subject is a human.Attorney Docket Number: J0365.70001WO00

[0036] In some embodiments, the therapeutic agent specifically targets liver cells, kidney cells, muscle cells, or adipose cells.

[0037] In some embodiments, the therapeutic agent comprises a targeting agent.

[0038] In some embodiments, the targeting agent is a peptide.

[0039] In some embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 9.

[0040] In some embodiments, the peptide is covalently linked to the therapeutic agent.

[0041] In some embodiments, the therapeutic agent is an siRNA and the peptide is covalently linked to the 3’ end of the sense strand of the siRNA.

[0042] In some embodiments, the targeting agent is N-acetylgalactosamine (GalNAc).

[0043] In some embodiments, the GalNAc is covalently linked to the therapeutic agent.

[0044] 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.

[0045] In some embodiments, the siRNA comprises: (a) a modified sense strand with at least 85% sequence identity to any one sense strand provided in Table 4; and (b) a modified antisense strand with at least 85% sequence identity to any one antisense strand provided in Table 4.

[0046] In some embodiments, the therapeutic agent is an siRNA and the siRNA is conjugated to a lipid.

[0047] In some embodiments, the lipid is conjugated to an internal nucleotide of a sense strand or an antisense strand of the siRNA.

[0048] In some embodiments, the lipid-conjugated internal nucleotide comprises a 2’-O-docosanoxyl (C22) nucleotide base-3 ’-phosphate.

[0049] In some embodiments, the lipid-conjugated internal nucleotide comprises a 2’-O-hexadecyl (Cl 6) nucleotide base-3 ’-phosphate.

[0050] In some embodiments, the nucleotide base is selected from the group consisting of adenine, guanine, cytosine, thymine, uracil and analogs thereof.

[0051] In some embodiments, the lipid is conjugated to a terminus of a sense strand or an antisense strand of the siRNA.

[0052] In some embodiments, the lipid comprises a C22 lipid monomer or a C16 lipid monomer.

[0053] In some embodiments, the siRNA comprises: (a) a modified sense strand with at least 85% sequence identity to any one sense strand provided in Table 5; and (b) a modifiedAttorney Docket Number: J0365.70001WO00antisense strand with at least 85% sequence identity to any one antisense strand provided in Table 5.

[0054] In some embodiments, the method results in an increase in expression of a metabolism related gene in the cell as compared to a corresponding untreated control.

[0055] Also provided herein is a pharmaceutical composition, comprising a therapeutic agent targeting an ATF4 pathway.

[0056] In some embodiments, the therapeutic agent is capable of lowering an mRNA level or a protein level of an ATF4 gene.

[0057] In some embodiments, the therapeutic agent is capable of inhibiting DNA binding to an ATF4 protein.

[0058] In some embodiments, the therapeutic agent is an siRNA molecule.

[0059] In some embodiments, the siRNA molecule is an siRNA molecule targeting an mRNA of the ATF4 gene.

[0060] In some embodiments, the siRNA molecule targets a sequence with at least 85% sequence identity to any one sense strand sequence provided in Table 1.

[0061] In some embodiments, the siRNA molecule comprises a sense strand with at least 85% sequence identity to any one sense strand sequence provided in Table 1.

[0062] In some embodiments, the siRNA molecule comprises an antisense strand with at least 85% sequence identity to any one antisense strand sequence provided in Table 1.

[0063] In some embodiments, the siRNA molecule comprises: (a) a sense strand with at least 85% sequence identity to any one sense strand sequence provided in Table 1; and (b) an antisense strand with at least 85% sequence identity to any one antisense strand sequence provided in Table 1.

[0064] In some embodiments, the siRNA molecule targets a sequence with at least 85% sequence identity to any one sense strand sequence provided in Table 2.

[0065] In some embodiments, the siRNA molecule comprises a sense strand with at least 85% sequence identity to any one of the sense strand sequences provided in Table 2.

[0066] In some embodiments, the siRNA molecule comprises an antisense strand with at least 85% sequence identity to any one of the antisense strand sequences provided in Table 2.

[0067] In some embodiments, the siRNA molecule comprises: (a) a sense strand with at least 85% sequence identity to any one sense strand sequence provided in Table 2; and (b) an antisense strand with at least 85% sequence identity to any one antisense strand sequence provided in Table 2.

[0068] In some embodiments, the therapeutic agent is an antisense oligonucleotide molecule.Attorney Docket Number: J0365.70001WO00

[0069] In some embodiments, the antisense oligonucleotide molecule is an antisense oligonucleotide molecule targeting an mRNA of the ATF4 gene.

[0070] In some embodiments, the siRNA molecule comprises at least one modification.

[0071] In some embodiments, the antisense oligonucleotide molecule comprises at least one modification.

[0072] In some embodiments, 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.

[0073] In some embodiments, the siRNA comprises a sense strand with at least 85% sequence identity to any one sense strand sequence provided in Table 3.

[0074] In some embodiments, the siRNA comprises an antisense strand with at least 85% sequence identity to any one antisense strand sequence provided in Table 3.

[0075] In some embodiments, the siRNA comprises: (a) a modified sense strand with at least 85% sequence identity to any one sense strand sequence provided in Table 3; and (b) a modified antisense strand with at least 85% sequence identity to any one antisense strand provided in Table 3.

[0076] In some embodiments, the therapeutic agent is a small molecule.

[0077] In some embodiments, the therapeutic agent comprises a targeting agent.

[0078] In some embodiments, the targeting agent is a peptide.

[0079] In some embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 9.

[0080] In some embodiments, the peptide is covalently linked to the therapeutic agent.

[0081] In some embodiments, the therapeutic agent is an siRNA and the peptide is covalently linked to the 3’ end of the sense strand of the siRNA.

[0082] In some embodiments, the targeting agent is N-acetylgalactosamine (GalNAc).

[0083] In some embodiments, the GalNAc is covalently linked to the therapeutic agent.

[0084] 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.

[0085] In some embodiments, the siRNA comprises: (a) a modified sense strand with at least 85% sequence identity to any one sense strand provided in Table 4; and (b) a modified antisense strand with at least 85% sequence identity to any one antisense strand provided in Table 4.

[0086] In some embodiments, the therapeutic agent is an siRNA and the siRNA is conjugated to a lipid.Attorney Docket Number: J0365.70001WO00

[0087] In some embodiments, the lipid is conjugated to an internal nucleotide of a sense strand or an antisense strand of the siRNA.

[0088] In some embodiments, the lipid-conjugated internal nucleotide comprises a 2’-O-docosanoxyl (C22) nucleotide base-3 ’-phosphate.

[0089] In some embodiments, the lipid-conjugated internal nucleotide comprises a 2’-O-hexadecyl (Cl 6) nucleotide base-3 ’-phosphate.

[0090] In some embodiments, the nucleotide base is selected from the group consisting of adenine, guanine, cytosine, thymine, uracil and analogs thereof.

[0091] In some embodiments, the lipid is conjugated to a terminus of a sense strand or an antisense strand of the siRNA.

[0092] In some embodiments, the lipid comprises a C22 lipid monomer or a C16 lipid monomer.

[0093] In some embodiments, the siRNA comprises: (a) a modified sense strand with at least 85% sequence identity to any one sense strand provided in Table 5; and (b) a modified antisense strand with at least 85% sequence identity to any one antisense strand provided in Table 5.

[0094] In some embodiments, the siRNA comprises an antisense strand comprising a region of complementarity of at least 8 nucleosides to an ATF4 RNA sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 3, 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, wherein 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 nucleosides to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942, optionally wherein the antisense strand comprises a region of complementary 15-21 nucleobases to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942. In some embodiments, the antisense strand comprises at least 8 consecutive nucleobases of the antisense strand of any one of the siRNAs listed in Tables 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469, optionally wherein the antisense strand comprises the nucleobase sequences of the antisense strand of any one of the siRNAs listed in Tables 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469. In some embodiments, the sense strand comprises at least 8 consecutive nucleobases of the senseAttorney Docket Number: J0365.70001WO00strand of any one of the siRNAs listed in Tables 1-5 or the sense strand sequence as set forth in any one of SEQ ID NOs: 3416-8942, optionally wherein the sense strand comprises the nucleobase sequences of the sense strand of any one of the siRNAs listed in Tables 1-5 or the sense strand sequence as set forth in any one of SEQ ID NOs: 3416-8942. In some embodiments, the antisense strand comprises at least 8 consecutive nucleobases of any one of SEQ ID NOs: 69, 159, 177, 265, 283, 305, 307, 323, 355, 415, 421, 427, 431, 433, 437, 439, 515, 605, 623, 711, 729, 751, 753, 769, 801, 861, 867, 873, 877, 879, 883, 885, 14471, 14473, 14475, 14477, 14479, 14481, 14483, 14485, 14487, and 14489, optionally wherein the antisense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 69, 159, 177, 265, 283, 305, 307, 323, 355, 415, 421, 427, 431, 433, 437, 439, 515, 605, 623, 711, 729, 751, 753, 769, 801, 861, 867, 873, 877, 879, 883, 885, 14471, 14473, 14475, 14477, 14479, 14481, 14483, 14485, 14487, and 14489. In some embodiments, the sense strand comprises least 8 consecutive nucleobases of any one of SEQ ID NOs: 68, 158, 176, 264, 282, 304, 306, 322, 354, 414, 420, 426, 430, 432, 436, 438, 514, 604, 622, 710, 728, 750, 752, 768, 800, 860, 866, 872, 876, 878, 882, 884, 14470, 14472, 14474, 14476, 14478, 14480, 14482, 14484, 14486, and 14488, optionally wherein the sense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 68, 158, 176, 264, 282, 304, 306, 322, 354, 414, 420, 426, 430, 432, 436, 438, 514, 604, 622, 710, 728, 750, 752, 768, 800, 860, 866, 872, 876, 878, 882, 884, 14470, 14472, 14474, 14476, 14478, 14480, 14482, 14484, 14486, and 14488. In some embodiments, the antisense strand comprises 15-23 consecutive nucleobases of any one of SEQ ID NOs: 265, 305, 421, 427, 431, 711, 751, 867, 873, 877, 14477, and 14487, and the sense strand comprises 15-21 nucleobases of any one of SEQ ID NOs: 264, 304, 420, 426, 430, 710, 750, 866, 872, 876, 14476, and 14486. In some embodiments, the siRNA comprises the nucleobase sequences of any one of siRNA-30, siRNA-75, siRNA-84, siRNA-128, siRNA-137, siRNA-148, siRNA-149, siRNA-157, siRNA-173, siRNA-203, siRNA-206, siRNA-209, siRNA-211, siRNA-212, siRNA-214, siRNA-215, siRNA-253, siRNA-298, siRNA-307, siRNA-351, siRNA-360, siRNA-371, siRNA-372, siRNA-380, siRNA-396, siRNA-426, siRNA-429, siRNA-432, siRNA-434, siRNA-435, siRNA-437, siRNA-438, siRNA-1116, siRNA-1117, siRNA-1118, siRNA-1119, siRNA-1120, siRNA-1121, siRNA-1122, siRNA-1123, siRNA-1124, siRNA-1125, optionally wherein the siRNA comprises the nucleobase sequences of any one of siRNA- 128, siRNA-148, siRNA-206, siRNA-209, siRNA-211, siRNA-351, siRNA-429, siRNA-432, siRNA-434, siRNA-1119, siRNA-1124. In some embodiments, the siRNA comprises one or more modified nucleosides, optionally wherein each nucleoside of the antisense strand is aAttorney Docket Number: J0365.70001WO00modified 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’-0-methoxyethyl (2’-M0E), 2’-O-aminopropyl (2’-O-AP), 2’-0-dimethylaminoethyl (2’-0-DMA0E), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-0-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-0-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’-0-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, optionally wherein 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’-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. In some embodiments, the siRNA comprises one or more modified intemucleoside linkages, optionally wherein the siRNA comprises one or more phosphorothioate intemucleoside linkages in at least one strand. In some embodiments, the sense strand comprises two to four phosphorothioate intemucleoside linkages, optionally wherein the first two and / or the last two intemucleoside linkages in the sense strand (from 5’ to 3’) are phosphorothioate intemucleoside linkages. In some embodiments, the antisense strand comprises four phosphorothioate intemucleoside linkages, optionally wherein the first two and / or the last two intemucleoside linkages in the antisense strand (from 5’ to 3’) are phosphorothioate intemucleoside linkages. In some embodiments, the nucleosides at positions 7, 9, 10, and 11 (counting 5’to 3’) of the sense strand are 2’-F modified nucleosides, the nucleosides at 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 and the last 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 fromAttomey Docket Number: J0365.70001WO005’ to 3 ’are phosphorothioate intemucleoside linkages. In some embodiments, the siRNA is selected from any one of the siRNAs listed in Table 3. In some embodiments, the siRNA is selected from: siRNA-476, siRNA-521, siRNA-530, siRNA-574, siRNA-583, siRNA-594, siRNA-595, siRNA-603, siRNA-619, siRNA-649, siRNA-652, siRNA-655, siRNA-657, siRNA-658, siRNA-660, siRNA-661, siRNA-1126, siRNA-1127, siRNA-1128, siRNA-1129, and siRNA-1130. In some embodiments, the siRNA further comprises a targeting agent, optionally wherein the targeting agent is covalently linked to the siRNA. In some embodiments, the targeting agent targets liver cells, kidney cells, muscle cells, or adipose cells. In some embodiments, the targeting agent comprises a peptide. In some embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 9. In some embodiments, the peptide is covalently linked to the 3’ end of the sense strand of the siRNA. In some embodiments, the targeting agent comprises a N-acetylgalactosamine (GalNAc). In some embodiments, 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 4. In some embodiments, the siRNA is selected from: siRNA-699, siRNA-744, siRNA-753, siRNA-797, siRNA-806, siRNA-817, siRNA-818, siRNA-826, siRNA-842, siRNA-872, siRNA-875, siRNA-878, siRNA-880, siRNA-881, siRNA-883, siRNA-884, siRNA-1131, siRNA-1132, siRNA-1133, siRNA-1134, siRNA-1135, siRNA-1141, siRNA-1142, siRNA-1143, siRNA-1144, siRNA-1145, and siRNA-1146. In some embodiments, the targeting agent comprises 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 nucleobase of the nucleotide 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 C16 lipid monomer. In some embodiments, any one of the siRNAs described herein further comprises a vinylphosphonate (e.g., at the 5’ end of the sense strand). In some embodiments, the siRNA is selected from the siRNAs listed in Table 5. In some embodiments, the siRNA is selected from: siRNA-922, siRNA-967, siRNA-976, siRNA-1020, siRNA-1029, siRNA-1040, siRNA-1041, siRNA-1049, siRNA-1065, siRNA-1095, siRNA-1098, siRNA-1101, siRNA-Attorney Docket Number: J0365.70001WO001103, siRNA-1104, siRNA-1106, siRNA-1107, siRNA-1136, siRNA-1137, siRNA-1138, siRNA-1139, siRNA-1140.

[0095] Uses of any one of the siRNAs described herein in any one of the methods described herein are also provided.

[0096] Also provided herein is a nanoparticle composition comprising the therapeutic agent, the siRNA, or pharmaceutical composition of any one of the preceding embodiments.

[0097] In some embodiments, the pharmaceutical composition comprises an adipose targeting peptide having a sequence set forth in SEQ ID NO: 9.

[0098] In some embodiments, the adipose targeting peptide is modified to bind to the therapeutic agent.

[0099] 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.

[0100] In some embodiments, the at least one positive charged amino acid comprises arginine, lysine, or histidine.

[0101] In some embodiments, the at least one positive charged amino acid is arginine.

[0102] In some embodiments, the therapeutic agent is siRNA.

[0103] In some embodiments, the therapeutic agent is siRNA and a ratio of the peptide to the siRNA is at least 10:1, 20:1, 30:1, or 40:1.

[0104] In some embodiments, the pH of the nanoparticle composition is from about 5.5 to about 7.5.

[0105] In some embodiments, the pH is from about 6 to about 6.5.

[0106] In some embodiments, the pH is about 6.INCORPORATION BY REFERENCE

[0107] 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.DETAILED DESCRIPTION

[0108] 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 describingAttorney Docket Number: J0365.70001WO00particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0109] 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 clearly dictates otherwise, between the upper and lower limit 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 encompassed within the invention, subject to 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.

[0110] 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.

[0111] 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.

[0112] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by 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

[0113] 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 derivatizedAttorney Docket Number: J0365.70001WO00amino 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 terms refer to a polymeric form of amino acids of any length which include genetically coded amino acids fused to a heterologous amino acid sequence.

[0114] The term “heterologous” refers to two components that are defined by structures derived from 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).

[0115] 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.

[0116] The terms “polynucleotide,” “polynucleic acid,” “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.

[0117] 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 not limited to, modifications which place new reactive groups such as, but not limited to, amines, alcohols, thiols, carboxylates, and alkylhalides.Attorney Docket Number: J0365.70001WO00

[0118] 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 nucleotide analogs 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.

[0119] 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’-0-methoxyethyl, 2’-0-aminoethyl, 2’-Flouro, N3’— > P5’ phosphoramidate, 2 ’dimethylaminooxy ethoxy, 2’ 2 'dimethylaminoethoxy ethoxy, 2'-guanidinidium, 2'-O-guanidinium ethyl, carbamate modified sugars, and bicyclic modifiedAttorney Docket Number: J0365.70001WO00sugars. 2’-0-methyl or 2’-0-methoxyethyl 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-carboxymethylaminomethyluracil, 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 beta-thiotriphosphates). 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.

[0120] 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 (Batzer et al., Nucleic Acid Res., 19:5081Attorney Docket Number: J0365.70001WO00(1991); Ohtsuka et al., J. Biol. Chem., 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes, 8:91-98 (1994)).

[0121] 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.

[0122] 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 are considered 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 acid molecules (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, but the nucleobase sequences of the two molecules must be sufficiently complementary over the entire length to result in a desired biological activity (e.g., RNA interference).

[0123] 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-type bases (T) or uracil-type bases (U), that cytosine-type bases (C) are complementary to guano sine-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.Attorney Docket Number: J0365.70001WO00

[0124] 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.

[0125] 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., ATF4 mRNA).

[0126] The term “contiguous” in the context of an oligonucleotide (e.g., siRNA) refers to nucleosides, nucleobases, sugar moieties, or intemucleoside linkages that are immediately adjacent to each other. For example, “contiguous nucleobases” means nucleobases that are immediately adjacent to each other in a sequence.

[0127] 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 receptor(s) facilitates cell-specificAttorney Docket Number: J0365.70001WO00targeting 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:Reference No. Application No. Filing DateUS 8,106,022 US 12 / 328,528 Dec. 4, 2008 US 10,246,709 US 15 / 452,423 Mar. 7, 2017 US 5,994,517 US 08 / 755,062 Nov. 22, 1996 US 6,906,182 US 09 / 998,497 Nov. 30, 2001 US 10,294,474 US 15 / 452,324 Mar. 7, 2017 US 2017305956 US 15 / 621,395 Jun. 13, 2017 US 10,233,448 US 15 / 504,855 Feb. 17, 2017 US 2016122761 US 14 / 898,873 Jun. 23, 2014 US 10,808,246 US 14 / 901,945 Dec. 29, 2015WO 2022 / 159158A1 PCT / US2021 / 057016 Oct. 28, 2021

[0128] The disclosures in these references related to GalNAc are hereby incorporated herein by reference.

[0129] 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.

[0130] The term “intemucleoside linkage,” as used herein, means a covalent linkage between adjacent nucleosides in an oligonucleotide (e.g., siRNA such as an siRNA described herein). An intemucleoside linkage may be a natural phosphodiester intemucleoside linkage, or may be a modified (non-natural) intemucleoside linkage. Modified intemucleoside 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 phosphonates comprising 3 ’alkylene phosphonates and chiral phosphonates,Attorney Docket Number: J0365.70001WO00phosphinates, phosphoramidates comprising 3 ’-amino phosphoramidate and aminoalkylphosphoramidates, 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.

[0131] 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).

[0132] 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).

[0133] 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 or nucleic acid. 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).

[0134] 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. Non-limiting 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.Attorney Docket Number: J0365.70001WO00

[0135] 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’-0-methoxyethyl (2’-MOE), 2’-0-aminopropyl (2’-O-AP), 2’-0-dimethylaminoethyl (2’-O-DMAOE), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-0-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-0-N-methylacetamido (2’-O-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).

[0136] 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 of 2’-modified nucleosides include: 2’-fluoro (2’-F), 2’-O-methyl (2’-O-Me), 2’-0-methoxyethyl (2’-MOE), 2’-deoxy, 2’-O-aminopropyl (2’-O-AP), 2’-0-dimethylaminoethyl (2’-O-DMAOE), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-0-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-0-N-methylacetamido (2’-O-NMA) modified nucleosides. 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’-O-Me) modified nucleoside or a 2’-fluoro (2’-F) modified nucleoside or combinations thereof.

[0137] 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 intemucleoside 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 modifiedAttorney Docket Number: J0365.70001WO00intemucleoside linkages and unmodified modified intemucleoside linkages. In some embodiments, each nucleoside of a modified oligonucleotide” or “modified siRNA molecule” or “modified siRNA” is a modified nucleoside, and / or each intemucleoside linkage of a “modified oligonucleotide” or “modified siRNA molecule” or “modified siRNA” is a modified intemucleoside linkage.

[0138] The term “oligonucleotide,” as used herein, As used herein, the term “oligonucleotide” refers to an oligomeric nucleic acid compound of up to 200 nucleotides in length. Examples of oligonucleotides include, but are not limited to, antisense oligonucleotides, RNAi oligonucleotides (e.g., siRNAs, shRNAs), microRNAs, gapmers, mixmers, phosphorodiamidite morpholinos, peptide nucleic acids, aptamers, guide nucleic acids (e.g., Cas9 guide RNAs), etc. Oligonucleotides may be single- stranded or double-stranded. In some embodiments, an oligonucleotide may comprise one or more modified nucleotides (e.g. 2'-O-methyl sugar modifications, purine or pyrimidine modifications). In some embodiments, an oligonucleotide may comprise one or more modified internucleotide linkage. In some embodiments, an oligonucleotide may comprise one or more phosphorothioate linkages, which may be in the Rp or Sp stereochemical conformation. It should be appreciated that, in some embodiments, oligonucleotides in one format (e.g., siRNA) may be suitably adapted to another format (e.g., antisense oligonucleotide) by incorporating functional sequences (e.g., antisense strand sequences) from one format to the other format. Accordingly, the present disclosure provided antisense oligonucleotides or siRNAs targeting ATF4 siRNA.

[0139] 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.

[0140] 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.Attorney Docket Number: J0365.70001WO00

[0141] 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 some embodiments, a region of complementarity contains 1, 2, 3, 4, or 5 mismatches compared with a cognate nucleobase sequence of a target nucleic acid.

[0142] 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) or pathway(s). While it is believed that RNAi 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 ATF4 in a cell, e.g., a cell within a subject, such as a mammalian subject. RNAi agents include, but are not limited to: single- stranded oligonucleotides, single- stranded antisense oligonucleotides, short interfering RNAs (siRNAs), double-strand RNAs (dsRNA), micro RNAs (miRNAs), short hairpin RNAs (shRNA), and dicer substrates. Any one of the RNAi agents described herein comprises a strand that is at least partially complementary to the mRNA being 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 RNAi agent is a double stranded siRNA.

[0143] In some embodiments, an RNAi agent (e.g., siRNA) described herein is doublestranded, 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., ATF4 mRNA. An RNAi agent (e.g.,Attorney Docket Number: J0365.70001WO00siRNA) described herein may comprise one or more modified nucleosides and / or one or more modified (e.g., non-phosphodiester) intemucleoside linkages.

[0144] 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’ OH group of the ribose sugar, e.g., the use of deoxyribonucleosides, e.g., deoxythymidine, instead of ribonucleosides, and modifications in the internucleoside 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 ATF4 target sequence, to direct the cleavage of the target RNA. In some embodiments, an RNAi agent described herein is a small interfering RNA (siRNA).

[0145] The term “siRNA,” as used herein, refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two 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 ATF4 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 40 nucleosides (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 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 genesilencing mechanism referred to herein as RNA interference or RNAi.

[0146] 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 - 10Attorney Docket Number: J0365.70001WO00(e.g., 1-10, 1-8, 1-5, 1-3, 1-2) nucleosides, such that the 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.

[0147] Without wishing to be bound by 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-III-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). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev. 15:188).

[0148] 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., ATF4 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 single- stranded 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.

[0149] 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., ATF4 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., ATF4 gene. In some embodiment, the target sequence is within the protein coding region of the target gene, e.g., ATF4.Attorney Docket Number: J0365.70001WO00

[0150] The term “vinylphosphonate” or “5’-vinylphosphonate” in the context of a 5’-phosphate of a nucleotide refers to a structure in which the bridging 5 '-oxygen atom is replaced with a methylidene ( — CH=) group (e.g., as illustrated below):t he- ■■!!<!» with a natural NuUeot fe with a (Ey phvspbaw st the end vinyl ph-si

[0151] A terminal 5 ’-vinylphosphonate nucleotide is a nucleotide in which the natural phosphate group at the 5’ end has been replaced with a vinylphosphonate. A 5’-vinylphosphonate is a 5’ biological mimic of a phosphate that is biostable (also referred to herein as a “biostable phosphate mimic.” A biological mimic is a molecule that is capable of carrying out the same function as and is structurally very similar to the original molecule that is being mimicked. In the context of the present disclosure, 5 ’-vinylphosphonate mimics the function of a normal 5’ phosphate, e.g., enabling efficient RISC loading, while being capable of stabilizing the 5’ end nucleotide by protecting it from dephosphorylation by enzymes such as phosphatases. siRNAs comprising a vinylphosphonate moiety or a 5 ’-vinylphosphonate nucleotide has been described, e.g., in US Patent No. 11560563 and US Patent No.10233448.

[0152] Other biostable phosphate mimics may also be used in an siRNA described herein. Non-limiting examples of other biostable phosphate mimics are described in, e.g., US Patent No. 8927513, US Patent No. 11078227, US Patent Application Publication No.US20190177729, and Varley et al., RSC Adv., 2021, 11, 2415-2426, each of which is incorporated herein by reference in their entirety.Attorney Docket Number: J0365.70001WO00

[0153] 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 adjacent to 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.

[0154] ‘ ‘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.

[0155] 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 length which 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 (ebi.ac.uk / jdispatcher / psa / emboss needle). The sequence identity is determined without consideration of chemical modification.

[0156] 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.Attorney Docket Number: J0365.70001WO00

[0157] 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.

[0158] By “treating or preventing a condition,” for example, as compared with an equivalent untreated 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 at least 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.

[0159] 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” or alleviates 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.

[0160] “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.

[0161] As used herein “onset” or “occurrence” of a disease includes initial onset and / or recurrence.Attorney Docket Number: J0365.70001WO00

[0162] “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.

[0163] 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.

[0164] 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, spleen necrosis 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.

[0165] 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 thatAttorney Docket Number: J0365.70001WO00occurs when pregnant women without a previous history of diabetes develop high blood sugar levels.ATF4 Pathway

[0166] Activating transcription factor 4 (ATF4), 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. ATF4 can also interact with proteins via its basic leucine zipper (bZIP) domain and modulate cellular functions independently of its transcriptional activity. The ATF4 gene can be a human ATF4 gene (Ensembl ID: ENSG00000128272). In some embodiments, the ATF4 gene comprises a nucleic acid sequence of:ACTTTGAGCAAGAAGCTTCATCCCATTGGGCCTCGGTTTACCATTGGAAAGGATT TGTGGGCGAGGTTGAATGAGCGCAGCAGATGGCCTGTGGTTATTTAGAGCAGTG CTTCCCTGGTTGTTTGATATCACAGCGCTCATACTTGTGTGGCCCAGTGAAATGG AGGCGGAAACTCAAAGTTTCCACCTTCACAGGGCCTGACTGGAAGGGGCTGAAG GATGATGGGGAGGTTTCTTGTATTCTTAAAACAGACTACCCCTTCCCAACGCACA ACCCCCAGTAAGTGGCCGTGGGTTCCCAAGCGCCTCTCCTCCCTGGGCCATGGGC GTGACTGCTGAAAAGCGGGTTAGGCCGGGGAGTTCAGAATCCGGAGTGAATCCG AACTACCCCAGGGAGACGGCAGCGAAGAAAATCTTGTTCTTAGGAGAACGCAAT CTTCGGACACCAGAAGTTCCTCTATGATGCTATTCTGTGGCAGCCTTGCACTTGA GCCGGATGAAAATTGTAAAAACCCAGGTTGGGCGACAGGACGGCGCGTCTTCCC GGCTCCTTTCCAGAGTTTAGGAGGAGCCATGCAGACTCAGCCGGCCTTTGGGGGT AGGTGGACAGGCCCGGCGCGCCCTCTCGAGGCCCCTTCAACCTCCCGGGGGCAG CAGCGCCGTGTCGGCTATGAATGGGGCCTCTGGAAAACTCAGGCTTGGAACAGG TAACCCCCCGGTTTCCGCAGGCCACAAATCACCACCCGCAACCGAAGGACGCGC AGGCTGGGAGCGGCGGCGGGGCCACCAGTGCGGACCTCCACTGAGGGCGGCGG GATCCGACCGCAAGGGCTGGTCCCTGAGGCCACTAAGGGGTGCGCTGGGCTAAG GCCGCCTGGGGGCAGGAGCCAGCGCGATCGTGGCGGGCCAGCAGGCGGGGCTG GCTGAGGACTAGCAGCGACCCGAGACCCCAACCCTTCCCACGCGGACCCCGGGA TCCCTCTCCCAGCAGCCGCCCATCTAGGGCCCTGAGCCAATAAGAGCTCGAGATA TATATGATTCACCGGGCCTGGGCCAATCACCTTGACGCGCGCTCTTCGCCAGCAC CTCGCGCGATAACCTGGCGTCCTCGGCCTTCACAATAAAAACTCTTCGCCGGAAA ACGACCTTTCCCCGCCCACTGCGCTGACACCGGAAGCGAGGCGTGTCTGGGAGA TCACTCCGCGCTCCGGCGGCGAAGGAAAGAACGGACTCTGATCATAGAAGCCTA GTAAAGTAGTACACCTCTCTCCTTTCGTGAGGCCATAAGAACAAACTCCTTTTCTAttorney Docket Number: J0365.70001WO00CGTCACAGCTACGCCCTGGGCATAAACGGTTGGGGCGTCAAAGGGAGGGAGGGA AGGGAGCGGGCGGGAGGAGACGGTCACGTGGTCGCGGCGGAAGGATGCGTCTG TGCTGCGTCCCCATAGAGACGAAGTCTATAAAGGGCCGGCGGGCGGCCACGGCA GCCATTTCTACTTTGCCCGCCCACAGATGTAGTTTTCTCTGCGCGTGTGCGTTTTC CCTCCTCCCCGCCCTCAGGGTCCACGGCCACCATGGCGTATTAGGGGCAGCAGTG CCTGCGGCAGCATTGGCCTTTGCAGCGGCGGCAGCAGCACCAGGCTCTGCAGCG GCAACCCCCAGCGGCTTAAGCCATGGCGTGAGTACCGGGGCGGGTCGTCCAGCT GTGCTCCTGGGGCCGGCGCGGGTTTTGGATTGGTGGGGTGCGGCCTGGGGCCAG GGCGGTGCCGCCAAGGGGGAAGCGATTTAACGAGCGCCCGGGACGCGTGGTCTT TGCTTGGGTGTCCCCGAGACGCTCGCGTGCCTGGGATCGGGAAAGCGTAGTCGG GTGCCCGGACTGCTTCCCCAGGAGCCCTACAGCCCTCGGACCCCGAGCCCCGCA AGGGTCCCAGGGGTCTTGGCTGTTGCCCCACGAAACGTGGCAGGAACCAAGATG GCGGCGGCAGGGCGGCGGCGCGGGCGTGAGTCAAGGGCGGGCGGTGGGCGGGG CGCGGCCGCCCTGGCCGTATTTGGACGTGGGGACGGAGCGCTTTCCTCTTGGCGG CCGGTGGAAGAATCCCCTGGTCTCCGTGAGCGTCCATTTTGTGGAACCTGAGTTG CAAGCAGGGAGGGGCAAATACAACTGCCCTGTTCCCGATTCTCTAGATGGCCGA TCTAGAGAAGTCCCGCCTCATAAGTGGAAGGATGAAATTCTCAGAACAGCTAAC CTCTAATGGGAGTTGGCTTCTGATTCTCATTCAGGCTTCTCACGGCATTCAGCAG CAGCGTTGCTGTAACCGACAAAGACACCTTCGAATTAAGCACATTCCTCGATTCC AGCAAAGCACCGCAACATGACCGAAATGAGCTTCCTGAGCAGCGAGGTGTTGGT GGGGGACTTGATGTCCCCCTTCGACCAGTCGGGTTTGGGGGCTGAAGAAAGCCT AGGTCTCTTAGATGATTACCTGGAGGTGGCCAAGCACTTCAAACCTCATGGGTTC TCCAGCGACAAGGCTAAGGCGGGCTCCTCCGAATGGCTGGCTGTGGATGGGTTG GTCAGTCCCTCCAACAACAGCAAGGGTGAGTGGGCCACCACCACATCGTCCTGG TGGGATCTAGGGTTAGGGGCCTCCTACCTTTGTATCTGACTCACTTGGCCCCATC ACTCAAATGTTTTGCAGAGGATGCCTTCTCCGGGACAGATTGGATGTTGGAGAAA ATGGATTTGAAGGAGTTCGACTTGGATGCCCTGTTGGGTATAGATGACCTGGAAA CCATGCCAGATGACCTTCTGACCACGTTGGATGACACTTGTGATCTCTTTGCCCC CCTAGTCCAGGAGACTAATAAGCAGCCCCCCCAGACGGTGAACCCAATTGGCCA TCTCCCAGAAAGTTTAACAAAACCCGACCAGGTTGCCCCCTTCACCTTCTTACAA CCTCTTCCCCTTTCCCCAGGGGTCCTGTCCTCCACTCCAGATCATTCCTTTAGTTT AGAGCTGGGCAGTGAAGTGGATATCACTGAAGGAGATAGGAAGCCAGACTACA CTGCTTACGTTGCCATGATCCCTCAGTGCATAAAGGAGGAAGACACCCCTTCAGA TAATGATAGTGGCATCTGTATGAGCCCAGAGTCCTATCTGGGGTCTCCTCAGCACAttorney Docket Number: J0365.70001WO00AGCCCCTCTACCAGGGGCTCTCCAAATAGGAGCCTCCCATCTCCAGGTGTTCTCT GTGGGTCTGCCCGTCCCAAACCTTACGATCCTCCTGGAGAGAAGATGGTAGCAG CAAAAGTAAAGGGTGAGAAACTGGATAAGAAGCTGAAAAAAATGGAGCAAAAC AAGACAGCAGCCACTAGGTACCGCCAGAAGAAGAGGGCGGAGCAGGAGGCTCT TACTGGTGAGTGCAAAGAGCTGGAAAAGAAGAACGAGGCTCTAAAAGAGAGGG CGGATTCCCTGGCCAAGGAGATCCAGTACCTGAAAGATTTGATAGAAGAGGTCC GCAAGGCAAGGGGGAAGAAAAGGGTCCCCTAGTTGAGGATAGTCAGGAGCGTC AATGTGCTTGTACATAGAGTGCTGTAGCTGTGTGTTCCAATAAATTATTTTGTAG GGAAAGTACTTGTGCGTTTGAATTCCTTTCCTGGCAAAGTAACCGAGTGAAGCGC CACCCACCCACCCCAAGCTGGTCTTAACATTTCCTGTGAGATCTGGGGGAGGAGG CAGTCCAAGGCTGAAGATCGGTTCCCAGAGTGGGATTTGCTCATCCCTGCTCGGT GTAGGCCACGATGGCTGATTCATGGGGCCCTGGAGCCGTATAGTTGGCCATTTAT AGTAAGCTGGGTCCTTTGCCCAGAGCTGAGTGCTGGTTGTGTAGGGGGAGGAGG CTGGAGATCTCTGGGAGATTCAGAGGGAGGGACAGCCTGGGCCTCCACCTGTTT ATTCAAGAGGGCTTCATGCCAACAGCTGTCGCATAAAACCCTGAATAAGGTTGC ACGGTCTTTGAGATAGCACACAAGATTAGGTTTCACTTGTTACCTGAACAGTTCT GCAGAAGCCTCATCCTGAAGAAAGAAATGGCTCCTTTTGGGAATTGATGCTGAA ACAGGACAGGAGCTGAGGGTTGGCCTCCGTTTCTCCTTACGGGGTGGAAGGATG ACAGCCTGCGCAGGTTCTGGCTAGAGCTGGGCACAAAGGCAGGCAACAGTTCCT GTGAAGGCT (SEQ ID NO: 1). In some embodiments, the ATF4 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: 1.

[0167] A transcript of the ATF4 gene is provided herein (NCBI Reference Sequence:NM_182810.3, with all T’s replaced with U’s to represent mRNA sequence):CATTTCTACTTTGCCCGCCCACAGATGTAGTTTTCTCTGCGCGTGTGCGTTTTCCC TCCTCCCCGCCCTCAGGGTCCACGGCCACCATGGCGTATTAGGGGCAGCAGTGCC TGCGGCAGCATTGGCCTTTGCAGCGGCGGCAGCAGCACCAGGCTCTGCAGCGGC AACCCCCAGCGGCTTAAGCCATGGCGCTTCTCACGGCATTCAGCAGCAGCGTTGC TGTAACCGACAAAGACACCTTCGAATTAAGCACATTCCTCGATTCCAGCAAAGC ACCGCAACATGACCGAAATGAGCTTCCTGAGCAGCGAGGTGTTGGTGGGGGACT TGATGTCCCCCTTCGACCAGTCGGGTTTGGGGGCTGAAGAAAGCCTAGGTCTCTT AGATGATTACCTGGAGGTGGCCAAGCACTTCAAACCTCATGGGTTCTCCAGCGAC AAGGCTAAGGCGGGCTCCTCCGAATGGCTGGCTGTGGATGGGTTGGTCAGTCCCTAttorney Docket Number: J0365.70001WO00CCAACAACAGCAAGGAGGATGCCTTCTCCGGGACAGATTGGATGTTGGAGAAAA TGGATTTGAAGGAGTTCGACTTGGATGCCCTGTTGGGTATAGATGACCTGGAAAC CATGCCAGATGACCTTCTGACCACGTTGGATGACACTTGTGATCTCTTTGCCCCC CTAGTCCAGGAGACTAATAAGCAGCCCCCCCAGACGGTGAACCCAATTGGCCAT CTCCCAGAAAGTTTAACAAAACCCGACCAGGTTGCCCCCTTCACCTTCTTACAAC CTCTTCCCCTTTCCCCAGGGGTCCTGTCCTCCACTCCAGATCATTCCTTTAGTTTA GAGCTGGGCAGTGAAGTGGATATCACTGAAGGAGATAGGAAGCCAGACTACACT GCTTACGTTGCCATGATCCCTCAGTGCATAAAGGAGGAAGACACCCCTTCAGATA ATGATAGTGGCATCTGTATGAGCCCAGAGTCCTATCTGGGGTCTCCTCAGCACAG CCCCTCTACCAGGGGCTCTCCAAATAGGAGCCTCCCATCTCCAGGTGTTCTCTGT GGGTCTGCCCGTCCCAAACCTTACGATCCTCCTGGAGAGAAGATGGTAGCAGCA AAAGTAAAGGGTGAGAAACTGGATAAGAAGCTGAAAAAAATGGAGCAAAACAA GACAGCAGCCACTAGGTACCGCCAGAAGAAGAGGGCGGAGCAGGAGGCTCTTA CTGGTGAGTGCAAAGAGCTGGAAAAGAAGAACGAGGCTCTAAAAGAGAGGGCG GATTCCCTGGCCAAGGAGATCCAGTACCTGAAAGATTTGATAGAAGAGGTCCGC AAGGCAAGGGGGAAGAAAAGGGTCCCCTAGTTGAGGATAGTCAGGAGCGTCAA TGTGCTTGTACATAGAGTGCTGTAGCTGTGTGTTCCAATAAATTATTTTGTAGGG AAA (SEQ ID NO: 2). In some embodiments, the ATF4 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: 2.

[0168] A transcript of the ATF4 gene is provided herein (NCBI Reference Sequence:NM_001675.4, with all T’s replaced with U’s to represent mRNA sequence):AGCCATTTCTACTTTGCCCGCCCACAGATGTAGTTTTCTCTGCGCGTGTGCGTTTT CCCTCCTCCCCGCCCTCAGGGTCCACGGCCACCATGGCGTATTAGGGGCAGCAGT GCCTGCGGCAGCATTGGCCTTTGCAGCGGCGGCAGCAGCACCAGGCTCTGCAGC GGCAACCCCCAGCGGCTTAAGCCATGGCGTGAGTACCGGGGCGGGTCGTCCAGC TGTGCTCCTGGGGCCGGCGCGGGTTTTGGATTGGTGGGGTGCGGCCTGGGGCCA GGGCGGTGCCGCCAAGGGGGAAGCGATTTAACGAGCGCCCGGGACGCGTGGTCT TTGCTTGGGTGTCCCCGAGACGCTCGCGTGCCTGGGATCGGGAAAGCGTAGTCG GGTGCCCGGACTGCTTCCCCAGGAGCCCTACAGCCCTCGGACCCCGAGCCCCGC AAGGGTCCCAGGGGTCTTGGCTGTTGCCCCACGAAACGTGGCAGGAACCAAGAT GGCGGCGGCAGGGCGGCGGCGCGGGCGTGAGTCAAGGGCGGGCGGTGGGCGGG GCGCGGCCGCCCTGGCCGTATTTGGACGTGGGGACGGAGCGCTTTCCTCTTGGCGAttorney Docket Number: J0365.70001WO00GCCGGTGGAAGAATCCCCTGGTCTCCGTGAGCGTCCATTTTGTGGAACCTGAGTT GCAAGCAGGGAGGGGCAAATACAACTGCCCTGTTCCCGATTCTCTAGATGGCCG ATCTAGAGAAGTCCCGCCTCATAAGTGGAAGGATGAAATTCTCAGAACAGCTAA CCTCTAATGGGAGTTGGCTTCTGATTCTCATTCAGGCTTCTCACGGCATTCAGCA GCAGCGTTGCTGTAACCGACAAAGACACCTTCGAATTAAGCACATTCCTCGATTC CAGCAAAGCACCGCAACATGACCGAAATGAGCTTCCTGAGCAGCGAGGTGTTGG TGGGGGACTTGATGTCCCCCTTCGACCAGTCGGGTTTGGGGGCTGAAGAAAGCCT AGGTCTCTTAGATGATTACCTGGAGGTGGCCAAGCACTTCAAACCTCATGGGTTC TCCAGCGACAAGGCTAAGGCGGGCTCCTCCGAATGGCTGGCTGTGGATGGGTTG GTCAGTCCCTCCAACAACAGCAAGGAGGATGCCTTCTCCGGGACAGATTGGATG TTGGAGAAAATGGATTTGAAGGAGTTCGACTTGGATGCCCTGTTGGGTATAGATG ACCTGGAAACCATGCCAGATGACCTTCTGACCACGTTGGATGACACTTGTGATCT CTTTGCCCCCCTAGTCCAGGAGACTAATAAGCAGCCCCCCCAGACGGTGAACCC AATTGGCCATCTCCCAGAAAGTTTAACAAAACCCGACCAGGTTGCCCCCTTCACC TTCTTACAACCTCTTCCCCTTTCCCCAGGGGTCCTGTCCTCCACTCCAGATCATTC CTTTAGTTTAGAGCTGGGCAGTGAAGTGGATATCACTGAAGGAGATAGGAAGCC AGACTACACTGCTTACGTTGCCATGATCCCTCAGTGCATAAAGGAGGAAGACAC CCCTTCAGATAATGATAGTGGCATCTGTATGAGCCCAGAGTCCTATCTGGGGTCT CCTCAGCACAGCCCCTCTACCAGGGGCTCTCCAAATAGGAGCCTCCCATCTCCAG GTGTTCTCTGTGGGTCTGCCCGTCCCAAACCTTACGATCCTCCTGGAGAGAAGAT GGTAGCAGCAAAAGTAAAGGGTGAGAAACTGGATAAGAAGCTGAAAAAAATGG AGCAAAACAAGACAGCAGCCACTAGGTACCGCCAGAAGAAGAGGGCGGAGCAG GAGGCTCTTACTGGTGAGTGCAAAGAGCTGGAAAAGAAGAACGAGGCTCTAAAA GAGAGGGCGGATTCCCTGGCCAAGGAGATCCAGTACCTGAAAGATTTGATAGAA GAGGTCCGCAAGGCAAGGGGGAAGAAAAGGGTCCCCTAGTTGAGGATAGTCAG GAGCGTCAATGTGCTTGTACATAGAGTGCTGTAGCTGTGTGTTCCAATAAATTAT TTTGTAGGGAAAGTAAAAAAAAAAAAAAA (SEQ ID NO: 3). In some embodiments, the ATF4 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: 3.

[0169] As used herein, the term “ATF4 protein” refers to Activating Transcription Factor 4 and functional variants thereof. For example, the ATF4 protein may encompass proteins that have at least 80% amino acid sequence identity to the amino acid sequence set forth as UniProt Accession No. P18848 and / or has ATF4 activity of binding to a regulatory region ofAttorney Docket Number: J0365.70001WO00the genes that can be activated by a wildtype ATF4 protein and activating gene expression. In certain embodiments, the ATF4 protein is a human ATF4 protein. In certain embodiments, the ATF4 protein is a mouse ATF4 protein or a non-human primate ATF4 protein. The wildtype human ATF4 protein can comprise an amino acid sequence of MTEMSFLSSEVLVGDLMSPFDQSGLGAEESLGLLDDYLEVAKHFKPHGFSSDKAKA GSSEWLAVDGLVSPSNNSKEDAFSGTDWMLEKMDLKEFDLDALLGIDDLETMPDDL LTTLDDTCDLFAPLVQETNKQPPQTVNPIGHLPESLTKPDQVAPFTFLQPLPLSPGVLS STPDHSFSLELGSEVDITEGDRKPDYTAYVAMIPQCIKEEDTPSDNDSGICMSPESYLG SPQHSPSTRGSPNRSLPSPGVLCGSARPKPYDPPGEKMVAAKVKGEKLDKKLKKME QNKTAATRYRQKKRAEQEALTGECKELEKKNEALKERADSLAKEIQYLKDLIEEVR KARGKKRVP (SEQ ID NO: 4). In some embodiments, the ATF4 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: 4.

[0170] A genomic ATF4 nucleic acid sequence in mouse is provided herein (Ensembl ID: ENSMUSG00000042406):GATCTTAAGGGAACTGACCCTATACAAACCGGCAGTGAGGGCCTCTATGATGGG AGGATGGGCATAGGAGGTTAGACCTGAGGTTAGGCATGTTTCCCCGGTTCAGGG GAAATCGCTGAACTGGAGGAACCGGAATATCTCCCAAGAAGACCCCAACACGAA CGCCCTGCCTCCAAGTGCCGTCCCTGTCCCAGGACTGACAGGAAGCTGAAGGTTT GGACCAGCTAACTCAGAAGGGTCTCTCCACATGCCTGAAGCCTGCCCACTCGGTT CTGGAAACAACAAATACATGAAAAGATGGCTTCCAGCCCAAAGGTCACGCCTGG AAGCTGTTTGCTCGGTGCGGAGCGATGCCGGAGAGAGCAAATACACATGGATCA CATCTGACAAGAGATGGCAGGTGTGACAGTCTGGCGCCCGGAACCTCTGGTGGC TCCTCCCTTTCCACGCAGACCCCTGATCCTAGAGCGCCCAGGTGCAGAGCCAATA GGAACTTGAGGTTTAGGTGACTCGCCACGCCTGGGCCAATCAGCTCGACGCGCG CTCCGACGGCGTCTCGCGTGATAACCTGGCAGCTTCGGCTTTGACCGTCAGAGCT TTGGCTAGGTGTCCCACCCCGCCTTGTAAGACACCGGAAATTCGTCAACGAGCGA TCCCTCCGCGCTCCGGAACCAGACCGCGGCTGGTCGTCAACCTATAAAGTAGTGC ACTTTTCTCTCATGGGGCCTTTAGGACGATCTCTAACGCCACAGTTACCCCCCGA GCACAGCGGAGAAGGGTTGGGGCGGGCGAGGGCGTCAGTGAGAGGCGGTTTGG TGGCGCTGCGGTAGGATCACGTGACCACAGTGGGAGGATACGCGGTGTGCTGCG TCCCTGGCCGAGGCTATAAAGGGCGGGTTTAGGGCGTGCCGCCGCCATTTCTGCT TGCTGTCTGCCGGTTTAAGTTGTGTGCTCGGGTGTCCCTTTCCTCTTCCCCTCCCGAttorney Docket Number: J0365.70001WO00CAGGGCTTGCGGCCACCATGGCGTATTAGAGGCAGCAGTGCCTGCGGCAGCGTT GGCCTTTGCAGCGGCGGCAGCAGCACCAGGCTCTGCAGCGGCAACCCCCACCGG CCTAAGCCATGGCGTGAGTATGGGGCCGGCCGCGGAGGGCGGGGGCCTCGCTGT GGTTGGGTGCGGCCCGGGCGCGGTGGCCGGCACACGCGGTTTTACAAGCGGCCG GACGCGTCGGCCTTGTTTGCGTTGCCTGCGACGCCGGCGCTCCCGGGCAGAGCTG GGCGGAGGAGTGTCTAAAGCGCTACTGCTGCCCCTTCGTCCTGTCTTAGCTTAAT CATCTCGGGCTCACCGGGGTCCCCGTGTCATCCTGCGAACGTGGCGATGCCCAAG ATGGCGGTGGGGCGGGGGTGTGAGTCACGGGGGCGGGGCGCGGCGGCCTTGGCC GTATTAGGACGCGAGGACAAGCTGCTTCCTCTGGGTGGCCGGTGAAGCAAAGCT AAGCCTCCATCTTGTGCAACCCGAGCTGGCGGCCGGGGAGGCTTACACAATGGC CTTGGGCCCGCGTGCTCTCCCTGTAGACGCTTCTGGGATTTGGCCATCCGGCATC TTAGATAGAAAGATGACTGGACTTGCTTTTGGGTCCCCATCCAGGCTCTTCACGA AATCCAGCAGCAGTGTTGCTGTAACGGACAAAGATACCTTCGAGTTAAGCACAT TCCTCGAATCCAGCAAAGCCCCACAACATGACCGAGATGAGCTTCCTGAACAGC GAAGTGTTGGCGGGGGACTTGATGTCCCCCTTCGACCAGTCGGGTTTGGGGGCTG AAGAAAGCCTAGGTCTCTTAGATGACTATCTGGAGGTGGCCAAGCACTTGAAAC CTCATGGGTTCTCCAGCGACAAGGCGGGCTCCTCGGAATGGCCGGCTATGGATG ATGGCTTGGCCAGTGCCTCAGACACCGGCAAGGGTGAGTAGGACGGCTGTCCTG GTGTGCCCTTTTCATATGGATCTGGTGTTCTAATGGCTTTCTGCCTCCCGAATATG ACATGAACCGTTCACACCTGAATTTCTTTTCCCAGAGGATGCCTTTTCCGGGACA GATTGGATGTTGGAGAAAATGGATCTGAAAGAGTTTGACTTCGATGCTCTGTTTC GAATGGATGACCTGGAAACCATGCCAGATGAGCTCTTGACCACGTTGGATGACA CATGTGATCTTTTTGCCCCTCTAGTCCAAGAGACTAATAAGGAGCCCCCTCAGAC AGTGAACCCAATTGGCCATCTCCCAGAAAGTTTAATAAAAGTCGACCAGGTTGC CCCCTTTACATTCTTGCAGCCTTTCCCCTGTTCCCCAGGGGTTCTGTCTTCCACTC CAGAGCATTCCTTTAGTTTAGAGCTAGGCAGTGAAGTTGATATCTCTGAAGGAGA CAGGAAGCCTGACTCTGCTGCTTACATTACTCTAATCCCTCCATGTGTAAAGGAG GAAGACACTCCCTCTGACAATGACAGTGGCATCTGTATGAGCCCAGAGTCCTACC TGGGCTCTCCCCAGCATAGCCCCTCCACCTCCAGGGCCCCACCAGACAATCTGCC TTCTCCAGGTGGTTCCCGTGGGTCTCCTCGGCCCAAACCTTATGACCCACCTGGA GTTAGTTTGACAGCTAAAGTGAAGACTGAGAAATTGGATAAGAAGCTGAAAAAG ATGGAGCAAAACAAGACAGCAGCCACTAGGTACCGCCAGAAGAAGCGGGCTGA GCAGGAGGCCCTCACTGGCGAGTGTAAGGAGCTAGAAAAAAAGAATGAGGCTCT GAAAGAGAAGGCAGATTCTCTGGCCAAGGAGATCCAGTATCTGAAAGACCTGATAttorney Docket Number: J0365.70001WO00AGAAGAGGTCCGTAAGGCAAGGGGGAAGAAGAGAGTTCCGTAATAGGGTAGTC AGGTGCTTTGTGCTTGTACATAGTCTTGTGTTGCTGTGTTTGCTGTAATAAATTAT TTTGTAGTGAAAGTACCTATGTGGGTTTTCAGTGTCATTCTTTGTAATAGACTTAA CTGCAGACGTTCCTGGGTTAGATACAATAACTACCTGGGTATATCCCAGGGCTGA GCTGAGCTGTTTGAGACGGTGAAGATGAGGGAGCTCTGGGTTAATGAAAGGAAC AGCCTGAATTCCACCTGTTCATACTGGCTTTGTGCCAGATAGCTGCCATGTAAGT ACCTAGATGAGGTACCCGCCTTGAGCACACAGAGGATTAGGTTTTTCTCAGGCTT AAGGGATAGAGCTCATATTCCCTCTGACACAGATGGCTGGACTGTTTCCACCTGG TGGAAGGGCTGGGGTGATAGTAAACAGTGGCAGGTACTGTCTACAGAGGTGAAA ATGAGCAATGTAGGCAGGAAGCTGGGAAGGGAACCTAGGCTTCCAGCTCCAGGG TCCTGGGCTACCTGCATCTTTACCTCTTAAATCTGGAAACTGTTAAAGCCTGCAG GGTTAAGAGGGATCTTTCAGCCTTCCCAATGCCAGTAGACTCACCTGAATGTTAG CTGTTGGGATGAATGTAGTCCATTGGGTTTGCTAATCTAGGATTCCTAAAACTAT GGAATCCACCCG (SEQ ID NO: 5). In some embodiments, the ATF4 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: 5.

[0171] A transcript of ATF4 in mouse is provided herein (NCBI Ref: NM_001287180.1): GGCTAGGTGTCCCACCCCGCCTTGTAAGACACCGGAAATTCGTCAACGAGCGAT CCCTCCGCGCTCCGGAACCAGACCGCGGCTGGTCGTCAACCTATAAAGGCTTGCG GCCACCATGGCGTATTAGAGGCAGCAGTGCCTGCGGCAGCGTTGGCCTTTGCAG CGGCGGCAGCAGCACCAGGCTCTGCAGCGGCAACCCCCACCGGCCTAAGCCATG GCGCTCTTCACGAAATCCAGCAGCAGTGTTGCTGTAACGGACAAAGATACCTTCG AGTTAAGCACATTCCTCGAATCCAGCAAAGCCCCACAACATGACCGAGATGAGC TTCCTGAACAGCGAAGTGTTGGCGGGGGACTTGATGTCCCCCTTCGACCAGTCGG GTTTGGGGGCTGAAGAAAGCCTAGGTCTCTTAGATGACTATCTGGAGGTGGCCA AGCACTTGAAACCTCATGGGTTCTCCAGCGACAAGGCGGGCTCCTCGGAATGGC CGGCTATGGATGATGGCTTGGCCAGTGCCTCAGACACCGGCAAGGAGGATGCCT TTTCCGGGACAGATTGGATGTTGGAGAAAATGGATCTGAAAGAGTTTGACTTCGA TGCTCTGTTTCGAATGGATGACCTGGAAACCATGCCAGATGAGCTCTTGACCACG TTGGATGACACATGTGATCTTTTTGCCCCTCTAGTCCAAGAGACTAATAAGGAGC CCCCTCAGACAGTGAACCCAATTGGCCATCTCCCAGAAAGTTTAATAAAAGTCG ACCAGGTTGCCCCCTTTACATTCTTGCAGCCTTTCCCCTGTTCCCCAGGGGTTCTG TCTTCCACTCCAGAGCATTCCTTTAGTTTAGAGCTAGGCAGTGAAGTTGATATCTAttorney Docket Number: J0365.70001WO00CTGAAGGAGACAGGAAGCCTGACTCTGCTGCTTACATTACTCTAATCCCTCCATG TGTAAAGGAGGAAGACACTCCCTCTGACAATGACAGTGGCATCTGTATGAGCCC AGAGTCCTACCTGGGCTCTCCCCAGCATAGCCCCTCCACCTCCAGGGCCCCACCA GACAATCTGCCTTCTCCAGGTGGTTCCCGTGGGTCTCCTCGGCCCAAACCTTATG ACCCACCTGGAGTTAGTTTGACAGCTAAAGTGAAGACTGAGAAATTGGATAAGA AGCTGAAAAAGATGGAGCAAAACAAGACAGCAGCCACTAGGTACCGCCAGAAG AAGCGGGCTGAGCAGGAGGCCCTCACTGGCGAGTGTAAGGAGCTAGAAAAAAA GAATGAGGCTCTGAAAGAGAAGGCAGATTCTCTGGCCAAGGAGATCCAGTATCT GAAAGACCTGATAGAAGAGGTCCGTAAGGCAAGGGGGAAGAAGAGAGTTCCGT AATAGGGTAGTCAGGTGCTTTGTGCTTGTACATAGTCTTGTGTTGCTGTGTTTGCT GTAATAAATTATTTTGTAGTGAAAGTACCTAAAAAAAAAAAAAAAAAA (SEQ ID NO: 6). In some embodiments, the ATF4 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: 6.

[0172] A transcript of ATF4 in mouse is provided herein (NCBI Ref: NM_009716.3):GGCTAGGTGTCCCACCCCGCCTTGTAAGACACCGGAAATTCGTCAACGAGCGAT CCCTCCGCGCTCCGGAACCAGACCGCGGCTGGTCGTCAACCTATAAAGTAGTGC ACTTTTCTCTCATGGGGCCTTTAGGACGATCTCTAACGCCACAGTTACCCCCCGA GCACAGCGGAGAAGGGTTGGGGCGGGCGAGGGCGTCAGTGAGAGGCGGTTTGG TGGCGCTGCGGTAGGATCACGTGACCACAGTGGGAGGATACGCGGTGTGCTGCG TCCCTGGCCGAGGCTATAAAGGGCGGGTTTAGGGCGTGCCGCCGCCATTTCTGCT TGCTGTCTGCCGGTTTAAGTTGTGTGCTCGGGTGTCCCTTTCCTCTTCCCCTCCCG CAGGGCTTGCGGCCACCATGGCGTATTAGAGGCAGCAGTGCCTGCGGCAGCGTT GGCCTTTGCAGCGGCGGCAGCAGCACCAGGCTCTGCAGCGGCAACCCCCACCGG CCTAAGCCATGGCGCTCTTCACGAAATCCAGCAGCAGTGTTGCTGTAACGGACA AAGATACCTTCGAGTTAAGCACATTCCTCGAATCCAGCAAAGCCCCACAACATG ACCGAGATGAGCTTCCTGAACAGCGAAGTGTTGGCGGGGGACTTGATGTCCCCC TTCGACCAGTCGGGTTTGGGGGCTGAAGAAAGCCTAGGTCTCTTAGATGACTATC TGGAGGTGGCCAAGCACTTGAAACCTCATGGGTTCTCCAGCGACAAGGCGGGCT CCTCGGAATGGCCGGCTATGGATGATGGCTTGGCCAGTGCCTCAGACACCGGCA AGGAGGATGCCTTTTCCGGGACAGATTGGATGTTGGAGAAAATGGATCTGAAAG AGTTTGACTTCGATGCTCTGTTTCGAATGGATGACCTGGAAACCATGCCAGATGA GCTCTTGACCACGTTGGATGACACATGTGATCTTTTTGCCCCTCTAGTCCAAGAGAttorney Docket Number: J0365.70001WO00ACTAATAAGGAGCCCCCTCAGACAGTGAACCCAATTGGCCATCTCCCAGAAAGT TTAATAAAAGTCGACCAGGTTGCCCCCTTTACATTCTTGCAGCCTTTCCCCTGTTC CCCAGGGGTTCTGTCTTCCACTCCAGAGCATTCCTTTAGTTTAGAGCTAGGCAGT GAAGTTGATATCTCTGAAGGAGACAGGAAGCCTGACTCTGCTGCTTACATTACTC TAATCCCTCCATGTGTAAAGGAGGAAGACACTCCCTCTGACAATGACAGTGGCA TCTGTATGAGCCCAGAGTCCTACCTGGGCTCTCCCCAGCATAGCCCCTCCACCTC CAGGGCCCCACCAGACAATCTGCCTTCTCCAGGTGGTTCCCGTGGGTCTCCTCGG CCCAAACCTTATGACCCACCTGGAGTTAGTTTGACAGCTAAAGTGAAGACTGAG AAATTGGATAAGAAGCTGAAAAAGATGGAGCAAAACAAGACAGCAGCCACTAG GTACCGCCAGAAGAAGCGGGCTGAGCAGGAGGCCCTCACTGGCGAGTGTAAGG AGCTAGAAAAAAAGAATGAGGCTCTGAAAGAGAAGGCAGATTCTCTGGCCAAG GAGATCCAGTATCTGAAAGACCTGATAGAAGAGGTCCGTAAGGCAAGGGGGAA GAAGAGAGTTCCGTAATAGGGTAGTCAGGTGCTTTGTGCTTGTACATAGTCTTGT GTTGCTGTGTTTGCTGTAATAAATTATTTTGTAGTGAAAGTACCTAAAAAAAAAA AAAAAAAA (SEQ ID NO: 7). In some embodiments, the ATF4 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: 7.

[0173] The mouse ATF4 protein can comprise a sequence of (Uniprot ID: Q06507):MTEMSFLNSEVLAGDLMSPFDQSGLGAEESLGLLDDYLEVAKHLKPHGFSSDKAGS SEWPAMDDGLASASDTGKEDAFSGTDWMLEKMDLKEFDFDALFRMDDLETMPDE LLTTLDDTCDLFAPLVQETNKEPPQTVNPIGHLPESLIKVDQVAPFTFLQPFPCSPGVL SSTPEHSFSLELGSEVDISEGDRKPDSAAYITLIPPCVKEEDTPSDNDSGICMSPESYLG SPQHSPSTSRAPPDNLPSPGGSRGSPRPKPYDPPGVSLTAKVKTEKLDKKLKKMEQN KTAATRYRQKKRAEQEALTGECKELEKKNEALKEKADSLAKEIQYLKDLIEEVRKA RGKKRVP (SEQ ID NO: 8). In some embodiments, the ATF4 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: 8.Methods of Treatment

[0174] Methods and compositions for treating a disease or condition is provided herein. In certain aspects, the method includes increasing activity of one or more of transcription factors (TFs). In certain aspects, the method includes decreasing activity of one or more ofAttorney Docket Number: J0365.70001WO00transcription factors (TFs). In certain aspects, the method includes decreasing the activity of Activating Transcription Factor 4 (ATF4) in the cells.

[0175] 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, skeletal muscle atrophy, sarcopenia, or a neurological disorder. In some embodiments, the liver disease is a non-alcoholic fatty liver disease (NAFLD). 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, 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.

[0176] In some embodiments, the method disclosed herein increases metabolic processes. Non-limiting 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%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 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 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%, 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.Attorney Docket Number: J0365.70001WO00

[0177] 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 measuring membrane potential (i.e., TMRE membrane potential marker), superoxide production, calcium levels, mitochondrial permeability, ATP production, or NAD / NADH levels.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] The compositions or methods described herein can include decreasing the activity of ATF4 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 ATF4 transiently. For example, decreasing the activity of ATF4 for a period of time that isAttorney Docket Number: J0365.70001WO00less 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 a day, less than 18 hours, less than 12 hours, less than 8 hours, less than 5 hours, or lesser, e.g., at least 1 hour.

[0182] In certain embodiments, the method may include administering to a subject in need thereof a composition comprising an ATF4 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 ATF4. 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-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 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 cases, the siRNA is conjugated to a GalNAc. In some cases, the siRNA is conjugated to a lipid.

[0183] In some embodiments, the composition comprises a protein that functions to decrease the activity of ATF4 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 ATF4 mRNA, such as a portion of the sequence of SEQ ID NO: 2 or a portion of the sequence of SEQ ID NO: 3.

[0184] In some embodiments, the ATF4 inhibitor is a small molecule.

[0185] 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).

[0186] The method provided herein can be performed in vivo, in situ, in vitro, ex vivo, or any combination thereof.Decreasing Activity of a TF

[0187] Provided herein is a method comprises decreasing the activity of ATF4 protein. In some instances, decreasing the activity of ATF4 protein comprises decreasing the mRNA level of ATF4 in a cell. In some instances, decreasing the activity of ATF4 protein comprisesAttorney Docket Number: J0365.70001WO00decreasing the protein level of ATF4 in a cell. In some instances, decreasing the activity of ATF4 protein comprises inhibiting or reducing the ATF4 protein binding to DNA.

[0188] 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)

[0189] In some embodiments, the target cell is a preadipocyte. A preadipocyte can differentiate into a mature adipose cell.

[0190] 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.

[0191] Decreasing the activity of a polypeptide such as ATF4 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.

[0192] In certain embodiments, decreasing the activity of ATF4 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%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 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 certain embodiments, decreasing the activity of ATF4 may encompass decreasing the mRNA level of ATF4 in cells by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, atAttorney Docket Number: J0365.70001WO00least 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%, at least 35%, at least 40%, at least 45%, at least 50%, at least 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 mRNA level of ATF4 is decreased in cells by at least 30%, at least 40%, or at least 50% as compared to a control cell. In some instances, the mRNA level of ATF4 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.

[0193] In certain embodiments, the method comprises decreasing the function of ATF4. Nonlimiting 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.

[0194] In certain embodiments, the method comprises decreasing the activity of ATF4, wherein decreasing the activity of ATF4 comprises decreasing the mRNA level of ATF4. In some embodiments, the method comprises inhibiting DNA binding to ATF4 protein.

[0195] In certain embodiments, decreasing the activity of ATF4 in a cell may encompass decreasing the activity of ATF4 in 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.

[0196] 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 encoding the protein, by introducing into the cells a polynucleic acid that interferes with translation of the mRNA encoding the protein, and the like.

[0197] In certain embodiments, decreasing the level of ATF4 may include decreasing the expression level of ATF4 by, e.g., decreasing transcription of the endogenous A TF4 gene encoding the ATF4 protein.

[0198] In certain embodiments, decreasing transcription of the gene encoding the protein may include introducing into the cell a Cas / guide RNA that suppresses expression of theAttorney Docket Number: J0365.70001WO00protein. In certain embodiments, the guide RNA may bind to a region in the promoter of the gene encoding the protein or in the coding region.

[0199] 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-beta-inducible early gene (TIEG), v-erbA, SID, MBD2, MBD3, Rb, or MeCP.

[0200] In certain embodiments, decreasing level of ATF4 may include contacting the 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 and alters 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.

[0201] In some embodiments, a method described herein comprises contacting the cell with an antisense oligonucleotide targeting ATF4 (e.g., an mRNA of ATF4 gene). In some embodiments, the antisense oligonucleotide comprises 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 ATF4_RNA (e.g., mRNA) sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 3. In some embodiments, the antisense oligonucleotide is 15-40 (e.g., 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40) nucleosides in length,

[0202] In some embodiments, an antisense oligonucleotide used in a method described herein comprises 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, 22, 23) nucleosides to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942. In some embodiments, the antisense oligonucleotide comprises a region of complementary 15-40 (e.g., 15, 16, 17, 18, 19, 20, or 21) nucleosides to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942. In some embodiments, the antisense oligonucleotide 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 siRNAsAttorney Docket Number: J0365.70001WO00listed in Tables 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469, optionally wherein the antisense strand comprises the nucleobase sequences of the antisense strand of any one of the siRNAs listed in Tables 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469.

[0203] In some embodiments, an antisense oligonucleotide used in a method described herein reduces ATF4 expression (e.g., protein and / or RNA) or activity by mediating degradation of ATF4 mRNA (e.g., by RNase H, or by binding to regulatory elements in the mRNA that destabilizes the mRNA). In some embodiments, any one of the antisense oligonucleotide used in a method described herein may be a gapmer. In some embodiments, any one of the antisense oligonucleotides described herein comprises one or more modified nucleosides and / or modified intemucleoside linkages. Gapmer configurations and chemical modifications that may be used in accordance with the present disclosure are described in, e.g., U. S. Pat. Nos. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711;5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; 5,700,922; 5,898,031; 7,432,250; and 7,683,036; U. S. patent publication Nos. US20090286969, US20100197762, and US20110112170, each of which is herein incorporated by reference in its entirety. In some embodiments, any one of the antisense oligonucleotide used in a method described herein may be a mixmer (e.g., comprising a mixture of both naturally and non-naturally occurring nucleotides or comprise two different types of non-naturally occurring nucleotides such as 2’-modified nucleosides as described herein). In some embodiments, the antisense oligonucleotide is a phosphorodiamidate morpholino oligomer.

[0204] 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 any sense strand sequence presented in Table 1. 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 antisense strand sequence presented in Table 1. In some embodiments, the siRNA comprises a sense strand sequence of Table 1 and a corresponding antisense strand sequence of Table 1.

[0205] 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 any sense strand sequence presented in Table 1 on the gene ATF4. 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, fromAttorney Docket Number: J0365.70001WO00position 400 to 600, from position 500 to 700, from position 600 to 800, or from position 700 to 900 of any one of SEQ ID NOs: 2, 3, 6, and 7. 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.

[0206] In some embodiments, the method comprises contacting the cells with an siRNA targeting ATF4 (e.g., an mRNA of ATF4 gene). In some embodiments, the siRNA comprises 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 ATF4 RNA (e.g., mRNA) sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 3, and a sense strand that is at least substantially complementary to the antisense strand. In some embodiments, the sense strand is 15-40 (e.g., 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40) nucleosides in length, and / or the antisense strand is 15-40 (e.g., 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40) 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.

[0207] In some embodiments, an siRNA used in a method described herein comprises 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, 22, 23) nucleosides to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942. In some embodiments, the antisense strand comprises a region of complementary 15-21 (e.g., 15, 16, 17, 18, 19, 20, or 21) nucleosides to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942. 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 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469, optionally wherein the antisense strand comprises the nucleobase sequences of the antisenseAttorney Docket Number: J0365.70001WO00strand of any one of the siRNAs listed in Tables 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469. In some embodiments, the siRNAs comprises a sense strand comprising at least 8 consecutive nucleobases of the sense strand of any one of the siRNAs listed in Tables 1-5 or the sense strand sequence as set forth in any one of SEQ ID NOs: 3416-8942, optionally wherein the sense strand comprises the nucleobase sequences of the sense strand of any one of the siRNAs listed in Tables 1-5 or the sense strand sequence as set forth in any one of SEQ ID NOs: 3416-8942.

[0208] 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: 69, 159, 177, 265, 283, 305, 307, 323, 355, 415, 421, 427, 431, 433, 437, 439, 515, 605, 623, 711, 729, 751, 753, 769, 801, 861, 867, 873, 877, 879, 883, 885, 14471, 14473, 14475, 14477, 14479, 14481, 14483, 14485, 14487, and 14489. In some embodiments, the antisense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 69, 159, 177, 265, 283, 305, 307, 323, 355, 415, 421, 427, 431, 433, 437, 439, 515, 605, 623, 711, 729, 751, 753, 769, 801, 861, 867, 873, 877, 879, 883, 885, 14471, 14473, 14475, 14477, 14479, 14481, 14483, 14485, 14487, and 14489. 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: 68, 158, 176, 264, 282, 304, 306, 322, 354, 414, 420, 426, 430, 432, 436, 438, 514, 604, 622, 710, 728, 750, 752, 768, 800, 860, 866, 872, 876, 878, 882, 884, 14470, 14472, 14474, 14476, 14478, 14480, 14482, 14484, 14486, and 14488. In some embodiments, the sense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 68, 158, 176, 264, 282, 304, 306, 322, 354, 414, 420, 426, 430, 432, 436, 438, 514, 604, 622, 710, 728, 750, 752, 768, 800, 860, 866, 872, 876, 878, 882, 884, 14470, 14472, 14474, 14476, 14478, 14480, 14482, 14484, 14486, and 14488.

[0209] 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 ID NOs: 265, 305, 421, 427, 431, 711, 751, 867, 873, 877, 14477, and 14487, and comprises a sense strand comprising 15-21 nucleobases of any one of SEQ ID NOs: 264, 304, 420, 426, 430, 710, 750, 866, 872, 876, 14476, and 14486.

[0210] In some embodiments, an siRNA used in a method described herein comprises the nucleobase sequences of any one of siRNA-30, siRNA-75, siRNA-84, siRNA- 128, siRNA-137, siRNA-148, siRNA-149, siRNA-157, siRNA-173, siRNA-203, siRNA-206, siRNA-209, siRNA-211, siRNA-212, siRNA-214, siRNA-215, siRNA-253, siRNA-298, siRNA-307,Attorney Docket Number: J0365.70001WO00siRNA-351, siRNA-360, siRNA-371, siRNA-372, siRNA-380, siRNA-396, siRNA-426, siRNA-429, siRNA-432, siRNA-434, siRNA-435, siRNA-437, siRNA-438, siRNA-1116, siRNA-1117, siRNA-1118, siRNA-1119, siRNA-1120, siRNA-1121, siRNA-1122, siRNA-1123, siRNA- 1124, siRNA- 1125, optionally wherein the siRNA comprises the nucleobase sequences of any one of siRNA-128, siRNA-148, siRNA-206, siRNA-209, siRNA-211, siRNA-351, siRNA-429, siRNA-432, siRNA-434, siRNA-1119, siRNA-1124.

[0211] In some embodiments, any one of the siRNAs used in a method described herein comprising nucleobase sequences (e.g., nucleobase sequences of the antisense strand and the sense strand) of the siRNAs listed in Tables 1-5, and as set forth in SEQ ID NOs: 3416-14469 can adopt known siRNA configurations and / or chemical modifications. In some embodiments, any one of the siRNAs described herein can include any of the siRNA configurations or chemical modifications as disclosed in Hu et al. Therapeutic siRNA: State of the Art. Sig Transduct Target Ther 5, 101 (2020), the entire contents of which is herein incorporated by reference.

[0212] In some embodiments, any one of the siRNAs used in a method described herein comprises any of the chemical modifications and / or modification patterns as disclosed in US10233448, US11504391, US9290760, US9796974, US9399775, US11015198, US10676742, US11661604, US11655473, US20170305956, and US20240182892. The disclosures in these references related to siRNA configurations and chemical modifications of oligonucleotides (e.g., siRNAs) are incorporated herein by reference.

[0213] 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’-0-methoxyethyl (2’-MOE), 2’-0-aminopropyl (2’-O-AP), 2’-0-dimethylaminoethyl (2’-O-DMAOE), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-0-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-0-N-methylacetamido (2’-O-NMA) modified nucleoside and combinations thereof.

[0214] 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.Attomey Docket Number: J0365.70001WO00

[0215] 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’ to 3’) of the sense strand are 2’-F modified nucleosides, optionally wherein 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. 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.

[0216] 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 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, the sense strand comprises four phosphorothioate intemucleoside linkages. In some embodiments, the first two and the last two intemucleoside linkages in the sense strand (from 5’ to 3’) are phosphorothioate intemucleoside linkages. 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’.

[0217] In some embodiments, in an siRNA used in a method described herein, the nucleosides at positions 7, 9, 10, and 11 (counting 5’to 3’) of the sense strand are 2’-F modified nucleosides, the nucleosides at 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 and the last 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.

[0218] In some embodiments, the siRNA is selected from any one of the siRNAs listed in Table 3. In some embodiments, the siRNA is selected from: siRNA-476, siRNA-521, siRNA-Attorney Docket Number: J0365.70001WO00530, siRNA-574, siRNA-583, siRNA-594, siRNA-595, siRNA-603, siRNA-619, siRNA-649, siRNA-652, siRNA-655, siRNA-657, siRNA-658, siRNA-660, siRNA-661, siRNA-1126, siRNA-1127, siRNA-1128, siRNA-1129, and siRNA-1130.

[0219] In some embodiments, any one of the siRNAs used in a method described herein further comprises a 5’-vinylphosphonate moiety (e.g., at the 5’ end of the antisense strand).

[0220] 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 targets liver cells, kidney cells, muscle cells, or adipose cells. Non-limiting examples of target agents (e.g., targeting extra-hepatic tissues such as adipose tissues) that may be used in accordance with the present disclosure are described in, e.g., US12258563B2, US12005074B2, US20240360455A1, US20220042015A1, US20230277675A1, US20230226193A1, WO2024148329A1, WO2025059326A1, US20250161464A1, EP4585602A1, and WO2024212237 Al, the disclosures in each of which relating to targeting ligands and their conjugation to oligonucleotides (e.g., siRNAs) are incorporated herein by reference. In some embodiments, the target agent comprises an adipose target agent. In some embodiments, the targeting agent comprises a peptide. In some embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 9. In some embodiments, the peptide is covalently linked to the 3’ end of the sense strand of the siRNA.

[0221] In some embodiments, the targeting agent conjugated to an siRNA used in a method described comprises 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).

[0222] In some embodiments, an siRNA used in a method described herein is selected from the siRNAs listed in Table 4. In some embodiments, the siRNA is selected from: siRNA-699, siRNA-744, siRNA-753, siRNA-797, siRNA-806, siRNA-817, siRNA-818, siRNA-826, siRNA-842, siRNA-872, siRNA-875, siRNA-878, siRNA-880, siRNA-881, siRNA-883, siRNA-884, siRNA-1131, siRNA-1132, siRNA-1133, siRNA-1134, siRNA-1135, siRNA-1141, siRNA-1142, siRNA-1143, siRNA-1144, siRNA-1145, and siRNA-1146.

[0223] In some embodiments, the targeting agent conjugated to an siRNA used in a method described comprises 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 ’-Attorney Docket Number: J0365.70001WO00phosphate. In some embodiments, the lipid-conjugated internal nucleotide comprises a 2’-O-hexadecyl (Cl 6) nucleotide base-3 ’-phosphate. In some embodiments, the nucleobase of the nucleotide is selected from the group consisting of adenine, guanine, cytosine, thymine, uracil and analogs thereof. In some embodiments, the lipid (e.g., a C22 lipid monomer or a C16 lipid monomer) is conjugated to a terminus of a sense strand or an antisense strand of the siRNA.

[0224] In some embodiments, an siRNA used in a method described herein is selected from the siRNAs listed in Table 5. In some embodiments, the siRNA is selected from: siRNA-922, siRNA-967, siRNA-976, siRNA-1020, siRNA-1029, siRNA-1040, siRNA-1041, siRNA-1049, siRNA-1065, siRNA-1095, siRNA-1098, siRNA-1101, siRNA-1103, siRNA-1104, siRNA-1106, siRNA-1107, siRNA-1136, siRNA-1137, siRNA-1138, siRNA-1139, siRNA- 1140.

[0225] In certain embodiments, the method comprises decreasing the activity of ATF4 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 ATF4 mRNA.

[0226] In certain embodiments, an RNA-guided transcriptional repressor of ATF4 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

[0227] 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. Nonlimiting examples of production methods include in vitro transcription methods, polymerase chain transcription (PCT), recombinant overexpression (e.g., in E. 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 in vitro 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 gelAttorney Docket Number: J0365.70001WO00electrophoresis (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, at least 91% purity, at least 92% purity, at least 93% purity, at least 94% purity, at least 95% purity, at least 96% purity, at least 97% purity, at least 98% purity, at least 99% purity, or at least 99.99%. Methods for 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.

[0228] 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 solidphase 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-phosphonate 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.Attorney Docket Number: J0365.70001WO00A. Chemical Synthesis

[0229] Where a polypeptide is chemically synthesized, the synthesis may proceed via liquidphase 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

[0230] 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. coli) 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 Cl 27 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.

[0231] In some embodiments, the host cells can be from a transgenic animal, e.g., mammary epithelial cell.

[0232] A variety of host-vector systems suitable for the expression of a polypeptide may be employed according to standard procedures known in the art. See, e.g., Sambrook et al., 1989 Current Protocols in Molecular Biology Cold Spring Harbor Press, New York; and Ausubel et al. 1995 Current Protocols in Molecular Biology, 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.

[0233] 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 andAttorney Docket Number: J0365.70001WO00translational regulatory sequences and may provide for inducible or constitutive expression where the coding region is 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.

[0234] 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.

[0235] 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.

[0236] A variety of enzymes can catalyze insertion of foreign DNA into a host genome. Nonlimiting examples of gene editing tools and techniques include CRISPR, TALEN, zinc finger nuclease (ZFN), meganuclease, Mega-TAL, and transposon-based systems.

[0237] 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.

[0238] 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, HepG2Attorney Docket Number: J0365.70001WO00cells, 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

[0239] Compositions comprising any polynucleic acid, cell, polypeptide, gene, gene product, or transcription factor described herein 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 ATF4.

[0240] 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

[0241] described herein, in certain embodiments, is a vector comprising one or more of the polynucleic acid molecules as described herein.

[0242] 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).

[0243] 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 MOMFV) 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.

[0244] Additionally, cells which have stably integrated the DNA into their chromosomes may be selected by introducing one or more markers which allow for 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 beAttomey Docket Number: J0365.70001WO00expressed, 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.

[0245] 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.

[0246] 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.

[0247] 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 lenti virus vectors (IDLV).

[0248] Non-viral vector delivery systems include electroporation, lipofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipidmucleic acid conjugates, naked DNA, artificial virions, and agent-enhanced uptake of DNA.

[0249] Cells may be isolated and subjected to the methods disclosed herein ex vivo for reintroduction into the subject.

[0250] 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-Attorney Docket Number: J0365.70001WO00associated virus vectors (rAAV) such as replication-deficient recombinant adenoviral vectors may be used for introduction of polynucleic acids encoding the polypeptides disclosed herein.

[0251] In some embodiments, polynucleic acids disclosed herein can be delivered using 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 expressed as 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.

[0252] 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.

[0253] 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).

[0254] 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.Attorney Docket Number: J0365.70001WO00

[0255] 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.

[0256] 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

[0257] 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), l,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), Cholesterol, l,2-dimyristoyl-rac-glycero-3-methoxypolyethylene 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 7, 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.

[0258] 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.

[0259] 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% noncationic 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-cationicAttorney Docket Number: J0365.70001WO00lipid. 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% noncationic 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.

[0260] 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.

[0261] 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 CKGGRAKDC (SEQ ID NO: 9).

[0262] 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.

[0263] In some embodiments, the molar ratio of the peptide to the polynucleotide targeting ATF4 disclosed herein is at least 5:1, at least 10:1, at least 15:1, 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 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 about 40:1 to about 70:1. In some embodiments, the molar ratio of the peptide to the polynucleotide 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 polynucleotide is about 20:1, about 25:1, about 30:1, aboutAttorney Docket Number: J0365.70001WO0035:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, 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.

[0264] In some embodiments, the adipose targeting peptide has a sequence of SEQ ID NO: 9. In some embodiments, the molar ratio of the peptide to the siRNA is at least 5:1, at least 10:1, at least 15:1, 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, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, 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.

[0265] In some embodiments, the targeting agent comprises a liver cell targeting agent. In some embodiments, the liver cell targeting agent comprises a GalNAc.

[0266] In some embodiments, the LNP formulation comprises a pH value that is less than 10, less than 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 value is about 7. In some embodiments, the pH value is about 6. In some embodiments, the pH value is about 5.Attorney Docket Number: J0365.70001WO00Compositions

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] In some embodiments, the composition provided herein comprises an inhibitor of a transcription factor involved in the ATF4 pathway, including but not limited to ATF4. In some embodiments, the inhibitor is a small molecule.

[0272] 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.

[0273] In some embodiments, the present disclosure provides antisense oligonucleotides targeting ATF4 (e.g., an mRNA of ATF4 gene). In some embodiments, the antisense oligonucleotide comprises a region of complementarity of at least 8 (e.g., at least 8, 9, 10, 11,Attorney Docket Number: J0365.70001WO0012, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more) nucleosides to an ATF4_RNA (e.g., mRNA) sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 3. In some embodiments, the antisense oligonucleotide is 15-40 (e.g., 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40) nucleosides in length,

[0274] In some embodiments, an antisense oligonucleotide described herein comprises 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, 22, 23) nucleosides to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942. In some embodiments, the antisense oligonucleotide comprises a region of complementary 15-40 (e.g., 15, 16, 17, 18, 19, 20, or 21) nucleosides to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942. In some embodiments, the antisense oligonucleotide 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 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469, optionally wherein the antisense strand comprises the nucleobase sequences of the antisense strand of any one of the siRNAs listed in Tables 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469.

[0275] In some embodiments, an antisense oligonucleotide reduces ATF4 expression (e.g., protein and / or RNA) or activity by mediating degradation of ATF4 mRNA (e.g., by RNase H, or by binding to regulatory elements in the mRNA that destabilizes the mRNA). In some embodiments, any one of the antisense oligonucleotide used in a method described herein may be a gapmer. In some embodiments, any one of the antisense oligonucleotides described herein comprises one or more modified nucleosides and / or modified internucleoside linkages. Gapmer configurations and chemical modifications that may be used in accordance with the present disclosure are described in, e.g., U. S. Pat. Nos. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; 5,700,922; 5,898,031; 7,432,250; and 7,683,036; U. S. patent publication Nos.US20090286969, US20100197762, and US20110112170, each of which is herein incorporated by reference in its entirety. In some embodiments, any one of the antisense oligonucleotide used in a method described herein may be a mixmer (e.g., comprising a mixture of both naturally and non-naturally occurring nucleotides or comprise two different types of non-naturally occurring nucleotides such as 2’-modified nucleosides as describedAttorney Docket Number: J0365.70001WO00herein). In some embodiments, the antisense oligonucleotide is a phosphorodiamidate morpholino oligomer.

[0276] In some embodiments, the present disclosure provides siRNAs targeting ATF4 (e.g., an mRNA of ATF4 gene). In some embodiments, the siRNA comprises 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 ATF4 RNA (e.g., mRNA) sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 3, and a sense strand that is at least substantially complementary to the antisense strand. In some embodiments, the sense strand is 15-40 (e.g., 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40) nucleosides in length, and / or the antisense strand is 15-40 (e.g., 15, 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 ) 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.

[0277] In some embodiments, an siRNA described herein comprises 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, 22, 23) nucleosides to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942. In some embodiments, the antisense strand comprises a region of complementary 15-21 (e.g., 15, 16, 17, 18, 19, 20, or 21) nucleosides to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942. 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 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469, optionally wherein the antisense strand comprises the nucleobase sequences of the antisense strand of any one of the siRNAs listed in Tables 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469. In some embodiments, the siRNAs comprises a sense strand comprising at least 8 consecutive nucleobases of the sense strand of any one of the siRNAs listed in Tables 1-5 or the sense strand sequence as set forth in any one of SEQ ID NOs: 3416-8942, optionally wherein the sense strand comprises the nucleobase sequences of the sense strand of any one of the siRNAs listed in Tables 1-5 or the sense strand sequence as set forth in any one of SEQ ID NOs: 3416-8942.Attorney Docket Number: J0365.70001WO00

[0278] In some embodiments, an siRNA 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: 69, 159, 177, 265, 283, 305, 307, 323, 355, 415, 421, 427, 431, 433, 437, 439, 515, 605, 623, 711, 729, 751, 753, 769, 801, 861, 867, 873, 877, 879, 883, 885, 14471, 14473, 14475, 14477, 14479, 14481, 14483, 14485, 14487, and 14489. In some embodiments, the antisense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 69, 159, 177, 265, 283, 305, 307, 323, 355, 415, 421, 427, 431, 433, 437, 439, 515, 605, 623, 711, 729, 751, 753, 769, 801, 861, 867, 873, 877, 879, 883, 885, 14471, 14473, 14475, 14477, 14479, 14481, 14483, 14485, 14487, and 14489. 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: 68, 158, 176, 264, 282, 304, 306, 322, 354, 414, 420, 426, 430, 432, 436, 438, 514, 604, 622, 710, 728, 750, 752, 768, 800, 860, 866, 872, 876, 878, 882, 884, 14470, 14472, 14474, 14476, 14478, 14480, 14482, 14484, 14486, and 14488. In some embodiments, the sense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 68, 158, 176, 264, 282, 304, 306, 322, 354, 414, 420, 426, 430, 432, 436, 438, 514, 604, 622, 710, 728, 750, 752, 768, 800, 860, 866, 872, 876, 878, 882, 884, 14470, 14472, 14474, 14476, 14478, 14480, 14482, 14484, 14486, and 14488.

[0279] In some embodiments, an siRNA described herein comprises an antisense strand comprising 15-23 consecutive nucleobases of any one of SEQ ID NOs: 265, 305, 421, 427, 431, 711, 751, 867, 873, 877, 14477, and 14487, and comprises a sense strand comprising 15-21 nucleobases of any one of SEQ ID NOs: 264, 304, 420, 426, 430, 710, 750, 866, 872, 876, 14476, and 14486.

[0280] In some embodiments, an siRNA described herein comprises the nucleobase sequences of any one of siRNA-30, siRNA-75, siRNA-84, siRNA-128, siRNA-137, siRNA-148, siRNA-149, siRNA-157, siRNA-173, siRNA-203, siRNA-206, siRNA-209, siRNA-211, siRNA-212, siRNA-214, siRNA-215, siRNA-253, siRNA-298, siRNA-307, siRNA-351, siRNA-360, siRNA-371, siRNA-372, siRNA-380, siRNA-396, siRNA-426, siRNA-429, siRNA-432, siRNA-434, siRNA-435, siRNA-437, siRNA-438, siRNA-1116, siRNA-1117, siRNA-1118, siRNA-1119, siRNA-1120, siRNA-1121, siRNA-1122, siRNA-1123, siRNA-1124, siRNA- 1125, optionally wherein the siRNA comprises the nucleobase sequences of any one of siRNA-128, siRNA-148, siRNA-206, siRNA-209, siRNA-211, siRNA-351, siRNA-429, siRNA-432, siRNA-434, siRNA-1119, siRNA-1124.Attorney Docket Number: J0365.70001WO00

[0281] In some embodiments, any one of the siRNAs described herein comprising nucleobase sequences (e.g., nucleobase sequences of the antisense strand and the sense strand) of the siRNAs listed in Tables 1-5, and as set forth in SEQ ID NOs: 3416-14469 can adopt known siRNA configurations and / or chemical modifications. In some embodiments, any one of the siRNAs described herein can include any of the siRNA configurations or chemical modifications as disclosed in Hu et al. Therapeutic siRNA: State of the Art. Sig Transduct Target Ther 5, 101 (2020), the entire contents of which is herein incorporated by reference.

[0282] In some embodiments, any one of the siRNAs described herein comprises any of the chemical modifications and / or modification patterns as disclosed in US 10233448, US11504391, US9290760, US9796974, US9399775, US11015198, US10676742, US11661604, US11655473, US20170305956, and US20240182892. The disclosures in these references related to siRNA configurations and chemical modifications of oligonucleotides (e.g., siRNAs) are incorporated herein by reference.

[0283] In some embodiments, any one of the siRNAs 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’-0-methoxyethyl (2’-MOE), 2’-O-aminopropyl (2’-O-AP), 2’-0-dimethylaminoethyl (2’-O-DMAOE), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-0-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-0-N-methylacetamido (2’-O-NMA) modified nucleoside and combinations thereof.

[0284] 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.

[0285] In some embodiments, in an siRNA described herein, the nucleosides at one or more positions 9, 10, and 11 (counting 5’to 3’) of the sense strand are 2’-F modified nucleosides, optionally wherein 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. In some embodiments, wherein theAttorney Docket Number: J0365.70001WO00nucleosides 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.

[0286] 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, the sense strand comprises four phosphorothioate intemucleoside linkages. In some embodiments, the first two and the last two intemucleoside linkages in the sense strand (from 5’ to 3’) are phosphorothioate intemucleoside linkages. 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’.

[0287] In some embodiments, in an siRNA described herein, the nucleosides at positions 7, 9, 10, and 11 (counting 5’to 3’) of the sense strand are 2’-F modified nucleosides, the nucleosides at 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 and the last 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.

[0288] In some embodiments, the siRNA is selected from any one of the siRNAs listed in Table 3. In some embodiments, the siRNA is selected from: siRNA-476, siRNA-521, siRNA-530, siRNA-574, siRNA-583, siRNA-594, siRNA-595, siRNA-603, siRNA-619, siRNA-649, siRNA-652, siRNA-655, siRNA-657, siRNA-658, siRNA-660, siRNA-661, siRNA-1126, siRNA-1127, siRNA-1128, siRNA-1129, and siRNA-1130.

[0289] In some embodiments, any one of the siRNAs described herein further comprises a 5’-vinylphosphonate moiety (e.g., at the 5’ end of the antisense strand).

[0290] 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 targets liver cells, kidney cells, muscle cells, or adipose cells. Non-limiting examples ofAttomey Docket Number: J0365.70001WO00target agents (e.g., targeting extra-hepatic tissues such as adipose tissues) that may be used in accordance with the present disclosure are described in, e.g., US12258563B2, US12005074B2, US20240360455A1, US20220042015A1, US20230277675A1, US20230226193A1, WO2024148329A1, WO2025059326A1, US20250161464A1, EP4585602A1, and WO2024212237 Al, the disclosures in each of which relating to targeting ligands and their conjugation to oligonucleotides (e.g., siRNAs) are incorporated herein by reference. In some embodiments, the target agent comprises an adipose target agent. In some embodiments, the targeting agent comprises a peptide. In some embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 9. In some embodiments, the peptide is covalently linked to the 3’ end of the sense strand of the siRNA.

[0291] In some embodiments, the targeting agent conjugated to an siRNA described comprises 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).

[0292] In some embodiments, an siRNA described herein is selected from the siRNAs listed in Table 4. In some embodiments, the siRNA is selected from: siRNA-699, siRNA-744, siRNA-753, siRNA-797, siRNA-806, siRNA-817, siRNA-818, siRNA-826, siRNA-842, siRNA-872, siRNA-875, siRNA-878, siRNA-880, siRNA-881, siRNA-883, siRNA-884, siRNA-1131, siRNA-1132, siRNA-1133, siRNA-1134, siRNA-1135, siRNA-1141, siRNA-1142, siRNA-1143, siRNA-1144, siRNA-1145, and siRNA-1146.

[0293] In some embodiments, the targeting agent conjugated to an siRNA described comprises 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 (Cl 6) nucleotide base-3 ’-phosphate. In some embodiments, the nucleobase of the nucleotide is selected from the group consisting of adenine, guanine, cytosine, thymine, uracil and analogs thereof. In some embodiments, the lipid (e.g., a C22 lipid monomer or a C 16 lipid monomer) is conjugated to a terminus of a sense strand or an antisense strand of the siRNA.

[0294] In some embodiments, an siRNA described herein is selected from the siRNAs listed in Table 5. In some embodiments, the siRNA is selected from: siRNA-922, siRNA-967, siRNA-976, siRNA- 1020, siRNA- 1029, siRNA- 1040, siRNA- 1041, siRNA- 1049, siRNA-Attorney Docket Number: J0365.70001WO001065, siRNA-1095, siRNA-1098, siRNA-1101, siRNA-1103, siRNA-1104, siRNA-1106, siRNA-1107, siRNA-1136, siRNA-1137, siRNA-1138, siRNA-1139, siRNA-1140.

[0295] 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 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 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 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%, 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 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 5. In some embodiments, the siRNA comprises a sense strand sequence of Table 2 and a corresponding antisense strand sequence of Table 2. In some embodiments, the siRNA comprises a sense strand sequence of Table 3 and a corresponding antisense strand sequence of Table 3. In some embodiments, the siRNA comprises a sense strand sequence of Table 4 and a corresponding antisense strand sequence of Table 4. In some embodiments, the siRNA comprises a sense strand sequence of Table 5 and a corresponding antisense strand sequence of Table 5.Attorney Docket Number: J0365.70001WO00

[0296] 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: 9. In some embodiments, the peptide has a sequence of SEQ ID NO: 9. 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 4). The GalNAc L96 can have a structure of Formula (I- a) as shown below:Formula (I-a)

[0297] 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:Attorney Docket Number: J0365.70001WO00Formula (I-b)

[0298] 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)

[0299] 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)

[0300] The GalNAc disclosed herein can be conjugated to any one of the siRNAs disclosed herein. In some embodiments, the GalNAc modified siRNA comprises a sense strand with atAttorney Docket Number: J0365.70001WO00least 80%, 85%, 90%, or 95% sequence identity to any one sense strand provided in Table 4.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 4.

[0301] 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.

[0302] 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-modification. In some embodiments, the nucleotide or nucleotide base analog is 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.

[0303] In some embodiments, the lipid moiety-conjugated siRNA comprises a structure of 2’-O- docosanoxyl (C22) nucleotide base-3 ’-phosphate (Formula Il-a).Attorney Docket Number: J0365.70001WO00wherein 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).

[0304] In some embodiments, the lipid moiety-conjugated siRNA comprises a structure of 2’-O-hexadecyl (C16) nucleotide base-3 ’-phosphate (Formula Il-b).o.x»1OHwherein 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).

[0305] 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 the 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 C16 lipid monomer. 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 antisense strand provided in Table 5. 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 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 5. In some cases, the siRNA comprises an antisense sequence having one, two, three, or four mismatches as compared to any one sense strand provided in Table 5.

[0306] 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 any sense strand sequence presented in Table 1 on the gene ATF4. In some embodiments, the siRNA specifically binds a target sequence from position 1Attorney Docket Number: J0365.70001WO00to 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 any one of SEQ ID NOs: 2, 3, 6, and 7. 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.

[0307] 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 modification is a vinylpho sphonate moiety. In some embodiments, the modification is a 5’ vinylpho sphonate moiety.

[0308] 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 1. 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 1. 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 1. 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 1.

[0309] 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 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 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 someAttorney Docket Number: J0365.70001WO00cases, the siRNA comprises an antisense sequence having one, two, three, or four mismatches as compared to any one antisense strand provided in Table 2.

[0310] 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 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 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 four mismatches as compared to any one antisense strand provided in Table 3.

[0311] 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 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 any one antisense strand sequence 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 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.

[0312] 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 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 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 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.Table 1. Exemplary siRNA SequencesSEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:GAAGAAAGCCUAGGUCU UAAGAGACCUAGGCUUsiRNA- 1 CUUA 10 UCUUCAG 11Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO:AAGAAAGCCUAGGUCUC CUAAGAGACCUAGGCUsiRNA-2 UUAG 12 UUCUUCA 13AAGCCUAGGUCUCUUAG UCAUCUAAGAGACCUAsiRNA-3 AUGA 14 GGCUUUC 15AGCCUAGGUCUCUUAGA AUCAUCUAAGAGACCUsiRNA-4 UGAU 16 AGGCUUU 17UACCUGGAGGUGGCCAA GUGCUUGGCCACCUCCsiRNA-5 GCAC 18 AGGUAAU 19ACCUGGAGGUGGCCAAG AGUGCUUGGCCACCUCsiRNA-6 CACU 20 CAGGUAA 21CCUGGAGGUGGCCAAGC AAGUGCUUGGCCACCUsiRNA-7 ACUU 22 CCAGGUA 23UCAAACCUCAUGGGUUC UGGAGAACCCAUGAGGsiRNA-8 UCCA 24 UUUGAAG 25CAAACCUCAUGGGUUCU CUGGAGAACCCAUGAGsiRNA-9 CCAG 26 GUUUGAA 27 siRNA- AAACCUCAUGGGUUCUC GCUGGAGAACCCAUGA10 CAGC 28 GGUUUGA 29 siRNA- CCUCAUGGGUUCUCCAG GUCGCUGGAGAACCCA11 CGAC 30 UGAGGUU 31 siRNA- CUCAUGGGUUCUCCAGC UGUCGCUGGAGAACCC12 GACA 32 AUGAGGU 33 siRNA- UCAUGGGUUCUCCAGCG UUGUCGCUGGAGAACC 13 ACAA 34 CAUGAGG 35 siRNA- CAUGGGUUCUCCAGCGA CUUGUCGCUGGAGAAC 14 CAAG 36 CCAUGAG 37 siRNA- AUGGGUUCUCCAGCGAC CCUUGUCGCUGGAGAA15 AAGG 38 CCCAUGA 39 siRNA- UGGGUUCUCCAGCGACA GCCUUGUCGCUGGAGA16 AGGC 40 ACCCAUG 41 siRNA- GGGUUCUCCAGCGACAA AGCCUUGUCGCUGGAG17 GGCU 42 AACCCAU 43 siRNA- UUCUCCGGGACAGAUUG CAUCCAAUCUGUCCCG18 GAUG 44 GAGAAGG 45 siRNA- UCUCCGGGACAGAUUGG ACAUCCAAUCUGUCCC19 AUGU 46 GGAGAAG 47 siRNA- CUCCGGGACAGAUUGGA AACAUCCAAUCUGUCC20 UGUU 48 CGGAGAA 49 siRNA- CCGGGACAGAUUGGAUG CCAACAUCCAAUCUGU21 UUGG 50 CCCGGAG 51 siRNA- CGGGACAGAUUGGAUGU UCCAACAUCCAAUCUG22 UGGA 52 UCCCGGA 53 siRNA- GGGACAGAUUGGAUGUU CUCCAACAUCCAAUCU23 GGAG 54 GUCCCGG 55 siRNA- GGACAGAUUGGAUGUUG UCUCCAACAUCCAAUC24 GAGA 56 UGUCCCG 57Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- ACAGAUUGGAUGUUGGA UUUCUCCAACAUCCAA25 GAAA 58 UCUGUCC 59 siRNA- UAGAUGACCUGGAAACC GCAUGGUUUCCAGGUC 26 AUGC 60 AUCUAUA 61 siRNA- AGAUGACCUGGAAACCA GGCAUGGUUUCCAGGU 27 UGCC 62 CAUCUAU 63 siRNA- GAUGACCUGGAAACCAU UGGCAUGGUUUCCAGG 28 GCCA 64 UCAUCUA 65 siRNA- AUGACCUGGAAACCAUG CUGGCAUGGUUUCCAG29 CCAG 66 GUCAUCU 67 siRNA- GACCUGGAAACCAUGCC AUCUGGCAUGGUUUCC 30 AGAU 68 AGGUCAU 69 siRNA- CCUGGAAACCAUGCCAG UCAUCUGGCAUGGUUU 31 AUGA 70 CCAGGUC 71 siRNA- CUGGAAACCAUGCCAGA GUCAUCUGGCAUGGUU 32 UGAC 72 UCCAGGU 73 siRNA- ACGGUGAACCCAAUUGG AUGGCCAAUUGGGUUC 33 CCAU 74 ACCGUCU 75 siRNA- GUGAACCCAAUUGGCCA GAGAUGGCCAAUUGGG 34 UCUC 76 UUCACCG 77 siRNA- UGAACCCAAUUGGCCAU GGAGAUGGCCAAUUGG 35 CUCC 78 GUUCACC 79 siRNA- AAUUGGCCAUCUCCCAG CUUUCUGGGAGAUGGC 36 AAAG 80 CAAUUGG 81 siRNA- AUUGGCCAUCUCCCAGA ACUUUCUGGGAGAUGG 37 AAGU 82 CCAAUUG 83 siRNA- GAUCAUUCCUUUAGUUU CUCUAAACUAAAGGAA 38 AGAG 84 UGAUCUG 85 siRNA- AUCAUUCCUUUAGUUUA GCUCUAAACUAAAGGA 39 GAGC 86 AUGAUCU 87 siRNA- UCAUUCCUUUAGUUUAG AGCUCUAAACUAAAGG 40 AGCU 88 AAUGAUC 89 siRNA- CAUUCCUUUAGUUUAGA CAGCUCUAAACUAAAG41 GCUG 90 GAAUGAU 91 siRNA- GAUAGUGGCAUCUGUAU GCUCAUACAGAUGCCA42 GAGC 92 CUAUCAU 93 siRNA- AUAGUGGCAUCUGUAUG GGCUCAUACAGAUGCC43 AGCC 94 ACUAUCA 95 siRNA- UAGUGGCAUCUGUAUGA GGGCUCAUACAGAUGC 44 GCCC 96 CACUAUC 97 siRNA- AGUGGCAUCUGUAUGAG UGGGCUCAUACAGAUG 45 CCCA 98 CCACUAU 99 siRNA- GCCACUAGGUACCGCCA CUUCUGGCGGUACCUA46 GAAG 100 GUGGCUG 101 siRNA- CCACUAGGUACCGCCAG UCUUCUGGCGGUACCU47 AAGA 102 AGUGGCU 103Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- CACUAGGUACCGCCAGA UUCUUCUGGCGGUACC48 AGAA 104 UAGUGGC 105 siRNA- UUCUGACCACGUUGGAU UGUCAUCCAACGUGGU49 GACA 106 CAGAAGG 107 siRNA- UCUGACCACGUUGGAUG GUGUCAUCCAACGUGG50 ACAC 108 UCAGAAG 109 siRNA- CUGACCACGUUGGAUGA AGUGUCAUCCAACGUG51 CACU 110 GUCAGAA 111 siRNA- UGGCCAUCUCCCAGAAA AAACUUUCUGGGAGAU 52 GUUU 112 GGCCAAU 113 siRNA- CAAGACAGCAGCCACUA UACCUAGUGGCUGCUG53 GGUA 114 UCUUGUU 115 siRNA- AAGACAGCAGCCACUAG GUACCUAGUGGCUGCU54 GUAC 116 GUCUUGU 117 siRNA- AGACAGCAGCCACUAGG GGUACCUAGUGGCUGC 55 UACC 118 UGUCUUG 119 siRNA- ACAGCAGCCACUAGGUA GCGGUACCUAGUGGCU56 CCGC 120 GCUGUCU 121 siRNA- AGCCACUAGGUACCGCC UUCUGGCGGUACCUAG57 AGAA 122 UGGCUGC 123 siRNA- UGGAGGUGGCCAAGCAC UGAAGUGCUUGGCCAC 58 UUCA 124 CUCCAGG 125 siRNA- GGAGGUGGCCAAGCACU UUGAAGUGCUUGGCCA 59 UCAA 126 CCUCCAG 127 siRNA- GAGGUGGCCAAGCACUU UUUGAAGUGCUUGGCC 60 CAAA 128 ACCUCCA 129 siRNA- AGGUGGCCAAGCACUUC GUUUGAAGUGCUUGGC 61 AAAC 130 CACCUCC 131 siRNA- GGUGGCCAAGCACUUCA GGUUUGAAGUGCUUGG 62 AACC 132 CCACCUC 133 siRNA- GUGGCCAAGCACUUCAA AGGUUUGAAGUGCUUG 63 ACCU 134 GCCACCU 135 siRNA- GCCAAGCACUUCAAACC AUGAGGUUUGAAGUGC 64 UCAU 136 UUGGCCA 137 siRNA- AGCACUUCAAACCUCAU ACCCAUGAGGUUUGAA 65 GGGU 138 GUGCUUG 139 siRNA- GCACUUCAAACCUCAUG AACCCAUGAGGUUUGA 66 GGUU 140 AGUGCUU 141 siRNA- ACUUCAAACCUCAUGGG AGAACCCAUGAGGUUU 67 UUCU 142 GAAGUGC 143 siRNA- CUUCAAACCUCAUGGGU GAGAACCCAUGAGGUU 68 UCUC 144 UGAAGUG 145 siRNA- CUGUGGAUGGGUUGGUC GACUGACCAACCCAUC69 AGUC 146 CACAGCC 147 siRNA- UCCUCCACUCCAGAUCA GGAAUGAUCUGGAGUG70 UUCC 148 GAGGACA 149Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- CCUCCACUCCAGAUCAU AGGAAUGAUCUGGAGU 71 UCCU 150 GGAGGAC 151 siRNA- CUCCACUCCAGAUCAUU AAGGAAUGAUCUGGAG 72 CCUU 152 UGGAGGA 153 siRNA- UCCACUCCAGAUCAUUC AAAGGAAUGAUCUGGA 73 CUUU 154 GUGGAGG 155 siRNA- CCACUCCAGAUCAUUCC UAAAGGAAUGAUCUGG 74 UUUA 156 AGUGGAG 157 siRNA- CACUCCAGAUCAUUCCU CUAAAGGAAUGAUCUG 75 UUAG 158 GAGUGGA 159 siRNA- ACUCCAGAUCAUUCCUU ACUAAAGGAAUGAUCU 76 UAGU 160 GGAGUGG 161 siRNA- CUCCAGAUCAUUCCUUU AACUAAAGGAAUGAUC 77 AGUU 162 UGGAGUG 163 siRNA- UCCAGAUCAUUCCUUUA AAACUAAAGGAAUGAU 78 GUUU 164 CUGGAGU 165 siRNA- CCAGAUCAUUCCUUUAG UAAACUAAAGGAAUGA 79 UUUA 166 UCUGGAG 167 siRNA- AGAUCAUUCCUUUAGUU UCUAAACUAAAGGAAU 80 UAGA 168 GAUCUGG 169 siRNA- AUUCCUUUAGUUUAGAG CCAGCUCUAAACUAAA81 CUGG 170 GGAAUGA 171 siRNA- UUCCUUUAGUUUAGAGC CCCAGCUCUAAACUAA82 UGGG 172 AGGAAUG 173 siRNA- UCCUUUAGUUUAGAGCU GCCCAGCUCUAAACUA83 GGGC 174 AAGGAAU 175 siRNA- AUGACCGAAAUGAGCUU CAGGAAGCUCAUUUCG84 CCUG 176 GUCAUGU 177 siRNA- UGACCGAAAUGAGCUUC UCAGGAAGCUCAUUUC 85 CUGA 178 GGUCAUG 179 siRNA- CCUGAGCAGCGAGGUGU ACCAACACCUCGCUGC86 UGGU 180 UCAGGAA 181 siRNA- CUGAGCAGCGAGGUGUU CACCAACACCUCGCUG87 GGUG 182 CUCAGGA 183 siRNA- UGAGCAGCGAGGUGUUG CCACCAACACCUCGCU88 GUGG 184 GCUCAGG 185 siRNA- GAUUACCUGGAGGUGGC CUUGGCCACCUCCAGG89 CAAG 186 UAAUCAU 187 siRNA- AUUACCUGGAGGUGGCC GCUUGGCCACCUCCAG90 AAGC 188 GUAAUCA 189 siRNA- UUACCUGGAGGUGGCCA UGCUUGGCCACCUCCA91 AGCA 190 GGUAAUC 191 siRNA- GGUUCUCCAGCGACAAG UAGCCUUGUCGCUGGA92 GCUA 192 GAACCCA 193 siRNA- GUUCUCCAGCGACAAGG UUAGCCUUGUCGCUGG93 CUAA 194 AGAACCC 195Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- UUCUCCAGCGACAAGGC CUUAGCCUUGUCGCUG94 UAAG 196 GAGAACC 197 siRNA- CUCCAGCGACAAGGCUA GCCUUAGCCUUGUCGC95 AGGC 198 UGGAGAA 199 siRNA- UCCAGCGACAAGGCUAA CGCCUUAGCCUUGUCG96 GGCG 200 CUGGAGA 201 siRNA- CCAGCGACAAGGCUAAG CCGCCUUAGCCUUGUC97 GCGG 202 GCUGGAG 203 siRNA- AAGGCGGGCUCCUCCGA CCAUUCGGAGGAGCCC98 AUGG 204 GCCUUAG 205 siRNA- AGGCGGGCUCCUCCGAA GCCAUUCGGAGGAGCC99 UGGC 206 CGCCUUA 207 siRNA- GGCGGGCUCCUCCGAAU AGCCAUUCGGAGGAGC 100 GGCU 208 CCGCCUU 209 siRNA- GCGGGCUCCUCCGAAUG CAGCCAUUCGGAGGAG 101 GCUG 210 CCCGCCU 211 siRNA- GGGCUCCUCCGAAUGGC GCCAGCCAUUCGGAGG102 UGGC 212 AGCCCGC 213 siRNA- GCUCCUCCGAAUGGCUG CAGCCAGCCAUUCGGA103 GCUG 214 GGAGCCC 215 siRNA- CUCCUCCGAAUGGCUGG ACAGCCAGCCAUUCGG104 CUGU 216 AGGAGCC 217 siRNA- UCCUCCGAAUGGCUGGC CACAGCCAGCCAUUCG105 UGUG 218 GAGGAGC 219 siRNA- CUGGCUGUGGAUGGGUU GACCAACCCAUCCACA106 GGUC 220 GCCAGCC 221 siRNA- UGGCUGUGGAUGGGUUG UGACCAACCCAUCCAC107 GUCA 222 AGCCAGC 223 siRNA- GGCUGUGGAUGGGUUGG CUGACCAACCCAUCCA108 UCAG 224 CAGCCAG 225 siRNA- GCUGUGGAUGGGUUGGU ACUGACCAACCCAUCC109 CAGU 226 ACAGCCA 227 siRNA- UGUGGAUGGGUUGGUCA GGACUGACCAACCCAU110 GUCC 228 CCACAGC 229 siRNA- GUGGAUGGGUUGGUCAG GGGACUGACCAACCCA 111 UCCC 230 UCCACAG 231 siRNA- UGGAUGGGUUGGUCAGU AGGGACUGACCAACCC112 CCCU 232 AUCCACA 233 siRNA- GUUGGUCAGUCCCUCCA UUGUUGGAGGGACUGA 113 ACAA 234 CCAACCC 235 siRNA- UGGUCAGUCCCUCCAAC UGUUGUUGGAGGGACU 114 AACA 236 GACCAAC 237 siRNA- GCAAGGAGGAUGCCUUC CGGAGAAGGCAUCCUC 115 UCCG 238 CUUGCUG 239 siRNA- CAAGGAGGAUGCCUUCU CCGGAGAAGGCAUCCU116 CCGG 240 CCUUGCU 241Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- AAGGAGGAUGCCUUCUC CCCGGAGAAGGCAUCC117 CGGG 242 UCCUUGC 243 siRNA- AGGAGGAUGCCUUCUCC UCCCGGAGAAGGCAUC 118 GGGA 244 CUCCUUG 245 siRNA- AGGAUGCCUUCUCCGGG CUGUCCCGGAGAAGGC 119 ACAG 246 AUCCUCC 247 siRNA- GGAUGCCUUCUCCGGGA UCUGUCCCGGAGAAGG 120 CAGA 248 CAUCCUC 249 siRNA- AUGCCUUCUCCGGGACA AAUCUGUCCCGGAGAA 121 GAUU 250 GGCAUCC 251 siRNA- UGCCUUCUCCGGGACAG CAAUCUGUCCCGGAGA122 AUUG 252 AGGCAUC 253 siRNA- GCCUUCUCCGGGACAGA CCAAUCUGUCCCGGAG123 UUGG 254 AAGGCAU 255 siRNA- CCUUCUCCGGGACAGAU UCCAAUCUGUCCCGGA124 UGGA 256 GAAGGCA 257 siRNA- CUUCUCCGGGACAGAUU AUCCAAUCUGUCCCGG125 GGAU 258 AGAAGGC 259 siRNA- UGGAUUUGAAGGAGUUC AGUCGAACUCCUUCAA126 GACU 260 AUCCAUU 261 siRNA- GGAUUUGAAGGAGUUCG AAGUCGAACUCCUUCA127 ACUU 262 AAUCCAU 263 siRNA- GAUUUGAAGGAGUUCGA CAAGUCGAACUCCUUC 128 CUUG 264 AAAUCCA 265 siRNA- UUGGAUGCCCUGUUGGG UAUACCCAACAGGGCA129 UAUA 266 UCCAAGU 267 siRNA- UGGAUGCCCUGUUGGGU CUAUACCCAACAGGGC130 AUAG 268 AUCCAAG 269 siRNA- GGAUGCCCUGUUGGGUA UCUAUACCCAACAGGG 131 UAGA 270 CAUCCAA 271 siRNA- GAUGCCCUGUUGGGUAU AUCUAUACCCAACAGG132 AGAU 272 GCAUCCA 273 siRNA- UGCCCUGUUGGGUAUAG UCAUCUAUACCCAACA133 AUGA 274 GGGCAUC 275 siRNA- GCCCUGUUGGGUAUAGA GUCAUCUAUACCCAAC134 UGAC 276 AGGGCAU 277 siRNA- CCCUGUUGGGUAUAGAU GGUCAUCUAUACCCAA135 GACC 278 CAGGGCA 279 siRNA- CCUGUUGGGUAUAGAUG AGGUCAUCUAUACCCA136 ACCU 280 ACAGGGC 281 siRNA- CUGUUGGGUAUAGAUGA CAGGUCAUCUAUACCC137 CCUG 282 AACAGGG 283 siRNA- UGUUGGGUAUAGAUGAC CCAGGUCAUCUAUACC 138 CUGG 284 CAACAGG 285 siRNA- GUUGGGUAUAGAUGACC UCCAGGUCAUCUAUAC139 UGGA 286 CCAACAG 287Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- UUGGGUAUAGAUGACCU UUCCAGGUCAUCUAUA 140 GGAA 288 CCCAACA 289 siRNA- UGGGUAUAGAUGACCUG UUUCCAGGUCAUCUAU 141 GAAA 290 ACCCAAC 291 siRNA- GGGUAUAGAUGACCUGG GUUUCCAGGUCAUCUA 142 AAAC 292 UACCCAA 293 siRNA- GGUAUAGAUGACCUGGA GGUUUCCAGGUCAUCU 143 AACC 294 AUACCCA 295 siRNA- GUAUAGAUGACCUGGAA UGGUUUCCAGGUCAUC 144 ACCA 296 UAUACCC 297 siRNA- UAUAGAUGACCUGGAAA AUGGUUUCCAGGUCAU 145 CCAU 298 CUAUACC 299 siRNA- UGGAAACCAUGCCAGAU GGUCAUCUGGCAUGGU 146 GACC 300 UUCCAGG 301 siRNA- GGAAACCAUGCCAGAUG AGGUCAUCUGGCAUGG 147 ACCU 302 UUUCCAG 303 siRNA- GAAACCAUGCCAGAUGA AAGGUCAUCUGGCAUG 148 CCUU 304 GUUUCCA 305 siRNA- AAACCAUGCCAGAUGAC GAAGGUCAUCUGGCAU 149 CUUC 306 GGUUUCC 307 siRNA- AGACGGUGAACCCAAUU GGCCAAUUGGGUUCAC 150 GGCC 308 CGUCUGG 309 siRNA- GACGGUGAACCCAAUUG UGGCCAAUUGGGUUCA 151 GCCA 310 CCGUCUG 311 siRNA- UUUAACAAAACCCGACC ACCUGGUCGGGUUUUG 152 AGGU 312 UUAAACU 313 siRNA- UUAACAAAACCCGACCA AACCUGGUCGGGUUUU 153 GGUU 314 GUUAAAC 315 siRNA- GGGUCCUGUCCUCCACU CUGGAGUGGAGGACAG 154 CCAG 316 GACCCCU 317 siRNA- CUGUCCUCCACUCCAGA AUGAUCUGGAGUGGAG 155 UCAU 318 GACAGGA 319 siRNA- UGUCCUCCACUCCAGAU AAUGAUCUGGAGUGGA 156 CAUU 320 GGACAGG 321 siRNA- GUCCUCCACUCCAGAUC GAAUGAUCUGGAGUGG 157 AUUC 322 AGGACAG 323 siRNA- CCUUUAGUUUAGAGCUG UGCCCAGCUCUAAACU158 GGCA 324 AAAGGAA 325 siRNA- CUUUAGUUUAGAGCUGG CUGCCCAGCUCUAAAC159 GCAG 326 UAAAGGA 327 siRNA- UUUAGUUUAGAGCUGGG ACUGCCCAGCUCUAAA160 CAGU 328 CUAAAGG 329 siRNA- UUAGUUUAGAGCUGGGC CACUGCCCAGCUCUAA161 AGUG 330 ACUAAAG 331 siRNA- UAGUUUAGAGCUGGGCA UCACUGCCCAGCUCUA162 GUGA 332 AACUAAA 333Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- AGUUUAGAGCUGGGCAG UUCACUGCCCAGCUCU163 UGAA 334 AAACUAA 335 siRNA- GUUUAGAGCUGGGCAGU CUUCACUGCCCAGCUC164 GAAG 336 UAAACUA 337 siRNA- UUUAGAGCUGGGCAGUG ACUUCACUGCCCAGCU165 AAGU 338 CUAAACU 339 siRNA- UUAGAGCUGGGCAGUGA CACUUCACUGCCCAGC166 AGUG 340 UCUAAAC 341 siRNA- UAGAGCUGGGCAGUGAA CCACUUCACUGCCCAG167 GUGG 342 CUCUAAA 343 siRNA- AGAGCUGGGCAGUGAAG UCCACUUCACUGCCCA168 UGGA 344 GCUCUAA 345 siRNA- GAGCUGGGCAGUGAAGU AUCCACUUCACUGCCC169 GGAU 346 AGCUCUA 347 siRNA- AGCUGGGCAGUGAAGUG UAUCCACUUCACUGCC170 GAUA 348 CAGCUCU 349 siRNA- GCUGGGCAGUGAAGUGG AUAUCCACUUCACUGC 171 AUAU 350 CCAGCUC 351 siRNA- CUGGGCAGUGAAGUGGA GAUAUCCACUUCACUG172 UAUC 352 CCCAGCU 353 siRNA- UGGGCAGUGAAGUGGAU UGAUAUCCACUUCACU173 AUCA 354 GCCCAGC 355 siRNA- GGCAGUGAAGUGGAUAU AGUGAUAUCCACUUCA 174 CACU 356 CUGCCCA 357 siRNA- GCAGUGAAGUGGAUAUC CAGUGAUAUCCACUUC 175 ACUG 358 ACUGCCC 359 siRNA- CAGUGAAGUGGAUAUCA UCAGUGAUAUCCACUU 176 CUGA 360 CACUGCC 361 siRNA- AGUGAAGUGGAUAUCAC UUCAGUGAUAUCCACU 177 UGAA 362 UCACUGC 363 siRNA- GUGAAGUGGAUAUCACU CUUCAGUGAUAUCCAC 178 GAAG 364 UUCACUG 365 siRNA- UGAAGUGGAUAUCACUG CCUUCAGUGAUAUCCA179 AAGG 366 CUUCACU 367 siRNA- GAAGUGGAUAUCACUGA UCCUUCAGUGAUAUCC 180 AGGA 368 ACUUCAC 369 siRNA- AAGUGGAUAUCACUGAA CUCCUUCAGUGAUAUC 181 GGAG 370 CACUUCA 371 siRNA- AGUGGAUAUCACUGAAG UCUCCUUCAGUGAUAU 182 GAGA 372 CCACUUC 373 siRNA- GUGGAUAUCACUGAAGG AUCUCCUUCAGUGAUA 183 AGAU 374 UCCACUU 375 siRNA- UUCAGAUAAUGAUAGUG AUGCCACUAUCAUUAU 184 GCAU 376 CUGAAGG 377 siRNA- UCAGAUAAUGAUAGUGG GAUGCCACUAUCAUUA185 CAUC 378 UCUGAAG 379Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- CAGAUAAUGAUAGUGGC AGAUGCCACUAUCAUU 186 AUCU 380 AUCUGAA 381 siRNA- AGAUAAUGAUAGUGGCA CAGAUGCCACUAUCAU187 UCUG 382 UAUCUGA 383 siRNA- GAUAAUGAUAGUGGCAU ACAGAUGCCACUAUCA 188 CUGU 384 UUAUCUG 385 siRNA- UAAUGAUAGUGGCAUCU AUACAGAUGCCACUAU 189 GUAU 386 CAUUAUC 387 siRNA- AAUGAUAGUGGCAUCUG CAUACAGAUGCCACUA190 UAUG 388 UCAUUAU 389 siRNA- AUGAUAGUGGCAUCUGU UCAUACAGAUGCCACU 191 AUGA 390 AUCAUUA 391 siRNA- AAAAGUAAAGGGUGAGA AGUUUCUCACCCUUUA192 AACU 392 CUUUUGC 393 siRNA- AAAGUAAAGGGUGAGAA CAGUUUCUCACCCUUU193 ACUG 394 ACUUUUG 395 siRNA- AAGUAAAGGGUGAGAAA CCAGUUUCUCACCCUU194 CUGG 396 UACUUUU 397 siRNA- AGUAAAGGGUGAGAAAC UCCAGUUUCUCACCCU195 UGGA 398 UUACUUU 399 siRNA- GAGAAACUGGAUAAGAA CAGCUUCUUAUCCAGU196 GCUG 400 UUCUCAC 401 siRNA- AGAAACUGGAUAAGAAG UCAGCUUCUUAUCCAG197 CUGA 402 UUUCUCA 403 siRNA- GAAACUGGAUAAGAAGC UUCAGCUUCUUAUCCA 198 UGAA 404 GUUUCUC 405 siRNA- AAACUGGAUAAGAAGCU UUUCAGCUUCUUAUCC 199 GAAA 406 AGUUUCU 407 siRNA- UGGCCAAGGAGAUCCAG GGUACUGGAUCUCCUU 200 UACC 408 GGCCAGG 409 siRNA- CCAAGGAGAUCCAGUAC UCAGGUACUGGAUCUC 201 CUGA 410 CUUGGCC 411 siRNA- CAAGGAGAUCCAGUACC UUCAGGUACUGGAUCU 202 UGAA 412 CCUUGGC 413 siRNA- AAGGAGAUCCAGUACCU UUUCAGGUACUGGAUC 203 GAAA 414 UCCUUGG 415 siRNA- AGGAGAUCCAGUACCUG CUUUCAGGUACUGGAU 204 AAAG 416 CUCCUUG 417 siRNA- GGAGAUCCAGUACCUGA UCUUUCAGGUACUGGA 205 AAGA 418 UCUCCUU 419 siRNA- GAGAUCCAGUACCUGAA AUCUUUCAGGUACUGG 206 AGAU 420 AUCUCCU 421 siRNA- AGAUCCAGUACCUGAAA AAUCUUUCAGGUACUG 207 GAUU 422 GAUCUCC 423 siRNA- GAUCCAGUACCUGAAAG AAAUCUUUCAGGUACU208 AUUU 424 GGAUCUC 425Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO: siRNA- AUCCAGUACCUGAAAGA CAAAUCUUUCAGGUAC209 UUUG 426 UGGAUCU 427 siRNA- CCAGUACCUGAAAGAUU AUCAAAUCUUUCAGGU210 UGAU 428 ACUGGAU 429 siRNA- CAGUACCUGAAAGAUUU UAUCAAAUCUUUCAGG211 GAUA 430 UACUGGA 431 siRNA- AGUACCUGAAAGAUUUG CUAUCAAAUCUUUCAG212 AUAG 432 GUACUGG 433 siRNA- GUACCUGAAAGAUUUGA UCUAUCAAAUCUUUCA213 UAGA 434 GGUACUG 435 siRNA- UACCUGAAAGAUUUGAU UUCUAUCAAAUCUUUC214 AGAA 436 AGGUACU 437 siRNA- ACCUGAAAGAUUUGAUA CUUCUAUCAAAUCUUU215 GAAG 438 CAGGUAC 439 siRNA- GAUAGAAGAGGUCCGCA GCCUUGCGGACCUCUU216 AGGC 440 CUAUCAA 441 siRNA- AUAGAAGAGGUCCGCAA UGCCUUGCGGACCUCU217 GGCA 442 UCUAUCA 443 siRNA- UAGAAGAGGUCCGCAAG UUGCCUUGCGGACCUC218 GCAA 444 UUCUAUC 445 siRNA- AGAAGAGGUCCGCAAGG CUUGCCUUGCGGACCU219 CAAG 446 CUUCUAU 447 siRNA- GAAGAGGUCCGCAAGGC CCUUGCCUUGCGGACC220 AAGG 448 UCUUCUA 449 siRNA- AAGAGGUCCGCAAGGCA CCCUUGCCUUGCGGAC221 AGGG 450 CUCUUCU 451 siRNA- CAAUGUGCUUGUACAUA ACUCUAUGUACAAGCA222 GAGU 452 CAUUGAC 453 siRNA- AAUGUGCUUGUACAUAG CACUCUAUGUACAAGC223 AGUG 454 ACAUUGA 455 siRNA- CAACAUGACCGAAAUGA 1447 AAGCUCAUUUCGGUCA 1116 GCUU 0 UGUUGCG 14471 siRNA- CAGACGGUGAACCCAAU 1447 GCCAAUUGGGUUCACC1117 UGGC 2 GUCUGGG 14473 siRNA- GAAAGUUUAACAAAACC 1447 GUCGGGUUUUGUUAAA 1118 CGAC 4 CUUUCUG 14475 siRNA- GAUUUGAUAGAAGAGGU 1447 GCGGACCUCUUCUAUC1119 CCGC 6 AAAUCUU 14477 siRNA- AUUUGAUAGAAGAGGUC 1447 UGCGGACCUCUUCUAU1120 CGCA 8 CAAAUCU 14479Table 2. Modified siRNA Sequences With 3’ A on Sense Strand and 5’U on Antisense StrandAttorney Docket Number: J0365.70001WO00SEQ ID SEQ IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- GAAGAAAGCCUAGG UAAGAGACCUAGGCUU224 UCUCUUA 456 UCUUCAG 457 siRNA- AAGAAAGCCUAGGU UUAAGAGACCUAGGCU225 CUCUUAA 458 UUCUUCA 459 siRNA- AAGCCUAGGUCUCU UCAUCUAAGAGACCUA226 UAGAUGA 460 GGCUUUC 461 siRNA- AGCCUAGGUCUCUU UUCAUCUAAGAGACCU227 AGAUGAA 462 AGGCUUU 463 siRNA- UACCUGGAGGUGGC UUGCUUGGCCACCUCC228 CAAGCAA 464 AGGUAAU 465 siRNA- ACCUGGAGGUGGCC UGUGCUUGGCCACCUC229 AAGCACA 466 CAGGUAA 467 siRNA- CCUGGAGGUGGCCA UAGUGCUUGGCCACCU230 AGCACUA 468 CCAGGUA 469 siRNA- UCAAACCUCAUGGG UGGAGAACCCAUGAGG231 UUCUCCA 470 UUUGAAG 471 siRNA- CAAACCUCAUGGGU UUGGAGAACCCAUGAG232 UCUCCAA 472 GUUUGAA 473 siRNA- AAACCUCAUGGGUU UCUGGAGAACCCAUGA233 CUCCAGA 474 GGUUUGA 475 siRNA- CCUCAUGGGUUCUC UUCGCUGGAGAACCCA234 CAGCGAA 476 UGAGGUU 477 siRNA- CUCAUGGGUUCUCC UGUCGCUGGAGAACCC235 AGCGACA 478 AUGAGGU 479 siRNA- UCAUGGGUUCUCCA UUGUCGCUGGAGAACC236 GCGACAA 480 CAUGAGG 481 siRNA- CAUGGGUUCUCCAG UUUGUCGCUGGAGAAC237 CGACAAA 482 CCAUGAG 483 siRNA- AUGGGUUCUCCAGC UCUUGUCGCUGGAGAA238 GACAAGA 484 CCCAUGA 485 siRNA- UGGGUUCUCCAGCG UCCUUGUCGCUGGAGA239 ACAAGGA 486 ACCCAUG 487 siRNA- GGGUUCUCCAGCGA UGCCUUGUCGCUGGAG240 CAAGGCA 488 AACCCAU 489 siRNA- UUCUCCGGGACAGA UAUCCAAUCUGUCCCG241 UUGGAUA 490 GAGAAGG 491 siRNA- UCUCCGGGACAGAU UCAUCCAAUCUGUCCC242 UGGAUGA 492 GGAGAAG 493 siRNA- CUCCGGGACAGAUU UACAUCCAAUCUGUCC243 GGAUGUA 494 CGGAGAA 495 siRNA- CCGGGACAGAUUGG UCAACAUCCAAUCUGU244 AUGUUGA 496 CCCGGAG 497 siRNA- CGGGACAGAUUGGA UCCAACAUCCAAUCUG245 UGUUGGA 498 UCCCGGA 499 siRNA- GGGACAGAUUGGAU UUCCAACAUCCAAUCU246 GUUGGAA 500 GUCCCGG 501Attorney Docket Number: J0365.70001WO00SEQ ID SEQ IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- GGACAGAUUGGAUG UCUCCAACAUCCAAUC247 UUGGAGA 502 UGUCCCG 503 siRNA- ACAGAUUGGAUGUU UUUCUCCAACAUCCAA248 GGAGAAA 504 UCUGUCC 505 siRNA- UAGAUGACCUGGAA UCAUGGUUUCCAGGUC249 ACCAUGA 506 AUCUAUA 507 siRNA- AGAUGACCUGGAAA UGCAUGGUUUCCAGGU250 CCAUGCA 508 CAUCUAU 509 siRNA- GAUGACCUGGAAAC UGGCAUGGUUUCCAGG251 CAUGCCA 510 UCAUCUA 511 siRNA- AUGACCUGGAAACC UUGGCAUGGUUUCCAG252 AUGCCAA 512 GUCAUCU 513 siRNA- GACCUGGAAACCAU UUCUGGCAUGGUUUCC253 GCCAGAA 514 AGGUCAU 515 siRNA- CCUGGAAACCAUGC UCAUCUGGCAUGGUUU254 CAGAUGA 516 CCAGGUC 517 siRNA- CUGGAAACCAUGCC UUCAUCUGGCAUGGUU255 AGAUGAA 518 UCCAGGU 519 siRNA- ACGGUGAACCCAAU UUGGCCAAUUGGGUUC256 UGGCCAA 520 ACCGUCU 521 siRNA- GUGAACCCAAUUGG UAGAUGGCCAAUUGGG257 CCAUCUA 522 UUCACCG 523 siRNA- UGAACCCAAUUGGC UGAGAUGGCCAAUUGG258 CAUCUCA 524 GUUCACC 525 siRNA- AAUUGGCCAUCUCC UUUUCUGGGAGAUGGC259 CAGAAAA 526 CAAUUGG 527 siRNA- AUUGGCCAUCUCCC UCUUUCUGGGAGAUGG260 AGAAAGA 528 CCAAUUG 529 siRNA- GAUCAUUCCUUUAG UUCUAAACUAAAGGAA261 UUUAGAA 530 UGAUCUG 531 siRNA- AUCAUUCCUUUAGU UCUCUAAACUAAAGGA262 UUAGAGA 532 AUGAUCU 533 siRNA- UCAUUCCUUUAGUU UGCUCUAAACUAAAGG263 UAGAGCA 534 AAUGAUC 535 siRNA- CAUUCCUUUAGUUU UAGCUCUAAACUAAAG264 AGAGCUA 536 GAAUGAU 537 siRNA- GAUAGUGGCAUCUG UCUCAUACAGAUGCCA265 UAUGAGA 538 CUAUCAU 539 siRNA- AUAGUGGCAUCUGU UGCUCAUACAGAUGCC266 AUGAGCA 540 ACUAUCA 541 siRNA- UAGUGGCAUCUGUA UGGCUCAUACAGAUGC267 UGAGCCA 542 CACUAUC 543 siRNA- AGUGGCAUCUGUAU UGGGCUCAUACAGAUG268 GAGCCCA 544 CCACUAU 545 siRNA- GCCACUAGGUACCG UUUCUGGCGGUACCUA269 CCAGAAA 546 GUGGCUG 547Attorney Docket Number: J0365.70001WO00SEQ ID SEQ IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- CCACUAGGUACCGCC UCUUCUGGCGGUACCU270 AGAAGA 548 AGUGGCU 549 siRNA- CACUAGGUACCGCC UUCUUCUGGCGGUACC271 AGAAGAA 550 UAGUGGC 551 siRNA- UUCUGACCACGUUG UGUCAUCCAACGUGGU272 GAUGACA 552 CAGAAGG 553 siRNA- UCUGACCACGUUGG UUGUCAUCCAACGUGG273 AUGACAA 554 UCAGAAG 555 siRNA- CUGACCACGUUGGA UGUGUCAUCCAACGUG274 UGACACA 556 GUCAGAA 557 siRNA- UGGCCAUCUCCCAG UAACUUUCUGGGAGAU275 AAAGUUA 558 GGCCAAU 559 siRNA- CAAGACAGCAGCCA UACCUAGUGGCUGCUG276 CUAGGUA 560 UCUUGUU 561 siRNA- AAGACAGCAGCCAC UUACCUAGUGGCUGCU277 UAGGUAA 562 GUCUUGU 563 siRNA- AGACAGCAGCCACU UGUACCUAGUGGCUGC278 AGGUACA 564 UGUCUUG 565 siRNA- ACAGCAGCCACUAG UCGGUACCUAGUGGCU279 GUACCGA 566 GCUGUCU 567 siRNA- AGCCACUAGGUACC UUCUGGCGGUACCUAG280 GCCAGAA 568 UGGCUGC 569 siRNA- UGGAGGUGGCCAAG UGAAGUGCUUGGCCAC281 CACUUCA 570 CUCCAGG 571 siRNA- GGAGGUGGCCAAGC UUGAAGUGCUUGGCCA282 ACUUCAA 572 CCUCCAG 573 siRNA- GAGGUGGCCAAGCA UUUGAAGUGCUUGGCC283 CUUCAAA 574 ACCUCCA 575 siRNA- AGGUGGCCAAGCAC UUUUGAAGUGCUUGGC284 UUCAAAA 576 CACCUCC 577 siRNA- GGUGGCCAAGCACU UGUUUGAAGUGCUUG285 UCAAACA 578 GCCACCUC 579 siRNA- GUGGCCAAGCACUU UGGUUUGAAGUGCUU286 CAAACCA 580 GGCCACCU 581 siRNA- GCCAAGCACUUCAA UUGAGGUUUGAAGUG287 ACCUCAA 582 CUUGGCCA 583 siRNA- AGCACUUCAAACCU UCCCAUGAGGUUUGAA288 CAUGGGA 584 GUGCUUG 585 siRNA- GCACUUCAAACCUC UACCCAUGAGGUUUGA289 AUGGGUA 586 AGUGCUU 587 siRNA- ACUUCAAACCUCAU UGAACCCAUGAGGUUU290 GGGUUCA 588 GAAGUGC 589 siRNA- CUUCAAACCUCAUG UAGAACCCAUGAGGUU291 GGUUCUA 590 UGAAGUG 591 siRNA- CUGUGGAUGGGUUG UACUGACCAACCCAUC292 GUCAGUA 592 CACAGCC 593Attorney Docket Number: J0365.70001WO00SEQ ID SEQ IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- UCCUCCACUCCAGAU UGAAUGAUCUGGAGU293 CAUUCA 594 GGAGGACA 595 siRNA- CCUCCACUCCAGAUC UGGAAUGAUCUGGAG294 AUUCCA 596 UGGAGGAC 597 siRNA- CUCCACUCCAGAUCA UAGGAAUGAUCUGGA295 UUCCUA 598 GUGGAGGA 599 siRNA- UCCACUCCAGAUCA UAAGGAAUGAUCUGG296 UUCCUUA 600 AGUGGAGG 601 siRNA- CCACUCCAGAUCAU UAAAGGAAUGAUCUG297 UCCUUUA 602 GAGUGGAG 603 siRNA- CACUCCAGAUCAUU UUAAAGGAAUGAUCU298 CCUUUAA 604 GGAGUGGA 605 siRNA- ACUCCAGAUCAUUC UCUAAAGGAAUGAUCU299 CUUUAGA 606 GGAGUGG 607 siRNA- CUCCAGAUCAUUCC UACUAAAGGAAUGAUC300 UUUAGUA 608 UGGAGUG 609 siRNA- UCCAGAUCAUUCCU UAACUAAAGGAAUGA301 UUAGUUA 610 UCUGGAGU 611 siRNA- CCAGAUCAUUCCUU UAAACUAAAGGAAUG302 UAGUUUA 612 AUCUGGAG 613 siRNA- AGAUCAUUCCUUUA UCUAAACUAAAGGAAU303 GUUUAGA 614 GAUCUGG 615 siRNA- AUUCCUUUAGUUUA UCAGCUCUAAACUAAA304 GAGCUGA 616 GGAAUGA 617 siRNA- UUCCUUUAGUUUAG UCCAGCUCUAAACUAA305 AGCUGGA 618 AGGAAUG 619 siRNA- UCCUUUAGUUUAGA UCCCAGCUCUAAACUA306 GCUGGGA 620 AAGGAAU 621 siRNA- AUGACCGAAAUGAG UAGGAAGCUCAUUUCG307 CUUCCUA 622 GUCAUGU 623 siRNA- UGACCGAAAUGAGC UCAGGAAGCUCAUUUC308 UUCCUGA 624 GGUCAUG 625 siRNA- CCUGAGCAGCGAGG UCCAACACCUCGCUGC309 UGUUGGA 626 UCAGGAA 627 siRNA- CUGAGCAGCGAGGU UACCAACACCUCGCUG310 GUUGGUA 628 CUCAGGA 629 siRNA- UGAGCAGCGAGGUG UCACCAACACCUCGCU311 UUGGUGA 630 GCUCAGG 631 siRNA- GAUUACCUGGAGGU UUUGGCCACCUCCAGG312 GGCCAAA 632 UAAUCAU 633 siRNA- AUUACCUGGAGGUG UCUUGGCCACCUCCAG313 GCCAAGA 634 GUAAUCA 635 siRNA- UUACCUGGAGGUGG UGCUUGGCCACCUCCA314 CCAAGCA 636 GGUAAUC 637 siRNA- GGUUCUCCAGCGAC UAGCCUUGUCGCUGGA315 AAGGCUA 638 GAACCCA 639Attorney Docket Number: J0365.70001WO00SEQ ID SEQ IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- GUUCUCCAGCGACA UUAGCCUUGUCGCUGG316 AGGCUAA 640 AGAACCC 641 siRNA- UUCUCCAGCGACAA UUUAGCCUUGUCGCUG317 GGCUAAA 642 GAGAACC 643 siRNA- CUCCAGCGACAAGG UCCUUAGCCUUGUCGC318 CUAAGGA 644 UGGAGAA 645 siRNA- UCCAGCGACAAGGC UGCCUUAGCCUUGUCG319 UAAGGCA 646 CUGGAGA 647 siRNA- CCAGCGACAAGGCU UCGCCUUAGCCUUGUC320 AAGGCGA 648 GCUGGAG 649 siRNA- AAGGCGGGCUCCUC UCAUUCGGAGGAGCCC321 CGAAUGA 650 GCCUUAG 651 siRNA- AGGCGGGCUCCUCC UCCAUUCGGAGGAGCC322 GAAUGGA 652 CGCCUUA 653 siRNA- GGCGGGCUCCUCCG UGCCAUUCGGAGGAGC323 AAUGGCA 654 CCGCCUU 655 siRNA- GCGGGCUCCUCCGA UAGCCAUUCGGAGGAG324 AUGGCUA 656 CCCGCCU 657 siRNA- GGGCUCCUCCGAAU UCCAGCCAUUCGGAGG325 GGCUGGA 658 AGCCCGC 659 siRNA- GCUCCUCCGAAUGG UAGCCAGCCAUUCGGA326 CUGGCUA 660 GGAGCCC 661 siRNA- CUCCUCCGAAUGGC UCAGCCAGCCAUUCGG327 UGGCUGA 662 AGGAGCC 663 siRNA- UCCUCCGAAUGGCU UACAGCCAGCCAUUCG328 GGCUGUA 664 GAGGAGC 665 siRNA- CUGGCUGUGGAUGG UACCAACCCAUCCACA329 GUUGGUA 666 GCCAGCC 667 siRNA- UGGCUGUGGAUGGG UGACCAACCCAUCCAC330 UUGGUCA 668 AGCCAGC 669 siRNA- GGCUGUGGAUGGGU UUGACCAACCCAUCCA331 UGGUCAA 670 CAGCCAG 671 siRNA- GCUGUGGAUGGGUU UCUGACCAACCCAUCC332 GGUCAGA 672 ACAGCCA 673 siRNA- UGUGGAUGGGUUGG UGACUGACCAACCCAU333 UCAGUCA 674 CCACAGC 675 siRNA- GUGGAUGGGUUGGU UGGACUGACCAACCCA334 CAGUCCA 676 UCCACAG 677 siRNA- UGGAUGGGUUGGUC UGGGACUGACCAACCC335 AGUCCCA 678 AUCCACA 679 siRNA- GUUGGUCAGUCCCU UUGUUGGAGGGACUG336 CCAACAA 680 ACCAACCC 681 siRNA- UGGUCAGUCCCUCC UGUUGUUGGAGGGAC337 AACAACA 682 UGACCAAC 683 siRNA- GCAAGGAGGAUGCC UGGAGAAGGCAUCCUC338 UUCUCCA 684 CUUGCUG 685Attorney Docket Number: J0365.70001WO00SEQ ID SEQ IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- CAAGGAGGAUGCCU UCGGAGAAGGCAUCCU339 UCUCCGA 686 CCUUGCU 687 siRNA- AAGGAGGAUGCCUU UCCGGAGAAGGCAUCC340 CUCCGGA 688 UCCUUGC 689 siRNA- AGGAGGAUGCCUUC UCCCGGAGAAGGCAUC341 UCCGGGA 690 CUCCUUG 691 siRNA- AGGAUGCCUUCUCC UUGUCCCGGAGAAGGC342 GGGACAA 692 AUCCUCC 693 siRNA- GGAUGCCUUCUCCG UCUGUCCCGGAGAAGG343 GGACAGA 694 CAUCCUC 695 siRNA- AUGCCUUCUCCGGG UAUCUGUCCCGGAGAA344 ACAGAUA 696 GGCAUCC 697 siRNA- UGCCUUCUCCGGGA UAAUCUGUCCCGGAGA345 CAGAUUA 698 AGGCAUC 699 siRNA- GCCUUCUCCGGGAC UCAAUCUGUCCCGGAG346 AGAUUGA 700 AAGGCAU 701 siRNA- CCUUCUCCGGGACA UCCAAUCUGUCCCGGA347 GAUUGGA 702 GAAGGCA 703 siRNA- CUUCUCCGGGACAG UUCCAAUCUGUCCCGG348 AUUGGAA 704 AGAAGGC 705 siRNA- UGGAUUUGAAGGAG UGUCGAACUCCUUCAA349 UUCGACA 706 AUCCAUU 707 siRNA- GGAUUUGAAGGAGU UAGUCGAACUCCUUCA350 UCGACUA 708 AAUCCAU 709 siRNA- GAUUUGAAGGAGUU UAAGUCGAACUCCUUC351 CGACUUA 710 AAAUCCA 711 siRNA- UUGGAUGCCCUGUU UAUACCCAACAGGGCA352 GGGUAUA 712 UCCAAGU 713 siRNA- UGGAUGCCCUGUUG UUAUACCCAACAGGGC353 GGUAUAA 714 AUCCAAG 715 siRNA- GGAUGCCCUGUUGG UCUAUACCCAACAGGG354 GUAUAGA 716 CAUCCAA 717 siRNA- GAUGCCCUGUUGGG UUCUAUACCCAACAGG355 UAUAGAA 718 GCAUCCA 719 siRNA- UGCCCUGUUGGGUA UCAUCUAUACCCAACA356 UAGAUGA 720 GGGCAUC 721 siRNA- GCCCUGUUGGGUAU UUCAUCUAUACCCAAC357 AGAUGAA 722 AGGGCAU 723 siRNA- CCCUGUUGGGUAUA UGUCAUCUAUACCCAA358 GAUGACA 724 CAGGGCA 725 siRNA- CCUGUUGGGUAUAG UGGUCAUCUAUACCCA359 AUGACCA 726 ACAGGGC 727 siRNA- CUGUUGGGUAUAGA UAGGUCAUCUAUACCC360 UGACCUA 728 AACAGGG 729 siRNA- UGUUGGGUAUAGAU UCAGGUCAUCUAUACC361 GACCUGA 730 CAACAGG 731Attorney Docket Number: J0365.70001WO00SEQ ID SEQ IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- GUUGGGUAUAGAUG UCCAGGUCAUCUAUAC362 ACCUGGA 732 CCAACAG 733 siRNA- UUGGGUAUAGAUGA UUCCAGGUCAUCUAUA363 CCUGGAA 734 CCCAACA 735 siRNA- UGGGUAUAGAUGAC UUUCCAGGUCAUCUAU364 CUGGAAA 736 ACCCAAC 737 siRNA- GGGUAUAGAUGACC UUUUCCAGGUCAUCUA365 UGGAAAA 738 UACCCAA 739 siRNA- GGUAUAGAUGACCU UGUUUCCAGGUCAUCU366 GGAAACA 740 AUACCCA 741 siRNA- GUAUAGAUGACCUG UGGUUUCCAGGUCAUC367 GAAACCA 742 UAUACCC 743 siRNA- UAUAGAUGACCUGG UUGGUUUCCAGGUCAU368 AAACCAA 744 CUAUACC 745 siRNA- UGGAAACCAUGCCA UGUCAUCUGGCAUGGU369 GAUGACA 746 UUCCAGG 747 siRNA- GGAAACCAUGCCAG UGGUCAUCUGGCAUGG370 AUGACCA 748 UUUCCAG 749 siRNA- GAAACCAUGCCAGA UAGGUCAUCUGGCAUG371 UGACCUA 750 GUUUCCA 751 siRNA- AAACCAUGCCAGAU UAAGGUCAUCUGGCAU372 GACCUUA 752 GGUUUCC 753 siRNA- AGACGGUGAACCCA UGCCAAUUGGGUUCAC373 AUUGGCA 754 CGUCUGG 755 siRNA- GACGGUGAACCCAA UGGCCAAUUGGGUUCA374 UUGGCCA 756 CCGUCUG 757 siRNA- UUUAACAAAACCCG UCCUGGUCGGGUUUUG375 ACCAGGA 758 UUAAACU 759 siRNA- UUAACAAAACCCGA UACCUGGUCGGGUUUU376 CCAGGUA 760 GUUAAAC 761 siRNA- GGGUCCUGUCCUCC UUGGAGUGGAGGACA377 ACUCCAA 762 GGACCCCU 763 siRNA- CUGUCCUCCACUCCA UUGAUCUGGAGUGGA378 GAUCAA 764 GGACAGGA 765 siRNA- UGUCCUCCACUCCAG UAUGAUCUGGAGUGG379 AUCAUA 766 AGGACAGG 767 siRNA- GUCCUCCACUCCAGA UAAUGAUCUGGAGUG380 UCAUUA 768 GAGGACAG 769 siRNA- CCUUUAGUUUAGAG UGCCCAGCUCUAAACU381 CUGGGCA 770 AAAGGAA 771 siRNA- CUUUAGUUUAGAGC UUGCCCAGCUCUAAAC382 UGGGCAA 772 UAAAGGA 773 siRNA- UUUAGUUUAGAGCU UCUGCCCAGCUCUAAA383 GGGCAGA 774 CUAAAGG 775 siRNA- UUAGUUUAGAGCUG UACUGCCCAGCUCUAA384 GGCAGUA 776 ACUAAAG 777Attorney Docket Number: J0365.70001WO00SEQ ID SEQ IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- UAGUUUAGAGCUGG UCACUGCCCAGCUCUA385 GCAGUGA 778 AACUAAA 779 siRNA- AGUUUAGAGCUGGG UUCACUGCCCAGCUCU386 CAGUGAA 780 AAACUAA 781 siRNA- GUUUAGAGCUGGGC UUUCACUGCCCAGCUC387 AGUGAAA 782 UAAACUA 783 siRNA- UUUAGAGCUGGGCA UCUUCACUGCCCAGCU388 GUGAAGA 784 CUAAACU 785 siRNA- UUAGAGCUGGGCAG UACUUCACUGCCCAGC389 UGAAGUA 786 UCUAAAC 787 siRNA- UAGAGCUGGGCAGU UCACUUCACUGCCCAG390 GAAGUGA 788 CUCUAAA 789 siRNA- AGAGCUGGGCAGUG UCCACUUCACUGCCCA391 AAGUGGA 790 GCUCUAA 791 siRNA- GAGCUGGGCAGUGA UUCCACUUCACUGCCC392 AGUGGAA 792 AGCUCUA 793 siRNA- AGCUGGGCAGUGAA UAUCCACUUCACUGCC393 GUGGAUA 794 CAGCUCU 795 siRNA- GCUGGGCAGUGAAG UUAUCCACUUCACUGC394 UGGAUAA 796 CCAGCUC 797 siRNA- CUGGGCAGUGAAGU UAUAUCCACUUCACUG395 GGAUAUA 798 CCCAGCU 799 siRNA- UGGGCAGUGAAGUG UGAUAUCCACUUCACU396 GAUAUCA 800 GCCCAGC 801 siRNA- GGCAGUGAAGUGGA UGUGAUAUCCACUUCA397 UAUCACA 802 CUGCCCA 803 siRNA- GCAGUGAAGUGGAU UAGUGAUAUCCACUUC398 AUCACUA 804 ACUGCCC 805 siRNA- CAGUGAAGUGGAUA UCAGUGAUAUCCACUU399 UCACUGA 806 CACUGCC 807 siRNA- AGUGAAGUGGAUAU UUCAGUGAUAUCCACU400 CACUGAA 808 UCACUGC 809 siRNA- GUGAAGUGGAUAUC UUUCAGUGAUAUCCAC401 ACUGAAA 810 UUCACUG 811 siRNA- UGAAGUGGAUAUCA UCUUCAGUGAUAUCCA402 CUGAAGA 812 CUUCACU 813 siRNA- GAAGUGGAUAUCAC UCCUUCAGUGAUAUCC403 UGAAGGA 814 ACUUCAC 815 siRNA- AAGUGGAUAUCACU UUCCUUCAGUGAUAUC404 GAAGGAA 816 CACUUCA 817 siRNA- AGUGGAUAUCACUG UCUCCUUCAGUGAUAU405 AAGGAGA 818 CCACUUC 819 siRNA- GUGGAUAUCACUGA UUCUCCUUCAGUGAUA406 AGGAGAA 820 UCCACUU 821 siRNA- UUCAGAUAAUGAUA UUGCCACUAUCAUUAU407 GUGGCAA 822 CUGAAGG 823Attorney Docket Number: J0365.70001WO00SEQ ID SEQ IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- UCAGAUAAUGAUAG UAUGCCACUAUCAUUA408 UGGCAUA 824 UCUGAAG 825 siRNA- CAGAUAAUGAUAGU UGAUGCCACUAUCAUU409 GGCAUCA 826 AUCUGAA 827 siRNA- AGAUAAUGAUAGUG UAGAUGCCACUAUCAU410 GCAUCUA 828 UAUCUGA 829 siRNA- GAUAAUGAUAGUGG UCAGAUGCCACUAUCA411 CAUCUGA 830 UUAUCUG 831 siRNA- UAAUGAUAGUGGCA UUACAGAUGCCACUAU412 UCUGUAA 832 CAUUAUC 833 siRNA- AAUGAUAGUGGCAU UAUACAGAUGCCACUA413 CUGUAUA 834 UCAUUAU 835 siRNA- AUGAUAGUGGCAUC UCAUACAGAUGCCACU414 UGUAUGA 836 AUCAUUA 837 siRNA- AAAAGUAAAGGGUG UGUUUCUCACCCUUUA415 AGAAACA 838 CUUUUGC 839 siRNA- AAAGUAAAGGGUGA UAGUUUCUCACCCUUU416 GAAACUA 840 ACUUUUG 841 siRNA- AAGUAAAGGGUGAG UCAGUUUCUCACCCUU417 AAACUGA 842 UACUUUU 843 siRNA- AGUAAAGGGUGAGA UCCAGUUUCUCACCCU418 AACUGGA 844 UUACUUU 845 siRNA- GAGAAACUGGAUAA UAGCUUCUUAUCCAGU419 GAAGCUA 846 UUCUCAC 847 siRNA- AGAAACUGGAUAAG UCAGCUUCUUAUCCAG420 AAGCUGA 848 UUUCUCA 849 siRNA- GAAACUGGAUAAGA UUCAGCUUCUUAUCCA421 AGCUGAA 850 GUUUCUC 851 siRNA- AAACUGGAUAAGAA UUUCAGCUUCUUAUCC422 GCUGAAA 852 AGUUUCU 853 siRNA- UGGCCAAGGAGAUC UGUACUGGAUCUCCUU423 CAGUACA 854 GGCCAGG 855 siRNA- CCAAGGAGAUCCAG UCAGGUACUGGAUCUC424 UACCUGA 856 CUUGGCC 857 siRNA- CAAGGAGAUCCAGU UUCAGGUACUGGAUCU425 ACCUGAA 858 CCUUGGC 859 siRNA- AAGGAGAUCCAGUA UUUCAGGUACUGGAUC426 CCUGAAA 860 UCCUUGG 861 siRNA- AGGAGAUCCAGUAC UUUUCAGGUACUGGAU427 CUGAAAA 862 CUCCUUG 863 siRNA- GGAGAUCCAGUACC UCUUUCAGGUACUGGA428 UGAAAGA 864 UCUCCUU 865 siRNA- GAGAUCCAGUACCU UUCUUUCAGGUACUGG429 GAAAGAA 866 AUCUCCU 867 siRNA- AGAUCCAGUACCUG UAUCUUUCAGGUACUG430 AAAGAUA 868 GAUCUCC 869Attorney Docket Number: J0365.70001WO00SEQ ID SEQ IDsiRNA Sense Sequence NO: Antisense Sequence NO: siRNA- GAUCCAGUACCUGA UAAUCUUUCAGGUACU431 AAGAUUA 870 GGAUCUC 871 siRNA- AUCCAGUACCUGAA UAAAUCUUUCAGGUAC432 AGAUUUA 872 UGGAUCU 873 siRNA- CCAGUACCUGAAAG UUCAAAUCUUUCAGGU433 AUUUGAA 874 ACUGGAU 875 siRNA- CAGUACCUGAAAGA UAUCAAAUCUUUCAGG434 UUUGAUA 876 UACUGGA 877 siRNA- AGUACCUGAAAGAU UUAUCAAAUCUUUCAG435 UUGAUAA 878 GUACUGG 879 siRNA- GUACCUGAAAGAUU UCUAUCAAAUCUUUCA436 UGAUAGA 880 GGUACUG 881 siRNA- UACCUGAAAGAUUU UUCUAUCAAAUCUUUC437 GAUAGAA 882 AGGUACU 883 siRNA- ACCUGAAAGAUUUG UUUCUAUCAAAUCUUU438 AUAGAAA 884 CAGGUAC 885 siRNA- GAUAGAAGAGGUCC UCCUUGCGGACCUCUU439 GCAAGGA 886 CUAUCAA 887 siRNA- AUAGAAGAGGUCCG UGCCUUGCGGACCUCU440 CAAGGCA 888 UCUAUCA 889 siRNA- UAGAAGAGGUCCGC UUGCCUUGCGGACCUC441 AAGGCAA 890 UUCUAUC 891 siRNA- AGAAGAGGUCCGCA UUUGCCUUGCGGACCU442 AGGCAAA 892 CUUCUAU 893 siRNA- GAAGAGGUCCGCAA UCUUGCCUUGCGGACC443 GGCAAGA 894 UCUUCUA 895 siRNA- AAGAGGUCCGCAAG UCCUUGCCUUGCGGAC444 GCAAGGA 896 CUCUUCU 897 siRNA- CAAUGUGCUUGUAC UCUCUAUGUACAAGCA445 AUAGAGA 898 CAUUGAC 899 siRNA- AAUGUGCUUGUACA UACUCUAUGUACAAGC446 UAGAGUA 900 ACAUUGA 901 siRNA- CAACAUGACCGAAA 14480 UAGCUCAUUUCGGUCA 14481 1121 UGAGCUA UGUUGCGsiRNA- CAGACGGUGAACCC 14482 UCCAAUUGGGUUCACC 14483 1122 AAUUGGA GUCUGGGsiRNA- GAAAGUUUAACAAA 14484 UUCGGGUUUUGUUAA 14485 1123 ACCCGAA ACUUUCUGsiRNA- GAUUUGAUAGAAGA 14486 UCGGACCUCUUCUAUC 14487 1124 GGUCCGA AAAUCUUsiRNA- AUUUGAUAGAAGAG 14488 UGCGGACCUCUUCUAU 144891125 GUCCGCA CAAAUCUTable 3. Chemically Modified siRNA Sequences (mN = 2’-O-Me; fN = 2’-F nucleoside; dN = deoxy nucleoside; * = phosphorothioate linkage)Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO:mG*mA*mAmGmAmAfAmGfCfCfUmAmGmG mU*fA*mAmGmAfGmAfCfCm siRNA mUmCmUmCmU*mU* U m AmGmGfCmU fU mU mCmU -447 mA 902 mUmC*mA*mG 903 mA*mA*mGmAmAmAfGmCfCfUfAmGmGmU mU*fU*mAmAmGfAmGfAfCm siRNA mCmUmCmUmU*mA* CmUmAmGfGmCfUmUmUmC -448 mA 904 mUmU*mC*mA 905 mA*mA*mGmCmCmUfAmGfGfUfCmUmCmU mU*fC*mAmUmCfUmAfAfGm siRNA mUmAmGmAmU*mG* AmGmAmCfCmUfAmGmGmC -449 mA 906 mUmU*mU*mC 907 mA*mG*mCmCmUmAfGmGfUfCfUmCmUmU mU*fU*mCmAmUfCmUfAfAm siRNA mAmGmAmUmG*mA* GmAmGmAfCmCfUmAmGmG -450 mA 908 mCmU*mU*mU 909 mU*mA*mCmCmUmGfGmAfGfGfUmGmGmC mU*fU*mGmCmUfUmGfGfCm siRNA mCmAmAmGmC *mA* CmAmCmCfUmCfCmAmGmGm -451 mA 910 UmA*mA*mU 911 mA*mC*mCmUmGmGfAmGfGfUfGmGmCmC mU*fG*mUmGmCfUmUfGfGm siRNA mAmAmGmCmA*mC * CmCmAmCfCmUfCmCmAmGm -452 mA 912 GmU*mA*mA 913 mC*mC*mUmGmGmAfGmGfUfGfGmCmCmA mU*fA*mGmUmGfCmUfUfGm siRNA mAmGmCmAmC *mU* GmCmCmAfCmCfUmCmCmAm -453 mA 914 GmG*mU*mA 915 mU*mC *mAmAmAmCfCmUfCfAfUmGmGmG mU*fG*mGmAmGfAmAfCfCm siRNA mUmUmCmUmC*mC* CmAmUmGfAmGfGmUmUmU -454 mA 916 mGmA*mA*mG 917 mC *mA*mAmAmCmCfUmCfAfUfGmGmGmU mU*fU*mGmGmAfGmAfAfCm siRNA mUmCmUmCmC*mA* CmCmAmUfGmAfGmGmUmU -455 mA 918 mUmG*mA*mA 919 mA*mA*mAmCmCmUfCmAfUfGfGmGmUmU mU*fC*mUmGmGfAmGfAfAm siRNA mCmUmCmCmA*mG* CmCmCmAfUmGfAmGmGmU -456 mA 920 mUmU*mG*mA 921 mC*mC*mUmCmAmUfGmGfGfUfUmCmUmC mU*fU*mCmGmCfUmGfGfAm siRNA mCmAmGmCmG*mA* GmAmAmCfCmCfAmUmGmA-457 mA 922 mGmG*mU*mU 923Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO:mC*mU*mCmAmUmGfGmGfUfUfCmUmCmC mU*fG*mUmCmGfCmUfGfGm siRNA mAmGmCmGmA*mC * AmGmAmAfCmCfCmAmUmG -458 mA 924 mAmG*mG*mU 925 mU*mC*mAmUmGmGfGmUfUfCfUmCmCmA mU*fU*mGmUmCfGmCfUfGm siRNA mGmCmGmAmC *mA* GmAmGmAfAmCfCmCmAmU -459 mA 926 mGmA*mG*mG 927 mC*mA*mUmGmGmGfUmUfCfUfCmCmAmG mU*fU*mUmGmUfCmGfCfUm siRNA mCmGmAmCmA*mA* GmGmAmGfAmAfCmCmCmA -460 mA 928 mUmG*mA*mG 929 mA*mU*mGmGmGmUfUmCfUfCfCmAmGmC mU*fC*mUmUmGfUmCfGfCm siRNA mGmAmCmAmA*mG* UmGmGmAfGmAfAmCmCmC -461 mA 930 mAmU*mG*mA 931 mU*mG*mGmGmUmUfCmUfCfCfAmGmCmG mU*fC*mCmUmUfGmUfCfGm siRNA mAmCmAmAmG*mG* CmUmGmGfAmGfAmAmCmC -462 mA 932 mCmA*mU*mG 933 mG*mGmUmUmCfUmCfCfAfGmCmGmA mU*fG*mCmCmUfUmGfUfCm siRNA mCmAmAmGmG*mC * GmCmUmGfGmAfGmAmAmC -463 mA 934 mCmC*mA*mU 935 mU*mU*mCmUmCmCfGmGfGfAfCmAmGmA mU*fA*mUmCmCfAmAfUfCm siRNA mUmUmGmGmA*mU* UmGmUmCfCmCfGmGmAmG -464 mA 936 mAmA*mG*mG 937 mU*mC*mUmCmCmGfGmGfAfCfAmGmAmU mU*fC*mAmUmCfCmAfAfUm siRNA mUmGmGmAmU*mG* CmUmGmUfCmCfCmGmGmAm -465 mA 938 GmA*mA*mG 939 mC*mU*mCmCmGmGfGm AfCf AfGm AmU mU mU*fA*mCmAmUfCmCfAfAm siRNA mGmGmAmUmG*mU* UmCmUmGfUmCfCmCmGmGm -466 mA 940 AmG*mA*mA 941 mC *mC *mGmGmGmAfCmAfGfAfUmUmGmG mU*fC*mAmAmCfAmUfCfCm siRNA mAmUmGmUmU*mG* AmAmUmCfUmGfUmCmCmCm -467 mA 942 GmG*mA*mG 943 mC*mGmGmAmCf AmGf AfU fU mGmGm mU*fC*mCmAmAfCmAfUfCm siRNA AmUmGmUmUmG*m CmAmAmUfCmUfGmUmCmCm-468 G*mA 944 CmG*mG*mA 945Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO:mG*mG*mGmAmCmAfGm AfU fU fGmGm Am mU*fU*mCmCmAfAmCfAfUm siRNA UmGmUmUmGmG*m CmCmAmAfUmCfUmGmUmCm -469 A*mA 946 CmC*mG*mG 947 mG*mG*mAmCmAmGf AmU fU fGfGm AmU m mU*fC*mUmCmCfAmAfCfAm siRNA GmUmUmGmGmA*m UmCmCmAfAmUfCmUmGmU -470 G*mA 948 mCmC*mC*mG 949 mA*mC *mAmGmAmUfU mGfGf AfU mGmU m mU*fU*mUmCmUfCmCfAfAm siRNA UmGmGmAmGmA*m Cm AmU mCfCm Af AmU mCmU m -471 A*mA 950 GmU*mC*mC 951 mU*mA*mGmAmUmGfAmCfCfUfGmGmAmA mU*fC*mAmUmGfGmUfUfUm siRNA mAmCmCmAmU*mG* CmCmAmGfGmUfCmAmUmCm -472 mA 952 UmA*mU*mA 953 mA*mG*mAmUmGmAfCmCfUfGfGmAmAmA mU*fG*mCmAmUfGmGfUfUm siRNA mCmCmAmUmG*mC* UmCmCmAfGmGfUmCmAmU -473 mA 954 mCmU*mA*mU 955 mG*mA*mUmGmAmCfCmUfGfGfAmAmAmC mU*fG*mGmCmAfUmGfGfUm siRNA mCmAmUmGmC*mC* UmUmCmCfAmGfGmUmCmA -474 mA 956 mUmC*mU*mA 957 mA*mU*mGmAmCmCfUmGfGfAfAmAmCmC mU*fU*mGmGmCfAmUfGfGm siRNA mAmUmGmCmC*mA* UmUmUmCfCmAfGmGmUmC -475 mA 958 mAmU*mC*mU 959 mG*mA*mCmCmUmGfGmAfAfAfCmCmAmU mU*fU*mCmUmGfGmCfAfUm siRNA mGmCmCmAmG*mA* GmGm U mU fU mCfCm AmGmG -476 mA 960 mUmC*mA*mU 961 mC*mC*mUmGmGmAfAmAfCfCfAmUmGmC mU*fC*mAmUmCfUmGfGfCm siRNA mCmAmGmAmU*mG* AmU mGmGfU mU fU mCmCm A -477 mA 962 mGmG*mU*mC 963 mC *mU*mGmGmAmAfAmCfCfAfUmGmCmC mU*fU*mCmAmUfCmUfGfGm siRNA mAmGmAmUmG*mA* CmAmUmGfGmUfUmUmCmC -478 mA 964 mAmG*mG*mU 965 mA*mC*mGmGmUmGfAmAfCfCfCmAmAmU mU*fU*mGmGmCfCmAfAfUm siRNA mUmGmGmCmC*mA* UmGmGmGfUmUfCmAmCmC-479 mA 966 mGmU*mC*mU 967Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence NO: Antisense Sequence NO:mG*mU*mGmAmAmCfCmCfAfAfUmUmGmG mU*fA*mGmAmUfGmGfCfCm siRNA mCmCmAmUmC*mU* Am AmU mU fGmGfGmU mU mC -480 mA 968 mAmC*mC*mG 969 mU*mG*mAmAmCmCfCmAfAfUfUmGmGmC mU*fG*mAmGmAfUmGfGfCm siRNA mCmAmUmCmU*mC* CmAmAmUfUmGfGmGmUmU -481 mA 970 mCmA*mC*mC 971 mA*mA*mUmUmGmGfCmCfAfUfCmUmCmC mU*fU*mUmUmCfUmGfGfGm siRNA mCmAmGmAmA*mA* AmGmAmUfGmGfCmCmAmA -482 mA 972 mUmU*mG*mG 973 mA*mU*mUmGmGmCfCmAfUfCfUmCmCmC mU*fC*mUmUmUfCmUfGfGm siRNA mAmGmAmAmA*mG* GmAmGmAfUmGfGmCmCmA -483 mA 974 mAmU*mU*mG 975 mG*mA*mUmCmAmUfU mCfCfU fU mU m A mG mU*fU*mCmUmAfAmAfCfUm siRNA mUmUmUmAmG*mA* Am Am AmGfGm Af AmU mGm A -484 mA 976 mUmC*mU*mG 977 mA*mU*mCmAmUmUfCmCfUfUfUm AmGmU mU*fC*mUmCmUfAmAfAfCm siRNA mUmUmAmGmA*mG* U m Am Am AfGmGf Am AmU mG -485 mA 978 mAmU*mC*mU 979 mU*mC*mAmUmUmCfCmU fU fU f AmGmU mU mU*fG*mCmUmCfUmAfAfAm siRNA mUmAmGmAmG*mC* CmUmAmAfAmGfGmAmAmU -486 mA 980 mGmA*mU*mC 981 mC*mA*mUmUmCmCfUmUfUfAfGmUmUmU mU*fA*mGmCmUfCmUfAfAm siRNA mAmGmAmGmC *mU* AmCmUmAfAmAfGmGmAmA -487 mA 982 mUmG*mA*mU 983 mG*mA*mUmAmGmUfGmGfCfAfUmCmUmG mU*fC*mUmCmAfUmAfCfAm siRNA mUmAmUmGmA*mG* GmAmUmGfCmCfAmCmUmA -488 mA 984 mUmC*mA*mU 985 mA*mU*mAmGmUmGfGmCfAfUfCmUmGmU mU*fG*mCmUmCfAmUfAfCm siRNA mAmUmGmAmG*mC* AmGmAmUfGmCfCmAmCmU -489 mA 986 mAmU*mC*mA 987 mU*mA*mGmUmGmGfCm AfUfCfUmGmUm A mU*fG*mGmCmUfCmAfUfAm siRNA mUmGmAmGmC*mC* CmAmGmAfUmGfCmCmAmCm-490 mA 988 UmA*mU*mC 989Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mA*mG*mUmGmGmCf AmUfCfUfGmUm AmU mU*fG*mGmGmCfUmCfAfUm siRNA mGmAmGmCmC*mC* AmCmAmGfAmUfGmCmCmA -491 mA 990 mCmU*mA*mU 991 mG*mC*mCmAmCmUfAmGfGfUfAmCmCmG mU*fU*mUmCmUfGmGfCfGm siRNA mCmCmAmGmA*mA* GmUmAmCfCmUfAmGmUmG -492 mA 992 mGmC*mU*mG 993 mC*mC*mAmCmUmAfGmGfUfAfCmCmGmC mU*fC*mUmUmCfUmGfGfCm siRNA mCmAmGmAmA*mG* GmGm U m AfCmCfUm AmGmU -493 mA 994 mGmG*mC*mU 995 mC*mA*mCmUmAmGfGmUfAfCfCmGmCmC mU*fU*mCmUmUfCmUfGfGm siRNA mAmGmAmAmG*mA* CmGmGmUfAmCfCmUmAmG -494 mA 996 mUmG*mG*mC 997 mU*mU*mCmUmGmAfCmCfAfCfGmUmUmG mU*fG*mUmCmAfUmCfCfAm siRNA mGmAmUmGmA*mC* AmCmGmUfGmGfUmCmAmG -495 mA 998 mAmA*mG*mG 999 mU*mC*mUmGmAmCfCmAfCfGfUmUmGmG mU*fU*mGmUmCfAmUfCfCm siRNA mAmUmGmAmC*mA* AmAmCmGfUmGfGmUmCmA -496 mA 1000 mGmA*mA*mG 1001 mC *mU *mGmAmCmCfAmCfGfUfUmGmGmA mU*fG*mUmGmUfCmAfUfCm siRNA mUmGmAmCmA*mC* CmAmAmCfGmUfGmGmUmC -497 mA 1002 mAmG*mA*mA 1003 mU*mGmCmCmAfUmCfUfCfCmCmAmG mU*fA*mAmCmUfUmUfCfUm siRNA mAmAmAmGmU*mU* GmGmGmAfGmAfUmGmGmC -498 mA 1004 mCmA*mA*mU 1005 mC *mA*mAmGmAmCfAmGfCfAfGmCmCmA mU*fA*mCmCmUfAmGfUfGm siRNA mCmUmAmGmG*mU* GmCmUmGfCmUfGmUmCmU -499 mA 1006 mUmG*mU*mU 1007 mA*mA*mGmAmCmAfGmCfAfGfCmCmAmC mU*fU*mAmCmCfUmAfGfUm siRNA mUmAmGmGmU*mA* GmGmCmUfGmCfUmGmUmC -500 mA 1008 mUmU*mG*mU 1009 mA*mG*mAmCmAmGfCmAfGfCfCmAmCmU mU*fG*mUmAmCfCmUfAfGm siRNA mAmGmGmUmA*mC* U mGmGmCfUmGfCmU mGmU-501 mA 1010 mCmU*mU*mG 1011Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mA*mC *mAmGmCmAfGmCfCfAfCmUmAmG mU*fC*mGmGmUfAmCfCfUm siRNA mGmUmAmCmC*mG* AmGmU mGfGmCfU mGmCmU -502 mA 1012 mGmU*mC*mU 1013 mA*mG*mCmCmAmCfUmAfGfGfUmAmCmC mU*fU*mCmUmGfGmCfGfGm siRNA mGmCmCmAmG*mA* UmAmCmCfUmAfGmUmGmG -503 mA 1014 mCmU*mG*mC 1015 mUWmGmAmGmGfUmGfGfCfCmAmAmG mU*fG*mAmAmGfUmGfCfUm siRNA mCmAmCmUmU*mC* UmGmGmCfCmAfCmCmUmCm -504 mA 1016 CmA*mG*mG 1017 mG*mAmGmGmUfGmGfCfCfAmAmGmC mU*fU*mGmAmAfGmUfGfCm siRNA mAmCmUmUmC*mA* U mU mGmGfCmCf AmCmCmU m -505 mA 1018 CmC*mA*mG 1019 mG*mA*mGmGmUmGfGmCfCfAfAmGmCmA mU*fU*mUmGmAfAmGfUfGm siRNA mCmUmUmCmA*mA* CmUmUmGfGmCfCmAmCmCm -506 mA 1020 UmC*mC*mA 1021 mAWmGmUmGmGfCmCfAfAfGmCmAmC mU*fU*mUmUmGfAmAfGfUm siRNA mUmUmCmAmA*mA* GmCmUmUfGmGfCmCmAmCm -507 mA 1022 CmU*mC*mC 1023 mG*mUmGmGmCfCmAfAfGfCmAmCmU mU*fG*mUmUmUfGmAfAfGm siRNA mUmCmAmAmA*mC* UmGmCmUfUmGfGmCmCmA -508 mA 1024 mCmC*mU*mC 1025 mG*mU *mGmGmCmCfAmAfGfCfAmCmUmU mU*fG*mGmUmUfUmGfAfAm siRNA mCmAmAmAmC*mC* GmUmGmCfUmUfGmGmCmC -509 mA 1026 mAmC*mC*mU 1027 mG*mC*mCmAmAmGfCmAfCfUfUmCmAmA mU*fU*mGmAmGfGmUfUfUm siRNA mAmCmCmUmC*mA* GmAmAmGfUmGfCmUmUmG -510 mA 1028 mGmC*mC*mA 1029 mA*mG*mCmAmCmUfUmCfAfAfAmCmCmU mU*fC*mCmCmAfUmGfAfGm siRNA mCmAmUmGmG* GmU mU mU fGmAf AmGmU mG -511 mA 1030 mCmU*mU*mG 1031 mG*mC*mAmCmUmUfCmAfAfAfCmCmUmC mU*fA*mCmCmCfAmUfGfAm siRNA mAmUmGmGmG*mU* GmGm U mU fU mGf Am AmGmU-512 mA 1032 mGmC*mU*mU 1033Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mA*mC*mUmUmCmAfAmAfCfCfUmCmAmU mU*fG*mAmAmCfCmCfAfUm siRNA mGmGmGmUmU*mC* Gm AmGmGfU mU fU mGm Am A -513 mA 1034 mGmU*mG*mC 1035 mC*mU*mUmCmAmAfAmCfCfUfCmAmUmG mU*fA*mGmAmAfCmCfCfAm siRNA mGmGmUmUmC*mU* U mGm AmGfGmU fUmU mGm A -514 mA 1036 mAmG*mU*mG 1037 mCWmGmUmGmGf AmU fGfGfGmU mU m mU*fA*mCmUmGfAmCfCfAm siRNA GmGmUmCmAmG*mU AmCmCmCfAmUfCmCmAmCm -515 *mA 1038 AmG*mC*mC 1039 mU*mC*mCmUmCmCfAmCfUfCfCmAmGmA mU*fG*mAmAmUfGmAfUfCm siRNA mUmCmAmUmU*mC* U mGmGm AfGmU fGmGm A mG -516 mA 1040 mGmA*mC*mA 1041 mC*mC*mUmCmCmAfCmUfCfCfAmGmAmU mU*fG*mGmAmAfUmGfAfUm siRNA mCmAmUmUmC*mC* CmUmGmGfAmGfUmGmGmA -517 mA 1042 mGmG*mA*mC 1043 mC *mU *mCmCmAmCfUmCfCfAfGmAmUmC mU*fA*mGmGmAfAmUfGfAm siRNA mAmUmUmCmC*mU* UmCmUmGfGmAfGmUmGmG -518 mA 1044 mAmG*mG*mA 1045 mU*mC*mCmAmCmUfCmCfAfGfAmUmCmA mU*fA*mAmGmGfAmAfUfGm siRNA mUmUmCmCmU*mU* AmUmCmUfGmGfAmGmUmG -519 mA 1046 mGmA*mG*mG 1047 mC*mC*mAmCmUmCfCmAfGfAfUmCmAmU mU*fA*mAmAmGfGmAfAfUm siRNA mUmCmCmUmU*mU* GmAmUmCfUmGfGmAmGmU -520 mA 1048 mGmG*mA*mG 1049 mC*mA*mCmUmCmCfAmGfAfUfCmAmUmU mU*fU*mAmAmAfGmGfAfAm siRNA mCmCmUmUmU*mA* U mGm AmU fCmU fGmGm AmG -521 mA 1050 mUmG*mG*mA 1051 mA*mC*mUmCmCmAfGmAfUfCfAmUmUmC mU*fC*mUmAmAfAmGfGfAm siRNA mCmUmUmUmA*mG* AmU mGm AfU mCfU mGmGm A -522 mA 1052 mGmU*mG*mG 1053 mC *mU *mCmCmAmGfAmUfCfAfUmUmCmC mU*fA*mCmUmAfAmAfGfGm siRNA mUmUmUmAmG*mU* AmAmUmGfAmUfCmUmGmG-523 mA 1054 mAmG*mU*mG 1055Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mU*mC *mCmAmGmAfUmCfAfUfUmCmCmU mU*fA*mAmCmUfAmAfAfGm siRNA mUmUmAmGmU*mU* Gm Am AmU fGm AfU mCmU mG -524 mA 1056 mGmA*mG*mU 1057 mC *mC *mAmGmAmUfCm AfUfUfCmCmUmU mU*fA*mAmAmCfUmAfAfAm siRNA mUmAmGmUmU*mU* GmGm Am AfU mGf AmU mCmU -525 mA 1058 mGmG*mA*mG 1059 mA*mG*mAmUmCmAfUmUfCfCfUmUmUmA mU*fC*mUmAmAfAmCfUfAm siRNA mGmUmUmUmA*mG* Am AmGmGf Am AfU mGm AmU -526 mA 1060 mCmU*mG*mG 1061 mA*mU*mUmCmCmUfU mU f AfGfU mU mU m mU*fC*mAmGmCfUmCfUfAm siRNA AmGmAmGmCmU*mG AmAmCmUfAmAfAmGmGmA -527 *mA 1062 mAmU*mG*mA 1063 mU*mU*mCmCmUmUfUmAfGfUfUmUmAm mU*fC*mCmAmGfCmUfCfUm siRNA GmAmGmCmUmG*mG AmAmAmCfUmAfAmAmGmG -528 *mA 1064 mAmA*mU*mG 1065 mU*mC*mCmUmUmUf AmGfU fU fU m AmGm mU*fC*mCmCmAfGmCfUfCm siRNA AmGmCmUmGmG*mG U m Am Am AfCmU f Am Am AmG -529 *mA 1066 mGmA*mA*mU 1067 mA*mU*mGmAmCmCfGm Af Af AfU mGm Am mU*fA*mGmGmAfAmGfCfUm siRNA GmCmUmUmCmC*mU CmAmUmUfUmCfGmGmUmC -530 *mA 1068 mAmU*mG*mU 1069 mU WmAmCmCmGfAmAfAfUfGmAmGmC mU*fC*mAmGmGfAmAfGfCm siRNA mUmUmCmCmU*mG* U mCm AmU fU mU fCmGmGmU -531 mA 1070 mCmA*mU*mG 1071 mC*mC*mUmGmAmGfCmAfGfCfGmAmGmG mU*fC*mCmAmAfCmAfCfCm siRNA mUmGmUmUmG*mG* UmCmGmCfUmGfCmUmCmAm -532 mA 1072 GmG*mA*mA 1073 mC *mU *mGmAmGmCfAmGfCfGfAmGmGmU mU*fA*mCmCmAfAmCfAfCm siRNA mGmUmUmGmG*mU* CmUmCmGfCmUfGmCmUmCm -533 mA 1074 AmG*mG*mA 1075 mU*mG*mAmGmCmAfGmCfGfAfGmGmUmG mU*fC*mAmCmCfAmAfCfAm siRNA mUmUmGmGmU*mG* CmCmUmCfGmCfUmGmCmUm-534 mA 1076 CmA*mG*mG 1077Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mG*mA*mUmUmAmCfCmUfGfGfAmGmGmU mU*fU*mUmGmGfCmCfAfCm siRNA mGmGmCmCmA*mA* CmUmCmCfAmGfGmUmAmA -535 mA 1078 mUmC*mA*mU 1079 mA*mU*mUmAmCmCfUmGfGfAfGmGmUm mU*fC*mUmUmGfGmCfCfAm siRNA GmGmCmCmAmA*mG CmCmUmCfCmAfGmGmUmAm -536 *mA 1080 AmU*mC*mA 1081 mU*mU*mAmCmCmUfGmGfAfGfGmUmGm mU*fG*mCmUmUfGmGfCfCm siRNA GmCmCmAmAmG*mC AmCmCmUfCmCfAmGmGmUm -537 *mA 1082 AmA*mU*mC 1083 mG*mG*mUmUmCmUfCmCfAfGfCmGmAmC mU*fA*mGmCmCfUmUfGfUm siRNA mAmAmGmGmC *mU* CmGmCmU fGmGf AmGmAmA -538 mA 1084 mCmC*mC*mA 1085 mG*mU*mUmCmUmCfCmAfGfCfGmAmCmA mU*fU*mAmGmCfCmUfUfGm siRNA mAmGmGmCmU*mA* UmCmGmCfUmGfGmAmGmA -539 mA 1086 mAmC*mC*mC 1087 mU*mU*mCmUmCmCfAmGfCfGfAmCmAmA mU*fU*mUmAmGfCmCfUfUm siRNA mGmGmCmUmA*mA* GmUmCmGfCmUfGmGmAmG -540 mA 1088 mAmA*mC*mC 1089 mC *mU *mCmCmAmGfCmGfAfCfAmAmGmG mU*fC*mCmUmUfAmGfCfCm siRNA mCmUmAmAmG*mG* U mU mGmU fCmGfCmU mGmG -541 mA 1090 mAmG*mA*mA 1091 mU *mC *mCmAmGmCfGmAfCfAfAmGmGmC mU*fG*mCmCmUfUmAfGfCm siRNA mUmAmAmGmG*mC* CmUmUmGfUmCfGmCmUmG -542 mA 1092 mGmA*mG*mA 1093 mC *mC *mAmGmCmGfAmCfAfAfGmGmCmU mU*fC*mGmCmCfUmUfAfGm siRNA mAmAmGmGmC *mG* CmCmUmUfGmUfCmGmCmUm -543 mA 1094 GmG*mA*mG 1095 mA*mA*mGmGmCmGfGmGfCfUfCmCmUmC mU*fC*mAmUmUfCmGfGfAm siRNA mCmGmAmAmU*mG* GmGmAmGfCmCfCmGmCmCm -544 mA 1096 UmU*mA*mG 1097 mA*mG*mGmCmGmGfGmCfUfCfCmUmCmC mU*fC*mCmAmUfUmCfGfGm siRNA mGmAmAmUmG*mG* AmGmGmAfGmCfCmCmGmCm-545 mA 1098 CmU*mU*mA 1099Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mG*mG*mCmGmGmGfCmUfCfCfUmCmCmG mU*fG*mCmCmAfUmUfCfGm siRNA mAmAmUmGmG*mC* GmAmGmGfAmGfCmCmCmG -546 mA 1100 mCmC*mU*mU 1101 mG*mC *mGmGmGmCfUmCfCfUfCmCmGmA mU*fA*mGmCmCfAmUfUfCm siRNA mAmUmGmGmC*mU* GmGmAmGfGmAfGmCmCmC -547 mA 1102 mGmC*mC*mU 1103 mG*mG*mGmCmUmCfCmUfCfCfGmAmAmU mU*fC*mCmAmGfCmCfAfUm siRNA mGmGmCmUmGW UmCmGmGfAmGfGmAmGmC -548 mA 1104 mCmC*mG*mC 1105 mG*mC*mUmCmCmUfCmCfGfAfAmUmGmG mU*fA*mGmCmCfAmGfCfCm siRNA mCmUmGmGmC*mU* AmUmUmCfGmGfAmGmGmA -549 mA 1106 mGmC*mC*mC 1107 mC*mU*mCmCmUmCfCmGfAfAfUmGmGmC mU*fC*mAmGmCfCmAfGfCm siRNA mUmGmGmCmUW CmAmUmUfCmGfGmAmGmG -550 mA 1108 mAmG*mC*mC 1109 mU*mC*mCmUmCmCfGmAfAfUfGmGmCmU mU*fA*mCmAmGfCmCfAfGm siRNA mGmGmCmUmGW CmCmAmUfUmCfGmGmAmG -551 mA 1110 mGmA*mG*mC 1111 mC *mU *mGmGmCmUfGmUfGfGfAmUmGm mU*fA*mCmCmAfAmCfCfCm siRNA GmGmUmUmGmG*m AmUmCmCfAmCfAmGmCmCm -552 U*mA 1112 AmG*mC*mC 1113 mUWmGmCmUmGfUmGfGfAfUmGmGm mU*fG*mAmCmCfAmAfCfCm siRNA GmUmUmGmGmU*mC CmAmUmCfCmAfCmAmGmCm -553 *mA 1114 CmA*mG*mC 1115 mGWmCmUmGmUfGmGfAfUfGmGmGm mU*fU*mGmAmCfCmAfAfCm siRNA UmUmGmGmUmC*mA CmCmAmU fCmCf AmCmAmGm -554 *mA 1116 CmC*mA*mG 1117 mG*mC*mUmGmUmGfGmAfUfGfGmGmUm mU*fC*mUmGmAfCmCfAfAm siRNA UmGmGmUmCmA*mG CmCmCmAfUmCfCmAmCmAm -555 *mA 1118 GmC*mC*mA 1119 mU*mG*mUmGmGmAfU mGfGfGfU mU mGm mU*fG*mAmCmUfGmAfCfCm siRNA GmUmCmAmGmU*mC AmAmCmCfCmAfUmCmCmAm-556 *mA 1120 CmA*mG*mC 1121Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mG*mU*mGmGmAmUfGmGfGfUfUmGmGm mU*fG*mGmAmCfUmGfAfCm siRNA UmCmAmGmUmC*mC CmAmAmCfCmCfAmUmCmCm -557 *mA 1122 AmC*mA*mG 1123 mU*mG*mGmAmUmGfGmGfUfUfGmGmUmC mU*fG*mGmGmAfCmUfGfAm siRNA mAmGmUmCmC*mC* CmCmAmAfCmCfCmAmUmCm -558 mA 1124 CmA*mC*mA 1125 mG*mU*mUmGmGmUfCmAfGfUfCmCmCmU mU*fU*mGmUmUfGmGfAfGm siRNA mCmCmAmAmC*mA* GmGmAmCfUmGfAmCmCmA -559 mA 1126 mAmC*mC*mC 1127 mU*mG*mGmUmCmAfGmUfCfCfCmUmCmC mU*fG*mUmUmGfUmUfGfGm siRNA mAmAmCmAmA*mC * AmGmGmGf AmCfU mGm AmC -560 mA 1128 mCmA*mA*mC 1129 mG*mC *mAmAmGmGfAmGfGfAfUmGmCmC mU*fG*mGmAmGfAmAfGfGm siRNA mUmUmCmUmC*mC* CmAmUmCfCmUfCmCmUmUm -561 mA 1130 GmC*mU*mG 1131 mC *mA*mAmGmGmAfGmGfAfUfGmCmCmU mU*fC*mGmGmAfGmAfAfGm siRNA mUmCmUmCmC*mG* GmCmAmUfCmCfUmCmCmUm -562 mA 1132 UmG*mC*mU 1133 mA*mA*mGmGmAmGfGmAfUfGfCmCmUmU mU*fC*mCmGmGfAmGfAfAm siRNA mCmUmCmCmG*mG* GmGmCmAfUmCfCmUmCmCm -563 mA 1134 UmU*mG*mC 1135 mA*mG*mGmAmGmGfAmUfGfCfCmUmUmC mU*fC*mCmCmGfGmAfGfAm siRNA mUmCmCmGmG*mG* AmGmGmCfAmUfCmCmUmCm -564 mA 1136 CmU*mU*mG 1137 mA*mG*mGmAmUmGfCmCfUfUfCmUmCmC mU*fU*mGmUmCfCmCfGfGm siRNA mGmGmGmAmC *mA* AmGmAmAfGmGfCmAmUmC -565 mA 1138 mCmU*mC*mC 1139 mG*mG*mAmUmGmCfCmUfUfCfUmCmCmG mU*fC*mUmGmUfCmCfCfGm siRNA mGmGmAmCmAW GmAmGmAfAmGfGmCmAmU -566 mA 1140 mCmC*mU*mC 1141 mA*mU*mGmCmCmUfUmCfUfCfCmGmGmG mU*fA*mUmCmUfGmUfCfCm siRNA mAmCmAmGmA*mU* CmGmGmAfGmAfAmGmGmC-567 mA 1142 mAmU*mC*mC 1143Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mU*mG*mCmCmUmUfCmUfCfCfGmGmGmA mU*fA*mAmUmCfUmGfUfCm siRNA mCmAmGmAmU*mU* CmCmGmGfAmGfAmAmGmG -568 mA 1144 mCmA*mU*mC 1145 mG*mC*mCmUmUmCfUmCfCfGfGmGmAmC mU*fC*mAmAmUfCmUfGfUm siRNA mAmGmAmUmU*mG* CmCmCmGfGmAfGmAmAmG -569 mA 1146 mGmC*mA*mU 1147 mC*mC*mUmUmCmUfCmCfGfGfGmAmCmA mU*fC*mCmAmAfUmCfUfGm siRNA mGmAmUmUmG*mG* UmCmCmCfGmGfAmGmAmA -570 mA 1148 mGmG*mC*mA 1149 mC*mU*mUmCmUmCfCmGfGfGfAmCmAmG mU*fU*mCmCmAfAmUfCfUm siRNA mAmUmUmGmG*mA* GmUmCmCfCmGfGmAmGmA -571 mA 1150 mAmG*mG*mC 1151 mU*mG*mGmAmUmUfUmGfAfAfGmGmAm mU*fG*mUmCmGfAmAfCfUm siRNA GmUmUmCmGmA*mC CmCmUmUfCmAfAmAmUmCm -572 *mA 1152 CmA*mU*mU 1153 mG*mG*mAmUmUmUfGmAfAfGfGmAmGm mU*fA*mGmUmCfGmAfAfCm siRNA UmUmCmGmAmC*mU UmCmCmUfUmCfAmAmAmU -573 *mA 1154 mCmC*mA*mU 1155 mG*mA*mUmUmUmGfAmAfGfGfAmGmUm mU*fA*mAmGmUfCmGfAfAm siRNA UmCmGmAmCmU*mU CmUmCmCfUmUfCmAmAmAm -574 *mA 1156 UmC*mC*mA 1157 mU*mU*mGmGmAmUfGmCfCfCfUmGmUmU mU*fA*mUmAmCfCmCfAfAm siRNA mGmGmGmUmA*mU* CmAmGmGfGmCfAmUmCmCm -575 mA 1158 AmA*mG*mU 1159 mU*mG*mGmAmUmGfCmCfCfUfGmUmUmG mU*fU*mAmUmAfCmCfCfAm siRNA mGmGmUmAmU*mA* AmCmAmGfGmGfCmAmUmC -576 mA 1160 mCmA*mA*mG 1161 mG*mG*mAmUmGmCfCmCfUfGfUmUmGmG mU*fC*mUmAmUfAmCfCfCm siRNA mGmUmAmUmA*mG* AmAmCmAfGmGfGmCmAmU -577 mA 1162 mCmC*mA*mA 1163 mG*mA*mUmGmCmCfCmUfGfUfUmGmGmG mU*fU*mCmUmAfUmAfCfCm siRNA mUmAmUmAmG*mA* CmAmAmCfAmGfGmGmCmA-578 mA 1164 mUmC*mC*mA 1165Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mU*mG*mCmCmCmUfGmU fU fGfGmGmU mA mU*fC*mAmUmCfUmAfUfAm siRNA mUmAmGmAmU*mG* CmCmCmAfAmCfAmGmGmGm -579 mA 1166 CmA*mU*mC 1167 mG*mC*mCmCmUmGfU mU fGfGfGmU m AmU mU*fU*mCmAmUfCmUfAfUm siRNA mAmGmAmUmG*mA* AmCmCmCfAmAfCmAmGmGm -580 mA 1168 GmC*mA*mU 1169 mC*mC*mCmUmGmUfU mGfGfGfU m AmU mA mU*fG*mUmCmAfUmCfUfAm siRNA mGmAmUmGmA*mC* UmAmCmCfCmAfAmCmAmGm -581 mA 1170 GmG*mC*mA 1171 mC*mC*mUmGmUmUfGmGfGfU f AmU m Am mU*fG*mGmUmCfAmUfCfUm siRNA GmAmUmGmAmC*mC AmUmAmCfCmCfAmAmCmAm -582 *mA 1172 GmG*mG*mC 1173 mC*mU*mGmUmUmGfGmGfU f AfU m AmGm mU*fA*mGmGmUfCmAfUfCm siRNA AmUmGmAmCmC*mU UmAmUmAfCmCfCmAmAmCm -583 *mA 1174 AmG*mG*mG 1175 mU*mG*mUmUmGmGfGmU f AfU f AmGm Am mU*fC*mAmGmGfUmCfAfUm siRNA UmGmAmCmCmU*mG CmUmAmUfAmCfCmCmAmAm -584 *mA 1176 CmA*mG*mG 1177 mG*mU*mUmGmGmGfU m AfU f AfGm AmU m mU*fC*mCmAmGfGmUfCfAm siRNA GmAmCmCmUmG*mG UmCmUmAfUmAfCmCmCmAm -585 *mA 1178 AmC*mA*mG 1179 mU*mU*mGmGmGmUf AmU f AfGf AmU mGm mU*fU*mCmCmAfGmGfUfCm siRNA AmCmCmUmGmG*mA AmU mCmU f AmU f AmCmCmCm -586 *mA 1180 AmA*mC*mA 1181 mU*mG*mGmGmUmAfUmAfGfAfUmGmAmC mU*fU*mUmCmCfAmGfGfUm siRNA mCmUmGmGmA*mA* CmAmUmCfUmAfUmAmCmCm -587 mA 1182 CmA*mA*mC 1183 mG*mG*mGmUmAmUfAmGfAfUfGmAmCmC mU*fU*mUmUmCfCmAfGfGm siRNA mUmGmGmAmA*mA* UmCmAmUfCmUfAmUmAmC -588 mA 1184 mCmC*mA*mA 1185 mG*mG*mUmAmUmAfGmAfUfGfAmCmCmU mU*fG*mUmUmUfCmCfAfGm siRNA mGmGmAmAmA*mC * GmUmCmAfUmCfUmAmUmA-589 mA 1186 mCmC*mC*mA 1187Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mG*mU*mAmUmAmGfAmUfGfAfCmCmUmG mU*fG*mGmUmUfUmCfCfAm siRNA mGmAmAmAmC *mC * GmGmU mCf AmU fCmU m AmU -590 mA 1188 mAmC*mC*mC 1189 mU*mA*mUmAmGmAfUmGfAfCfCmUmGmG mU*fU*mGmGmUfUmUfCfCm siRNA mAmAmAmCmC *mA* AmGmGmU fCm AfU mCmU mA -591 mA 1190 mUmA*mC*mC 1191 mU*mG*mGmAmAmAfCmCfAfUfGmCmCmA mU*fG*mUmCmAfUmCfUfGm siRNA mGmAmUmGmA*mC* GmCmAmUfGmGfUmUmUmC -592 mA 1192 mCmA*mG*mG 1193 mG*mG*mAmAmAmCfCmAfUfGfCmCmAmG mU*fG*mGmUmCfAmUfCfUm siRNA mAmUmGmAmC*mC* GmGmCmAfUmGfGmUmUmU -593 mA 1194 mCmC*mA*mG 1195 mG*mA*mAmAmCmCfAmUfGfCfCmAmGmA mU*fA*mGmGmUfCmAfUfCm siRNA mUmGmAmCmC*mU* UmGmGmCfAmUfGmGmUmU -594 mA 1196 mUmC*mC*mA 1197 mA*mA*mAmCmCmAfUmGfCfCfAmGmAmU mU*fA*mAmGmGfUmCfAfUm siRNA mGmAmCmCmU*mU* CmUmGmGfCmAfUmGmGmU -595 mA 1198 mUmU*mC*mC 1199 mA*mG*mAmCmGmGfUmGfAfAfCmCmCmA mU*fG*mCmCmAfAmUfUfGm siRNA mAmUmUmGmG*mC* GmGmU mU fCm AfCmCmGmU -596 mA 1200 mCmU*mG*mG 1201 mG*mA*mCmGmGmUfGmAfAfCfCmCmAmA mU*fG*mGmCmCfAmAfUfUm siRNA mUmUmGmGmC*mC* GmGmGmU fU mCf AmCmCmG -597 mA 1202 mUmC*mU*mG 1203 mU*mU*mUmAmAmCfAmAfAfAfCmCmCmG mU*fC*mCmUmGfGmUfCfGm siRNA mAmCmCmAmG*mG* GmGmU mU fU mU fGmU mU mA -598 mA 1204 mAmA*mC*mU 1205 mU*mU*mAmAmCmAfAmAfAfCfCmCmGmA mU*fA*mCmCmUfGmGfUfCm siRNA mCmCmAmGmG*mU * GmGmGmU fU mU fU mGmU mU -599 mA 1206 mAmA*mA*mC 1207 mG*mG*mGmUmCmCfUmGfUfCfCmUmCmC mU*fU*mGmGmAfGmUfGfGm siRNA mAmCmUmCmC*mA* AmGmGmAfCmAfGmGmAmC-600 mA 1208 mCmC*mC*mU 1209Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mC*mU*mGmUmCmCfUmCfCfAfCmUmCmC mU*fU*mGmAmUfCmUfGfGm siRNA mAmGmAmUmC*mA* AmGmU mGfGm AfGmGm AmC -601 mA 1210 mAmG*mG*mA 1211 mU*mG*mUmCmCmUfCmCfAfCfUmCmCmA mU*fA*mUmGmAfUmCfUfGm siRNA mGmAmUmCmA*mU* Gm AmGmU fGmGf AmGmGm A -602 mA 1212 mCmA*mG*mG 1213 mG*mU*mCmCmUmCfCmAfCfUfCmCmAmG mU*fA*mAmUmGfAmUfCfUm siRNA mAmUmCmAmU*mU* GmGmAmGfUmGfGmAmGmG -603 mA 1214 mAmC*mA*mG 1215 mC*mC*mUmUmUmAfGmU fU fU f AmGm Am mU*fG*mCmCmCfAmGfCfUm siRNA GmCmUmGmGmG*mC CmUmAmAfAmCfUmAmAmA -604 *mA 1216 mGmG*mA*mA 1217 mC*mU*mUmUmAmGfU mU fU f AfGm AmGmC mU*fU*mGmCmCfCmAfGfCm siRNA mUmGmGmGmC*mA* U mCmU m Af Am AfCmU m Am A -605 mA 1218 mAmG*mG*mA 1219 mU*mU*mUmAmGmUfU mU f AfGf AmGmCmU mU*fC*mUmGmCfCmCfAfGm siRNA mGmGmGmCmAW CmUmCmUfAmAfAmCmUmA -606 mA 1220 mAmA*mG*mG 1221 mU*mU*mAmGmUmUfUmAfGfAfGmCmUmG mU*fA*mCmUmGfCmCfCfAm siRNA mGmGmCmAmG*mU * GmCmUmCfUmAfAmAmCmU -607 mA 1222 mAmA*mA*mG 1223 mU*mA*mGmUmUmUfAmGfAfGfCmUmGmG mU*fC*mAmCmUfGmCfCfCm siRNA mGmCmAmGmU *mG* AmGmCmUfCmUfAmAmAmC -608 mA 1224 mUmA*mA*mA 1225 mA*mG*mUmUmUmAfGmAfGfCfUmGmGmG mU*fU*mCmAmCfUmGfCfCm siRNA mCmAmGmUmG*mA* CmAmGmCfUmCfUmAmAmA -609 mA 1226 mCmU*mA*mA 1227 mG*mU*mUmUmAmGfAmGfCfUfGmGmGmC mU*fU*mUmCmAfCmUfGfCm siRNA mAmGmUmGmA*mA* CmCmAmGfCmUfCmUmAmAm -610 mA 1228 AmC*mU*mA 1229 mU*mU*mUmAmGmAfGmCfUfGfGmGmCmA mU*fC*mUmUmCfAmCfUfGm siRNA mGmUmGmAmA*mG* CmCmCmAfGmCfUmCmUmAm-611 mA 1230 AmA*mC*mU 1231Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mU*mU*mAmGmAmGfCmUfGfGfGmCmAmG mU*fA*mCmUmUfCmAfCfUm siRNA mUmGmAmAmG*mU* GmCmCmCfAmGfCmUmCmUm -612 mA 1232 AmA*mA*mC 1233 mU*mA*mGmAmGmCfUmGfGfGfCmAmGmU mU*fC*mAmCmUfUmCfAfCm siRNA mGmAmAmGmU*mG* UmGmCmCfCmAfGmCmUmCm -613 mA 1234 UmA*mA*mA 1235 mA*mG*mAmGmCmUfGmGfGfCfAmGmUmG mU*fC*mCmAmCfUmUfCfAm siRNA mAmAmGmUmG*mG* CmUmGmCfCmCfAmGmCmUm -614 mA 1236 CmU*mA*mA 1237 mG*mA*mGmCmUmGfGmGfCfAfGmUmGmA mU*fU*mCmCmAfCmUfUfCm siRNA mAmGmUmGmG*mA* AmCmUmGfCmCfCmAmGmCm -615 mA 1238 UmC*mU*mA 1239 mA*mG*mCmUmGmGfGmCfAfGfUmGmAmA mU*fA*mUmCmCfAmCfUfUm siRNA mGmUmGmGmA*mU* CmAmCmU fGmCfCmCmAmGm -616 mA 1240 CmU*mC*mU 1241 mG*mC*mUmGmGmGfCmAfGfUfGmAmAmG mU*fU*mAmUmCfCmAfCfUm siRNA mUmGmGmAmU*mA* UmCmAmCfUmGfCmCmCmAm -617 mA 1242 GmC*mU*mC 1243 mC *mU *mGmGmGmCfAmGfUfGfAmAmGm mU*fA*mUmAmUfCmCfAfCm siRNA UmGmGmAmUmA*m UmUmCmAfCmUfGmCmCmCm -618 U*mA 1244 AmG*mC*mU 1245 mU WmGmGmCmAfGmU fGf Af AmGmU m mU*fG*mAmUmAfUmCfCfAm siRNA GmGmAmUmAmU*mC CmUmUmCfAmCfUmGmCmCm -619 *mA 1246 CmA*mG*mC 1247 mG*mG*mCmAmGmUfGmAfAfGfUmGmGm mU*fG*mUmGmAfUmAfUfCm siRNA AmUmAmUmCmA*mC CmAmCmUfUmCfAmCmUmGm -620 *mA 1248 CmC*mC*mA 1249 mG*mC*mAmGmUmGfAmAfGfUfGmGmAm mU*fA*mGmUmGfAmUfAfUm siRNA UmAmUmCmAmC*mU CmCmAmCfUmUfCmAmCmUm -621 *mA 1250 GmC*mC*mC 1251 mC*mA*mGmUmGmAf AmGfU fGfGm AmU m mU*fC*mAmGmUfGmAfUfAm siRNA AmUmCmAmCmU*mG UmCmCmAfCmUfUmCmAmCm-622 *mA 1252 UmG*mC*mC 1253Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mA*mG*mUmGmAmAfGmU fGfGf AmU m Am mU*fU*mCmAmGfUmGfAfUm siRNA UmCmAmCmUmG*mA AmUmCmCfAmCfUmUmCmAm -623 *mA 1254 CmU*mG*mC 1255 mG*mU*mGmAmAmGfU mGfGf AfU m AmU mC mU*fU*mUmCmAfGmUfGfAm siRNA mAmCmUmGmA*mA* UmAmUmCfCmAfCmUmUmCm -624 mA 1256 AmC*mU*mG 1257 mU*mG*mAmAmGmUfGmGfAfUfAmUmCmA mU*fC*mUmUmCfAmGfUfGm siRNA mCmUmGmAmA*mG* AmUmAmUfCmCfAmCmUmU -625 mA 1258 mCmA*mC*mU 1259 mG*mA*mAmGmUmGfGmAfUfAfUmCmAmC mU*fC*mCmUmUfCmAfGfUm siRNA mUmGmAmAmG*mG* Gm AmU m AfU mCfCm AmCmU -626 mA 1260 mUmC*mA*mC 1261 mA*mA*mGmUmGmGf AmUf AfUfCm AmCmU mU*fU*mCmCmUfUmCfAfGm siRNA mGmAmAmGmG*mA* U mGm AmU f AmU fCmCm AmC -627 mA 1262 mUmU*mC*mA 1263 mA*mG*mUmGmGmAfUm AfUfCf AmCmUmG mU*fC*mUmCmCfUmUfCfAm siRNA mAmAmGmGmA*mG* GmU mGm AfU m AfU mCmCm A -628 mA 1264 mCmU*mU*mC 1265 mG*mU*mGmGmAmUfAmUfCfAfCmUmGmA mU*fU*mCmUmCfCmUfUfCm siRNA mAmGmGmAmG*mA* AmGmU mGf AmU f AmU mCmC -629 mA 1266 mAmC*mU*mU 1267 mU*mU*mCmAmGmAfU m Af AfU fGm AmU m mU*fU*mGmCmCfAmCfUfAm siRNA AmGmUmGmGmC*mA UmCmAmUfUmAfUmCmUmG -630 *mA 1268 mAmA*mG*mG 1269 mU*mC *mAmGmAmUf Am AfU fGf AmU m Am mU*fA*mUmGmCfCmAfCfUm siRNA GmUmGmGmCmA*mU AmUmCmAfUmUfAmUmCmU -631 *mA 1270 mGmA*mA*mG 1271 mC*mA*mGmAmUmAf AmU fGf AfU m AmGm mU*fG*mAmUmGfCmCfAfCm siRNA UmGmGmCmAmU*mC UmAmUmCfAmUfUmAmUmC -632 *mA 1272 mUmG*mA*mA 1273 mA*mG*mAmUmAmAfU mGf AfU f AmGmU m mU*fA*mGmAmUfGmCfCfAm siRNA GmGmCmAmUmC*mU CmUmAmUfCmAfUmUmAmU-633 *mA 1274 mCmU*mG*mA 1275Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mG*mA*mUmAmAmUfGm AfU f AfGmU mGm mU*fC*mAmGmAfUmGfCfCm siRNA GmCmAmUmCmU*mG AmCmUmAfUmCfAmUmUmA -634 *mA 1276 mUmC*mU*mG 1277 mU*mA*mAmUmGmAfUmAfGfUfGmGmCmA mU*fU*mAmCmAfGmAfUfGm siRNA mUmCmUmGmU*mA* CmCmAmCfUmAfUmCmAmUm -635 mA 1278 UmA*mU*mC 1279 mA*mA*mUmGmAmUfAmGfUfGfGmCmAmU mU*fA*mUmAmCfAmGfAfUm siRNA mCmUmGmUmA*mU* GmCmCmAfCmUfAmUmCmAm -636 mA 1280 UmU*mA*mU 1281 mA*mU*mGmAmUmAfGmUfGfGfCmAmUmC mU*fC*mAmUmAfCmAfGfAm siRNA mUmGmUmAmU*mG* UmGmCmCfAmCfUmAmUmCm -637 mA 1282 AmU*mU*mA 1283 mA*mA*mAmAmGmUfAmAfAfGfGmGmUm mU*fG*mUmUmUfCmUfCfAm siRNA GmAmGmAmAmA*mC CmCmCmUfUmUfAmCmUmUm -638 *mA 1284 UmU*mG*mC 1285 mA*mA*mAmGmUmAfAmAfGfGfGmUmGm mU*fA*mGmUmUfUmCfUfCm siRNA AmGmAmAmAmC *mU AmCmCmCfUmUfUmAmCmUm -639 *mA 1286 UmU*mU*mG 1287 mA*mA*mGmUmAmAfAmGfGfGfUmGmAm mU*fC*mAmGmUfUmUfCfUm siRNA GmAmAmAmCmU*mG CmAmCmCfCmUfUmUmAmCm -640 *mA 1288 UmU*mU*mU 1289 mA*mG*mUmAmAmAfGmGfGfUfGmAmGm mU*fC*mCmAmGfUmUfUfCm siRNA AmAmAmCmUmG*mG UmCmAmCfCmCfUmUmUmAm -641 *mA 1290 CmU*mU*mU 1291 mG*mA*mGmAmAmAfCmUfGfGfAmUmAmA mU*fA*mGmCmUfUmCfUfUm siRNA mGmAmAmGmC *mU* AmUmCmCfAmGfUmUmUmC -642 mA 1292 mUmC*mA*mC 1293 mA*mG*mAmAmAmCfU mGfGf AfU m Am Am mU*fC*mAmGmCfUmUfCfUm siRNA GmAmAmGmCmU*mG UmAmUmCfCmAfGmUmUmU -643 *mA 1294 mCmU*mC*mA 1295 mG*mA*mAmAmCmUfGmGfAfUfAmAmGm mU*fU*mCmAmGfCmUfUfCm siRNA AmAmGmCmUmG*mA U mU m AmU fCmCf AmGmU mU-644 *mA 1296 mUmC*mU*mC 1297Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mA*mA*mAmCmUmGfGm AfU f Af AmGm Am mU*fU*mUmCmAfGmCfUfUm siRNA AmGmCmUmGmA*mA CmUmUmAfUmCfCmAmGmU -645 *mA 1298 mUmU*mC*mU 1299 mU*mGmCmCmAfAmGfGfAfGmAmUmC mU*fG*mUmAmCfUmGfGfAm siRNA mCmAmGmUmA*mC* UmCmUmCfCmUfUmGmGmCm -646 mA 1300 CmA*mG*mG 1301 mC *mC *mAmAmGmGfAmGfAfUfCmCmAmG mU*fC*mAmGmGfUmAfCfUm siRNA mUmAmCmCmU*mG* GmGm AmU fCmU fCmCmU mU -647 mA 1302 mGmG*mC*mC 1303 mC *mA*mAmGmGmAfGmAfUfCfCmAmGmU mU*fU*mCmAmGfGmUfAfCm siRNA mAmCmCmUmG*mA* U mGmGm AfU mCfU mCmCmU -648 mA 1304 mUmG*mG*mC 1305 mA*mA*mGmGmAmGfAmUfCfCfAmGmUmA mU*fU*mUmCmAfGmGfUfAm siRNA mCmCmUmGmA*mA* CmU mGmGf AmU fCmU mCmCm -649 mA 1306 UmU*mG*mG 1307 mA*mG*mGmAmGmAfUmCfCfAfGmUmAmC mU*fU*mUmUmCfAmGfGfUm siRNA mCmUmGmAmA*mA* AmCmUmGfGmAfUmCmUmC -650 mA 1308 mCmU*mU*mG 1309 mG*mG*mAmGmAmUfCmCfAfGfUmAmCmC mU*fC*mUmUmUfCmAfGfGm siRNA mUmGmAmAmA*mG* UmAmCmUfGmGfAmUmCmU -651 mA 1310 mCmC*mU*mU 1311 mG*mA*mGmAmUmCfCmAfGfUfAmCmCmU mU*fU*mCmUmUfUmCfAfGm siRNA mGmAmAmAmG*mA* GmUmAmCfUmGfGmAmUmC -652 mA 1312 mUmC*mC*mU 1313 mA*mG*mAmUmCmCfAmGfUfAfCmCmUmG mU*fA*mUmCmUfUmUfCfAm siRNA mAmAmAmGmA*mU* GmGm U m AfCmU fGmGm AmU -653 mA 1314 mCmU*mC*mC 1315 mG*mA*mUmCmCmAfGmUfAfCfCmUmGmA mU*fA*mAmUmCfUmUfUfCm siRNA mAmAmGmAmU*mU* AmGmGmU f AmCfU mGmGm A -654 mA 1316 mUmC*mU*mC 1317 mA*mU*mCmCmAmGfUmAfCfCfUmGmAmA mU*fA*mAmAmUfCmUfUfUm siRNA mAmGmAmUmU*mU* Cm AmGmGfU m AfCmU mGmG-655 mA 1318 mAmU*mC*mU 1319Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mC*mC*mAmGmUmAfCmCfUfGfAmAmAmG mU*fU*mCmAmAfAmUfCfUm siRNA mAmUmUmUmG*mA* UmUmCmAfGmGfUmAmCmU -656 mA 1320 mGmG*mA*mU 1321 mC*mA*mGmUmAmCfCmUfGfAfAmAmGmA mU*fA*mUmCmAfAmAfUfCm siRNA mUmUmUmGmA*mU* UmUmUmCfAmGfGmUmAmC -657 mA 1322 mUmG*mG*mA 1323 mA*mG*mUmAmCmCfU mGf Af Af AmGm Am mU*fU*mAmUmCfAmAfAfUm siRNA UmUmUmGmAmU*m CmUmUmUfCmAfGmGmUmA -658 A*mA 1324 mCmU*mG*mG 1325 mG*mU*mAmCmCmUfGm Af Af AfGm AmU m mU*fC*mUmAmUfCmAfAfAm siRNA UmUmGmAmUmA*m UmCmUmUfUmCfAmGmGmU -659 G*mA 1326 mAmC*mU*mG 1327 mU*mA*mCmCmUmGf Am Af AfGf AmU mU m mU*fU*mCmUmAfUmCfAfAm siRNA UmGmAmUmAmG*m AmU mCmU fU mU fCm AmGmG -660 A*mA 1328 mUmA*mC*mU 1329 mA*mC*mCmUmGmAf Am AfGf AfU mU mU m mU*fU*mUmCmUfAmUfCfAm siRNA GmAmUmAmGmA*m AmAmUmCfUmUfUmCmAmG -661 A*mA 1330 mGmU*mA*mC 1331 mG*mA*mUmAmGmAfAmGfAfGfGmUmCmC mU*fC*mCmUmUfGmCfGfGm siRNA mGmCmAmAmGW AmCmCmUfCmUfUmCmUmAm -662 mA 1332 UmC*mA*mA 1333 mA*mU*mAmGmAmAfGmAfGfGfUmCmCmG mU*fG*mCmCmUfUmGfCfGm siRNA mCmAmAmGmG*mC * GmAmCmCfUmCfUmUmCmUm -663 mA 1334 AmU*mC*mA 1335 mU*mA*mGmAmAmGfAmGfGfUfCmCmGmC mU*fU*mGmCmCfUmUfGfCm siRNA mAmAmGmGmC *mA* GmGmAmCfCmUfCmUmUmCm -664 mA 1336 UmA*mU*mC 1337 mA*mG*mAmAmGmAfGmGfUfCfCmGmCmA mU*fU*mUmGmCfCmUfUfGm siRNA mAmGmGmCmA*mA* CmGmGmAfCmCfUmCmUmUm -665 mA 1338 CmU*mA*mU 1339 mG*mA*mAmGmAmGfGmUfCfCfGmCmAmA mU*fC*mUmUmGfCmCfUfUm siRNA mGmGmCmAmAW GmCmGmGfAmCfCmUmCmUm-666 mA 1340 UmC*mU*mA 1341Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence NO: Antisense Sequence NO:mA*mA*mGmAmGmGfUmCfCfGfCmAmAmG mU*fC*mCmUmUfGmCfCfUm siRNA mGmCmAmAmGW UmGmCmGfGmAfCmCmUmCm-667 mA 1342 UmU*mC*mU 1343 mC*mA*mAmUmGmUfGmCfUfUfGmUmAmC mU*fC*mUmCmUfAmUfGfUm siRNA mAmUmAmGmA*mG* AmCmAmAfGmCfAmCmAmU-668 mA 1344 mUmG*mA*mC 1345 mA*mA*mUmGmUmGfCmUfUfGfUm AmCm A mU*fA*mCmUmCfUmAfUfGm siRNA mUmAmGmAmG*mU* UmAmCmAfAmGfCmAmCmA-669 mA 1346 mUmU*mG*mA 1347 siRNA mC *mA*mAmCmAmU 14490 mU*fA*mGmCmUfCmAfUfUm 14491 -1126 fGmAfCfCfGmAmAmA UmCmGmGfUmCfAmUmGmU mUmGmAmGmC*mU* mUmG*mC*mGmAsiRNA mC *mA*mGmAmCmG 14492 mU*fC*mCmAmAfUmUfGfGm 14493 -1127 fGmUfGfAfAmCmCmC GmUmUmCfAmCfCmGmUmCm mAmAmUmUmG*mG* UmG*mG*mGmAsiRNA mG*mA*mAmAmGmU 14494 mU*fU*mCmGmGfGmUfUfUm 14495 -1128 fU mU f Af AfCm Am Am A U mGmU mU f Am Af AmCmU mU mAmCmCmCmG*mA* mUmC*mU*mGmAsiRNA mG*mA*mUmUmUmG 14496 mU*fC*mGmGmAfCmCfUfCm 14497 -1129 f AmU f AfGf Am AmGm U mU mCmU f AmU fCm Am Am A AmGmGmUmCmC*mG mUmC*mU*mU*mAsiRNA mA*mU*mUmUmGmA 14498 mU*fG*mCmGmGfAmCfCfUm 14499 -1130 fU m AfGf Af AmGm Am CmUmUmCfUmAfUmCmAmA GmGmUmCmCmG*mC mAmU*mC*mU*mATable 4. GalNAc Modified siRNAsSEQ SEQ ID IDsiRNA Sense Sequence* NO: Antisense SequenceANO:mG*mA*mAmGmAmAfAmGf mU*fA*mAmGmAfGmAfCfC siRNA CfCfUmAmGmGmUmCmUm mU m AmGmGfCmU fU mU mC -670 CmU*mU*mA(GalNAc-5) 1348 mUmUmC*mA*mG 903 mA*mA*mGmAmAmAfGmCf mU*fU*mAmAmGfAmGfAfC siRNA CfUfAmGmGmUmCmUmCm mCmUmAmGfGmCfUmUmU-671 UmU*mA*mA(GalNAc-5) 1349 mCmUmU*mC*mA 905Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence* NO: Antisense SequenceANO:mA*mA*mGmCmCmUfAmGf mU*fC*mAmUmCfUmAfAfG siRNA GfU fCmU mCmU mU m AmGm mAmGmAmCfCmUfAmGmG -672 AmU*mG*mA(GalNAc-5) 1350 mCmUmU*mU*mC 907 mA*mG*mCmCmUmAfGmGf mU*fU*mCmAmUfCmUfAfA siRNA UfCfUmCmUmUmAmGmAm mGmAmGmAfCmCfUmAmG -673 UmG*mA*mA(GalNAc-5) 1351 mGmCmU*mU*mU 909 mU*mA*mCmCmUmGfGmAf mU*fU*mGmCmUfUmGfGfC siRNA GfGfUmGmGmCmCmAmAm mCmAmCmCfUmCfCmAmG-674 GmC*mA*mA(GalNAc-5) 1352 mGmUmA*mA*mU 911 mA*mC*mCmUmGmGfAmGf mU*fG*mUmGmCfUmUfGfG siRNA GfUfGmGmCmCmAmAmGm mCmCmAmCfCmUfCmCmAm -675 CmA*mC*mA(GalNAc-5) 1353 GmGmU*mA*mA 913 mC*mC*mUmGmGmAfGmGf mU*fA*mGmUmGfCmUfUfG siRNA UfGfGmCmCmAmAmGmCm mGmCmCmAfCmCfUmCmCm -676 AmC*mU*mA(GalNAc-5) 1354 AmGmG*mU*mA 915 mU*mC*mAmAmAmCfCmUf mU*fG*mGmAmGfAmAfCfC siRNA Cf AfU mGmGmGmU mU mCm mCmAmUmGfAmGfGmUmU -677 UmC*mC*mA(GalNAc-5) 1355 mUmGmA*mA*mG 917 mC*mA*mAmAmCmCfUmCf mU*fU*mGmGmAfGmAfAfC siRNA AfUfGmGmGmUmUmCmUm mCmCmAmUfGmAfGmGmU -678 CmC*mA*mA(GalNAc-5) 1356 mUmUmG*mA*mA 919 mA*mA*mAmCmCmUfCmAf mU*fC*mUmGmGfAmGfAfA siRNA U fGfGmGmU mU mCmU mCm mCmCmCmAfUmGfAmGmG -679 CmA*mG*mA(GalNAc-5) 1357 mUmUmU*mG*mA 921 mC*mC*mUmCmAmUfGmGf mU*fU*mCmGmCfUmGfGfA siRNA GfU fU mCmU mCmCm AmGm mGmAmAmCfCmCfAmUmG -680 CmG*mA*mA(GalNAc-5) 1358 mAmGmG*mU*mU 923 mC*mU*mCmAmUmGfGmGf mU*fG*mUmCmGfCmUfGfG siRNA UfUfCmUmCmCmAmGmCm mAmGmAmAfCmCfCmAmU -681 GmA*mC*mA(GalNAc-5) 1359 mGmAmG*mG*mU 925 mU*mC*mAmUmGmGfGmUf mU*fU*mGmUmCfGmCfUfG siRNA UfCfUmCmCmAmGmCmGm mGmAmGmAfAmCfCmCmA -682 AmC*mA*mA(GalNAc-5) 1360 mUmGmA*mG*mG 927 mC*mA*mUmGmGmGfUmUf mU*fU*mUmGmUfCmGfCfU siRNA CfUfCmCmAmGmCmGmAmC mGmGmAmGfAmAfCmCmC -683 mA*mA*mA(GalNAc-5) 1361 mAmUmG*mA*mG 929 mA*mU*mGmGmGmUfUmCf mU*fC*mUmUmGfUmCfGfC siRNA UfCfCmAmGmCmGmAmCm mU mGmGm AfGm Af AmCmC -684 AmA*mG*mA(GalNAc-5) 1362 mCmAmU*mG*mA 931 mU*mG*mGmGmUmUfCmUf mU*fC*mCmUmUfGmUfCfG siRNA CfCfAmGmCmGmAmCmAm mCmUmGmGfAmGfAmAmC -685 AmG*mG*mA(GalNAc-5) 1363 mCmCmA*mU*mG 933 mG*mG*mGmUmUmCfUmCf mU*fG*mCmCmUfUmGfUfC siRNA CfAfGmCmGmAmCmAmAm mGmCmUmGfGmAfGmAmA-686 GmG*mC*mA(GalNAc-5) 1364 mCmCmC *mA*mU 935Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence* NO: Antisense SequenceANO:mU*mU*mCmUmCmCfGmGf mU*fA*mUmCmCfAmAfUfC siRNA Gf AfCm AmGm AmU mU mGm mUmGmUmCfCmCfGmGmA -687 GmA*mU*mA(GalNAc-5) 1365 mGmAmA*mG*mG 937 mU*mC*mUmCmCmGfGmGf mU*fC*mAmUmCfCmAfAfU siRNA AfCfAmGmAmUmUmGmGm mCmUmGmUfCmCfCmGmG -688 AmU*mG*mA(GalNAc-5) 1366 mAmGmA*mA*mG 939 mC*mU*mCmCmGmGfGmAf mU*fA*mCmAmUfCmCfAfA siRNA CfAfGmAmUmUmGmGmAm mUmCmUmGfUmCfCmCmG-689 UmG*mU*mA(GalNAc-5) 1367 mGmAmG*mA*mA 941 mC*mC*mGmGmGmAfCmAf mU*fC*mAmAmCfAmUfCfC siRNA GfAfUmUmGmGmAmUmGm mAmAmUmCfUmGfUmCmC -690 UmU*mG*mA(GalNAc-5) 1368 mCmGmG*mA*mG 943 mC*mG*mGmGmAmCfAmGf mU*fC*mCmAmAfCmAfUfC siRNA AfUfUmGmGmAmUmGmUm mCmAmAmUfCmUfGmUmC -691 UmG*mG*mA(GalNAc-5) 1369 mCmCmG*mG*mA 945 mG*mG*mGmAmCmAfGmAf mU*fU*mCmCmAfAmCfAfU siRNA U fU fGmGm AmU mGmU mU m mCmCm Am AfU mCfU mGmU -692 GmG*mA*mA(GalNAc-5) 1370 mCmCmCWmG 947 mG*mG*mAmCmAmGfAmUf mU*fC*mUmCmCfAmAfCfA siRNA U fGfGm AmU mGmU mU mGm mUmCmCmAfAmUfCmUmG -693 GmA*mG*mA(GalNAc-5) 1371 mUmCmC*mC*mG 949 mA*mC*mAmGmAmUfUmGf mU*fU*mUmCmUfCmCfAfA siRNA GfAfUmGmUmUmGmGmAm mCm AmU mCfCm Af AmU mC -694 GmA*mA*mA(GalNAc-5) 1372 mUmGmU*mC*mC 951 mU*mA*mGmAmUmGfAmCf mU*fC*mAmUmGfGmUfUfU siRNA CfUfGmGmAmAmAmCmCm mCmCmAmGfGmUfCmAmU -695 AmU*mG*mA(GalNAc-5) 1373 mCmUmA*mU*mA 953 mA*mG*mAmUmGmAfCmCf mU*fG*mCmAmUfGmGfUfU siRNA UfGfGmAmAmAmCmCmAm mUmCmCmAfGmGfUmCmA -696 UmG*mC*mA(GalNAc-5) 1374 mUmCmU*mA*mU 955 mG*mA*mUmGmAmCfCmUf mU*fG*mGmCmAfUmGfGfU siRNA GfGfAmAmAmCmCmAmUm mU mU mCmCf A mGfGm U mC -697 GmC*mC*mA(GalNAc-5) 1375 mAmUmC*mU*mA 957 mA*mU*mGmAmCmCfUmGf mU*fU*mGmGmCfAmUfGfG siRNA GfAfAmAmCmCmAmUmGm mUmUmUmCfCmAfGmGmU -698 CmC*mA*mA(GalNAc-5) 1376 mCmAmU*mC*mU 959 mG*mA*mCmCmUmGfGmAf mU*fU*mCmUmGfGmCfAfU siRNA AfAfCmCmAmUmGmCmCm mGmGmU mU fU mCfCm A mG -699 AmG*mA*mA(GalNAc-5) 1377 mGmUmC*mA*mU 961 mC*mC*mUmGmGmAfAmAf mU*fC*mAmUmCfUmGfGfC siRNA CfCfAmUmGmCmCmAmGm m AmU mGmGfU mU fU mCmC -700 AmU*mG*mA(GalNAc-5) 1378 mAmGmG*mU*mC 963 mC*mU*mGmGmAmAfAmCf mU*fU*mCmAmUfCmUfGfG siRNA CfAfUmGmCmCmAmGmAm mCmAmUmGfGmUfUmUmC-701 UmG*mA*mA(GalNAc-5) 1379 mCmAmG*mG*mU 965Attorney Docket Number: J0365.70001WO00SEQ SEQ ID IDsiRNA Sense Sequence* NO: Antisense SequenceANO:mA*mC*mGmGmUmGfAmAf mU*fU*mGmGmCfCmAfAfU siRNA CfCfCmAmAmUmUmGmGm mUmGmGmGfUmUfCmAmC -702 CmC*mA*mA(GalNAc-5) 1380 mCmGmU*mC*mU 967 mG*mU*mGmAmAmCfCmCf mU*fA*mGmAmUfGmGfCfC siRNA AfAfUmUmGmGmCmCmAm m Am AmU mU fGmGfGmU mU -703 UmC*mU*mA(GalNAc-5) 1381 mCmAmC*mC*mG 969 mU*mG*mAmAmCmCfCmAf mU*fG*mAmGmAfUmGfGfC siRNA AfUfUmGmGmCmCmAmUm mCmAmAmUfUmGfGmGmU -704 CmU*mC*mA(GalNAc-5) 1382 mUmCmA*mC*mC 971 mA*mA*mUmUmGmGfCmCf mU*fU*mUmUmCfUmGfGfG siRNA AfUfCmUmCmCmCmAmGm mAmGmAmUfGmGfCmCmA -705 AmA*mA*mA(GalNAc-5) 1383 mAmUmU*mG*mG 973 mA*mU*mUmGmGmCfCmAf mU*fC*mUmUmUfCmUfGfG siRNA UfCfUmCmCmCmAmGmAm mGm AmGm AfU mGfGmCmC -706 AmA*mG*mA(GalNAc-5) 1384 mAmAmU*mU*mG 975 mG*mA*mUmCmAmUfUmCf mU*fU*mCmUmAfAmAfCfU siRNA CfUfUmUmAmGmUmUmUm m Am Am AmGfGm Af AmU mG -707 AmG*mA*mA(GalNAc-5) 1385 mAmUmC*mU*mG 977 mA*mU*mCmAmUmUfCmCf mU*fC*mUmCmUfAmAfAfC siRNA UfUfUmAmGmUmUmUmAm mU m Am Am AfGmGf Am AmU -708 GmA*mG*mA(GalNAc-5) 1386 mGmAmU*mC *mU 979 mU*mC*mAmUmUmCfCmUf mU*fG*mCmUmCfUmAfAfA siRNA U fU f AmGmU mU mU m AmGm mCmUmAmAfAmGfGmAmA -709 AmG*mC*mA(GalNAc-5) 1387 mUmGmA*mU*mC 981 mC*mA*mUmUmCmCfUmUf mU*fA*mGmCmUfCmUfAfA siRNA U f AfGmU mU mU m AmGm Am mAmCmUmAfAmAfGmGmA -710 GmC*mU*mA(GalNAc-5) 1388 mAmUmG*mA*mU 983 mG*mA*mUmAmGmUfGmGf mU*fC*mUmCmAfUmAfCfA siRNA CfAfUmCmUmGmUmAmUm mGmAmUmGfCmCfAmCmU -711 GmA*mG*mA(GalNAc-5) 1389 mAmUmC*mA*mU 985 mA*mU*mAmGmUmGfGmCf mU*fG*mCmUmCfAmUfAfC siRNA AfU fCmU mGmU m AmU mGm m AmGm AmU fGmCfCm AmC -712 AmG*mC*mA(GalNAc-5) 1390 mUmAmU*mC*mA 987 mU*mA*mGmUmGmGfCmAf mU*fG*mGmCmUfCmAfUfA siRNA UfCfUmGmUmAmUmGmAm mCmAmGmAfUmGfCmCmA -713 GmC*mC*mA(GalNAc-5) 1391 mCmUmA*mU*mC 989 mA*mG*mUmGmGmCfAmUf mU*fG*mGmGmCfUmCfAfU siRNA CfUfGmUmAmUmGmAmGm mAmCmAmGfAmUfGmCmC -714 CmC*mC*mA(GalNAc-5) 1392 mAmCmU*mA*mU 991 mG*mC*mCmAmCmUfAmGf mU*fU*mUmCmUfGmGfCfG siRNA GfUfAmCmCmGmCmCmAm mGmUmAmCfCmUfAmGmU -715 GmA*mA*mA(GalNAc-5) 1393 mGmGmCWmG 993 mC*mC*mAmCmUmAfGmGf mU*fC*mUmUmCfUmGfGfC siRNA UfAfCmCmGmCmCmAmGm mGmGmU m AfCmCfUm AmG-716 AmA*mG*mA(GalNAc-5) 1394 mUmGmG*mC*mU 995Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mC*mA*mCmUmAmGfGmUf mU*fU*mCmUmUfCmUfGfG siRNA AfCfCmGmCmCmAmGmAm mCmGmGmUfAmCfCmUmA-717 AmG*mA*mA(GalNAc-5) 1395 mGmUmGWmC 997 mU*mU*mCmUmGmAfCmCf mU*fG*mUmCmAfUmCfCfA siRNA AfCfGmUmUmGmGmAmUm mAmCmGmUfGmGfUmCmA -718 GmA*mC*mA(GalNAc-5) 1396 mGmAmA*mG*mG 999 mU*mC*mUmGmAmCfCmAf mU*fU*mGmUmCfAmUfCfC siRNA CfGfUmUmGmGmAmUmGm mAmAmCmGfUmGfGmUmC -719 AmC*mA*mA(GalNAc-5) 1397 mAmGmA*mA*mG 1001 mC WmGmAmCmCf AmCf mU*fG*mUmGmUfCmAfUfC siRNA GfUfUmGmGmAmUmGmAm mCmAmAmCfGmUfGmGmU -720 CmA*mC*mA(GalNAc-5) 1398 mCmAmG*mA*mA 1003 mU*mG*mGmCmCmAfUmCf mU*fA*mAmCmUfUmUfCfU siRNA UfCfCmCmAmGmAmAmAm mGmGmGm AfGm AfU mGmG -721 GmU*mU*mA(GalNAc-5) 1399 mCmCmA*mA*mU 1005 mC *mA*mAmGmAmCf AmGf mU*fA*mCmCmUfAmGfUfG siRNA CfAfGmCmCmAmCmUmAm mGmCmUmGfCmUfGmUmC -722 GmG*mU*mA(GalNAc-5) 1400 mUmUmG*mU*mU 1007 mA*mA*mGmAmCmAfGmCf mU*fU*mAmCmCfUmAfGfU siRNA AfGfCmCmAmCmUmAmGm mGmGmCmUfGmCfUmGmU -723 GmU*mA*mA(GalNAc-5) 1401 mCmUmU*mG*mU 1009 mA*mG*mAmCmAmGfCmAf mU*fG*mUmAmCfCmUfAfG siRNA GfCfCmAmCmUmAmGmGm mU mGmGmCfUmGfCmU mG -724 UmA*mC*mA(GalNAc-5) 1402 mUmCmU*mU*mG 1011 mA*mC *mAmGmCmAfGmCf mU*fC*mGmGmUfAmCfCfU siRNA CfAfCmUmAmGmGmUmAm m AmGmU mGfGmCfU mGmC -725 CmC*mG*mA(GalNAc-5) 1403 mUmGmU*mC*mU 1013 mA*mG*mCmCmAmCfUmAf mU*fU*mCmUmGfGmCfGfG siRNA GfGfUmAmCmCmGmCmCm mUmAmCmCfUmAfGmUmG -726 AmG*mA*mA(GalNAc-5) 1404 mGmCmU*mG*mC 1015 mU*mG*mGmAmGmGfUmGf mU*fG*mAmAmGfUmGfCfU siRNA GfCfCmAmAmGmCmAmCm mUmGmGmCfCmAfCmCmU-727 UmU*mC*mA(GalNAc-5) 1405 mCmCmA*mG*mG 1017 mG*mG*mAmGmGmUfGmGf mU*fU*mGmAmAfGmUfGfC siRNA CfCfAmAmGmCmAmCmUm mUmUmGmGfCmCfAmCmC -728 UmC*mA*mA(GalNAc-5) 1406 mUmCmC*mA*mG 1019 mG*mA*mGmGmUmGfGmCf mU*fU*mUmGmAfAmGfUfG siRNA CfAfAmGmCmAmCmUmUm mCmUmUmGfGmCfCmAmC-729 CmA*mA*mA(GalNAc-5) 1407 mCmUmC*mC*mA 1021 mA*mG*mGmUmGmGfCmCf mU*fU*mUmUmGfAmAfGfU siRNA Af AfGmCm AmCmU mU mCm mGmCmUmUfGmGfCmCmA -730 AmA*mA*mA(GalNAc-5) 1408 mCmCmU*mC*mC 1023 mG*mG*mUmGmGmCfCmAf mU*fG*mUmUmUfGmAfAfG siRNA AfGfCm AmCmU mU mCm Am mUmGmCmUfUmGfGmCmC-731 AmA*mC*mA(GalNAc-5) 1409 mAmCmC*mU*mC 1025Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mG*mU*mGmGmCmCfAmAf mU*fG*mGmUmUfUmGfAfA siRNA GfCfAmCmUmUmCmAmAm mGmUmGmCfUmUfGmGmC -732 AmC*mC*mA(GalNAc-5) 1410 mCmAmC*mC*mU 1027 mG*mC *mCmAmAmGfCmAf mU*fU*mGmAmGfGmUfUfU siRNA CfUfUmCmAmAmAmCmCm mGmAmAmGfUmGfCmUmU -733 UmC*mA*mA(GalNAc-5) 1411 mGmGmC*mC*mA 1029 mA*mG*mCmAmCmUfUmCf mU*fC*mCmCmAfUmGfAfG siRNA Af Af AmCmCmU mCm AmU m mGmU mU mU fGm Af AmGmU -734 GmG*mG*mA(GalNAc-5) 1412 mGmCmU*mU*mG 1031 mG*mC*mAmCmUmUfCmAf mU*fA*mCmCmCfAmUfGfA siRNA Af AfCmCmU mCm AmU mGm mGmGmU mU fU mGf Am A mG -735 GmG*mU*mA(GalNAc-5) 1413 mUmGmC*mU*mU 1033 mA*mC*mUmUmCmAfAmAf mU*fG*mAmAmCfCmCfAfU siRNA CfCfUmCmAmUmGmGmGm mGmAmGmGfUmUfUmGmA -736 UmU*mC*mA(GalNAc-5) 1414 mAmGmU*mG*mC 1035 mC*mU*mUmCmAmAfAmCf mU*fA*mGmAmAfCmCfCfA siRNA CfUfCmAmUmGmGmGmUm mU mGm AmGfGmU fU mU mG -737 UmC*mU*mA(GalNAc-5) 1415 mAmAmG*mU*mG 1037 mC*mU*mGmUmGmGfAmUf mU*fA*mCmUmGfAmCfCfA siRNA GfGfGmUmUmGmGmUmCm mAmCmCmCfAmUfCmCmA-738 AmG*mU*mA(GalNAc-5) 1416 mCmAmG*mC*mC 1039 mU*mC*mCmUmCmCfAmCf mU*fG*mAmAmUfGmAfUfC siRNA UfCfCmAmGmAmUmCmAm mU mGmGm AfGmU fGmGm A -739 UmU*mC*mA(GalNAc-5) 1417 mGmGmA*mC *mA 1041 mC*mC*mUmCmCmAfCmUf mU*fG*mGmAmAfUmGfAfU siRNA CfCfAmGmAmUmCmAmUm mCmUmGmGfAmGfUmGmG -740 UmC*mC*mA(GalNAc-5) 1418 mAmGmG*mA*mC 1043 mC*mU*mCmCmAmCfUmCf mU*fA*mGmGmAfAmUfGfA siRNA CfAfGmAmUmCmAmUmUm mUmCmUmGfGmAfGmUmG -741 CmC*mU*mA(GalNAc-5) 1419 mGmAmG*mG*mA 1045 mU*mC*mCmAmCmUfCmCf mU*fA*mAmGmGfAmAfUfG siRNA AfGf AmU mCm AmU mU mCm m AmUmC mUfGmGf AmGmU -742 CmU*mU*mA(GalNAc-5) 1420 mGmGmAWmG 1047 mC*mC*mAmCmUmCfCmAf mU*fA*mAmAmGfGmAfAfU siRNA Gf AfU mCm AmU mU mCmCm mGmAmUmCfUmGfGmAmG -743 UmU*mU*mA(GalNAc-5) 1421 mUmGmG*mA*mG 1049 mC*mA*mCmUmCmCfAmGf mU*fU*mAmAmAfGmGfAfA siRNA AfU fCm AmU mU mCmCmU m mU mGm AmU fCmU fGmGm A -744 UmU*mA*mA(GalNAc-5) 1422 mGmUmG*mG*mA 1051 mA*mC*mUmCmCmAfGmAf mU*fC*mUmAmAfAmGfGfA siRNA UfCfAmUmUmCmCmUmUm m AmU mGm AfU mCfU mGmG -745 UmA*mG*mA(GalNAc-5) 1423 mAmGmU*mG*mG 1053 mC*mU*mCmCmAmGfAmUf mU*fA*mCmUmAfAmAfGfG siRNA CfAfUmUmCmCmUmUmUm mAmAmUmGfAmUfCmUmG-746 AmG*mU*mA(GalNAc-5) 1424 mGmAmG*mU*mG 1055Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mU*mC*mCmAmGmAfUmCf mU*fA*mAmCmUfAmAfAfG siRNA AfUfUmCmCmUmUmUmAm mGm Am AmU fGm AfU mCmU -747 GmU*mU*mA(GalNAc-5) 1425 mGmGmA*mG*mU 1057 mC*mC*mAmGmAmUfCmAf mU*fA*mAmAmCfUmAfAfA siRNA U fU fCmCmU mU mU m AmGm mGmGm Am AfU mGf AmU mC -748 UmU*mU*mA(GalNAc-5) 1426 mUmGmG*mA*mG 1059 mA*mG*mAmUmCmAfUmUf mU*fC*mUmAmAfAmCfUfA siRNA CfCfUmUmUmAmGmUmUm m Am AmGmGf Am AfU mGm A -749 UmA*mG*mA(GalNAc-5) 1427 mUmCmU*mG*mG 1061 mA*mU*mUmCmCmUfUmUf mU*fC*mAmGmCfUmCfUfA siRNA AfGfUmUmUmAmGmAmGm mAmAmCmUfAmAfAmGmG -750 CmU*mG*mA(GalNAc-5) 1428 mAmAmU*mG*mA 1063 mU*mU*mCmCmUmUfUmAf mU*fC*mCmAmGfCmUfCfU siRNA GfUfUmUmAmGmAmGmCm mAmAmAmCfUmAfAmAmG -751 UmG*mG*mA(GalNAc-5) 1429 mGmAmA*mU*mG 1065 mU*mC*mCmUmUmUfAmGf mU*fC*mCmCmAfGmCfUfC siRNA UfUfUmAmGmAmGmCmUm mU m Am Am AfCmU f Am Am A -752 GmG*mG*mA(GalNAc-5) 1430 mGmGmA*mA*mU 1067 mA*mU*mGmAmCmCfGmAf mU*fA*mGmGmAfAmGfCfU siRNA Af AfU mGm AmGmCmU mU m mCmAmUmUfUmCfGmGmU -753 CmC*mU*mA(GalNAc-5) 1431 mCmAmU*mG*mU 1069 mU*mG*mAmCmCmGfAmAf mU*fC*mAmGmGfAmAfGfC siRNA AfU fGm AmGmCmU mU mCm mU mCm AmU fU mU fCmGmG -754 CmU*mG*mA(GalNAc-5) 1432 mUmCmA*mU*mG 1071 mC*mC*mUmGmAmGfCmAf mU*fC*mCmAmAfCmAfCfC siRNA GfCfGmAmGmGmUmGmUm mUmCmGmCfUmGfCmUmC-755 UmG*mG*mA(GalNAc-5) 1433 mAmGmG*mA*mA 1073 mC*mU*mGmAmGmCfAmGf mU*fA*mCmCmAfAmCfAfC siRNA CfGfAmGmGmUmGmUmUm mCmUmCmGfCmUfGmCmU-756 GmG*mU*mA(GalNAc-5) 1434 mCmAmG*mG*mA 1075 mU*mG*mAmGmCmAfGmCf mU*fC*mAmCmCfAmAfCfA siRNA Gf AfGmGmU mGmU mU mGm mCmCmUmCfGmCfUmGmC-757 GmU*mG*mA(GalNAc-5) 1435 mUmCmA*mG*mG 1077 mG*mA*mUmUmAmCfCmUf mU*fU*mUmGmGfCmCfAfC siRNA GfGfAmGmGmUmGmGmCm mCmUmCmCfAmGfGmUmA -758 CmA*mA*mA(GalNAc-5) 1436 mAmUmC*mA*mU 1079 mA*mU*mUmAmCmCfUmGf mU*fC*mUmUmGfGmCfCfA siRNA GfAfGmGmUmGmGmCmCm mCmCmUmCfCmAfGmGmU-759 AmA*mG*mA(GalNAc-5) 1437 mAmAmU*mC *mA 1081 mU*mU*mAmCmCmUfGmGf mU*fG*mCmUmUfGmGfCfC siRNA AfGfGmUmGmGmCmCmAm mAmCmCmUfCmCfAmGmG-760 AmG*mC*mA(GalNAc-5) 1438 mUmAmA*mU*mC 1083 mG*mG*mUmUmCmUfCmCf mU*fA*mGmCmCfUmUfGfU siRNA AfGfCmGmAmCmAmAmGm mCmGmCmUfGmGfAmGmA-761 GmC*mU*mA(GalNAc-5) 1439 mAmCmC*mC*mA 1085Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mG*mU*mUmCmUmCfCmAf mU*fU*mAmGmCfCmUfUfG siRNA GfCfGmAmCmAmAmGmGm mUmCmGmCfUmGfGmAmG -762 CmU*mA*mA(GalNAc-5) 1440 mAmAmC*mC*mC 1087 mU*mU*mCmUmCmCfAmGf mU*fU*mUmAmGfCmCfUfU siRNA CfGfAmCmAmAmGmGmCm mGmUmCmGfCmUfGmGmA -763 UmA*mA*mA(GalNAc-5) 1441 mGmAmA*mC *mC 1089 mC*mU*mCmCmAmGfCmGf mU*fC*mCmUmUfAmGfCfC siRNA AfCfAmAmGmGmCmUmAm mU mU mGmU fCmGfCmU mG -764 AmG*mG*mA(GalNAc-5) 1442 mGmAmG*mA*mA 1091 mU*mC*mCmAmGmCfGmAf mU*fG*mCmCmUfUmAfGfC siRNA CfAfAmGmGmCmUmAmAm mCmUmUmGfUmCfGmCmU -765 GmG*mC*mA(GalNAc-5) 1443 mGmGmA*mG*mA 1093 mC*mC*mAmGmCmGfAmCf mU*fC*mGmCmCfUmUfAfG siRNA Af AfGmGmCmU m Am AmGm mCmCmUmUfGmUfCmGmC -766 GmC*mG*mA(GalNAc-5) 1444 mUmGmG*mA*mG 1095 mA*mA*mGmGmCmGfGmGf mU*fC*mAmUmUfCmGfGfA siRNA CfUfCmCmUmCmCmGmAmA mGmGmAmGfCmCfCmGmC-767 mU*mG*mA(GalNAc-5) 1445 mCmUmU*mA*mG 1097 mA*mG*mGmCmGmGfGmCf mU*fC*mCmAmUfUmCfGfG siRNA UfCfCmUmCmCmGmAmAm mAmGmGmAfGmCfCmCmG -768 UmG*mG*mA(GalNAc-5) 1446 mCmCmU*mU*mA 1099 mG*mG*mCmGmGmGfCmUf mU*fG*mCmCmAfUmUfCfG siRNA CfCfUmCmCmGmAmAmUm mGmAmGmGfAmGfCmCmC -769 GmG*mC*mA(GalNAc-5) 1447 mGmCmC*mU*mU 1101 mG*mC*mGmGmGmCfUmCf mU*fA*mGmCmCfAmUfUfC siRNA CfUfCmCmGmAmAmUmGm mGmGmAmGfGmAfGmCmC -770 GmC*mU*mA(GalNAc-5) 1448 mCmGmC*mC*mU 1103 mG*mG*mGmCmUmCfCmUf mU*fC*mCmAmGfCmCfAfU siRNA CfCfGmAmAmUmGmGmCm mUmCmGmGfAmGfGmAmG -771 UmG*mG*mA(GalNAc-5) 1449 mCmCmCWmC 1105 mG*mC*mUmCmCmUfCmCf mU*fA*mGmCmCfAmGfCfC siRNA Gf Af AmU mGmGmCmU mGm mAmUmUmCfGmGfAmGmG -772 GmC*mU*mA(GalNAc-5) 1450 mAmGmC*mC*mC 1107 mC*mU*mCmCmUmCfCmGf mU*fC*mAmGmCfCmAfGfC siRNA Af AfU mGmGmCmU mGmGm mCmAmUmUfCmGfGmAmG -773 CmU*mG*mA(GalNAc-5) 1451 mGmAmG*mC*mC 1109 mU*mC*mCmUmCmCfGmAf mU*fA*mCmAmGfCmCfAfG siRNA AfU fGmGmCmU mGmGmCm mCmCm AmU fU mCfGmGm A-774 UmG*mU*mA(GalNAc-5) 1452 mGmGmA*mG*mC 1111 mC*mU*mGmGmCmUfGmUf mU*fA*mCmCmAfAmCfCfC siRNA GfGf AmU mGmGmGmU mU m mAmUmCmCfAmCfAmGmC-775 GmG*mU*mA(GalNAc-5) 1453 mCmAmG*mC*mC 1113 mU*mG*mGmCmUmGfUmGf mU*fG*mAmCmCfAmAfCfC siRNA GfAfUmGmGmGmUmUmGm mCmAmUmCfCmAfCmAmG-776 GmU*mC*mA(GalNAc-5) 1454 mCmCmA*mG*mC 1115Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mG*mG*mCmUmGmUfGmGf mU*fU*mGmAmCfCmAfAfC siRNA AfU fGmGmGmU mU mGmGm mCmCmAmUfCmCfAmCmA-777 UmC*mA*mA(GalNAc-5) 1455 mGmCmC*mA*mG 1117 mG*mC*mUmGmUmGfGmAf mU*fC*mUmGmAfCmCfAfA siRNA U fGfGmGmU mU mGmGmU m mCmCmCmAfUmCfCmAmCm -778 CmA*mG*mA(GalNAc-5) 1456 AmGmC*mC*mA 1119 mU*mG*mUmGmGmAfUmGf mU*fG*mAmCmUfGmAfCfC siRNA GfGfUmUmGmGmUmCmAm mAmAmCmCfCmAfUmCmC-779 GmU*mC*mA(GalNAc-5) 1457 mAmCmA*mG*mC 1121 mG*mU*mGmGmAmUfGmGf mU*fG*mGmAmCfUmGfAfC siRNA GfU fU mGmGmU mCm AmGm mCmAmAmCfCmCfAmUmC-780 UmC*mC*mA(GalNAc-5) 1458 mCmAmC*mA*mG 1123 mU*mG*mGmAmUmGfGmGf mU*fG*mGmGmAfCmUfGfA siRNA U fU fGmGmU mCm AmGmU m mCmCmAmAfCmCfCmAmU-781 CmC*mC*mA(GalNAc-5) 1459 mCmCmA*mC *mA 1125 mG*mU*mUmGmGmUfCmAf mU*fU*mGmUmUfGmGfAfG siRNA GfUfCmCmCmUmCmCmAmA mGmGmAmCfUmGfAmCmC -782 mC*mA*mA(GalNAc-5) 1460 mAmAmC*mC*mC 1127 mU*mG*mGmUmCmAfGmUf mU*fG*mUmUmGfUmUfGfG siRNA CfCfCmUmCmCmAmAmCmA m AmGmGmGf AmCfU mGm A -783 mA*mC*mA(GalNAc-5) 1461 mCmCmA*mA*mC 1129 mG*mC*mAmAmGmGfAmGf mU*fG*mGmAmGfAmAfGfG siRNA Gf AfU mGmCmCmU mU mCm mCmAmUmCfCmUfCmCmU-784 UmC*mC*mA(GalNAc-5) 1462 mUmGmC*mU*mG 1131 mC*mA*mAmGmGmAfGmGf mU*fC*mGmGmAfGmAfAfG siRNA AfU fGmCmCmU mU mCmU m mGmCmAmUfCmCfUmCmC-785 CmC*mG*mA(GalNAc-5) 1463 mUmUmG*mC*mU 1133 mA*mA*mGmGmAmGfGmAf mU*fC*mCmGmGfAmGfAfA siRNA UfGfCmCmUmUmCmUmCmC mGmGmCmAfUmCfCmUmC -786 mG*mG*mA(GalNAc-5) 1464 mCmUmU*mG*mC 1135 mA*mG*mGmAmGmGfAmUf mU*fC*mCmCmGfGmAfGfA siRNA GfCfCmUmUmCmUmCmCmG mAmGmGmCfAmUfCmCmU -787 mG*mG*mA(GalNAc-5) 1465 mCmCmU*mU*mG 1137 mA*mG*mGmAmUmGfCmCf mU*fU*mGmUmCfCmCfGfG siRNA U fU fCmU mCmCmGmGmGm mAmGmAmAfGmGfCmAmU -788 AmC*mA*mA(GalNAc-5) 1466 mCmCmU*mC*mC 1139 mG*mG*mAmUmGmCfCmUf mU*fC*mUmGmUfCmCfCfG siRNA UfCfUmCmCmGmGmGmAm mGmAmGmAfAmGfGmCmA -789 CmA*mG*mA(GalNAc-5) 1467 mUmCmC*mU*mC 1141 mA*mU*mGmCmCmUfUmCf mU*fA*mUmCmUfGmUfCfC siRNA UfCfCmGmGmGmAmCmAm mCmGmGmAfGmAfAmGmG -790 GmA*mU*mA(GalNAc-5) 1468 mCmAmU*mC*mC 1143 mU*mG*mCmCmUmUfCmUf mU*fA*mAmUmCfUmGfUfC siRNA CfCfGmGmGmAmCmAmGm mCmCmGmGfAmGfAmAmG-791 AmU*mU*mA(GalNAc-5) 1469 mGmCmA*mU*mC 1145Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mG*mC*mCmUmUmCfUmCf mU*fC*mAmAmUfCmUfGfU siRNA CfGfGmGmAmCmAmGmAm mCmCmCmGfGmAfGmAmA -792 UmU*mG*mA(GalNAc-5) 1470 mGmGmC *mA*mU 1147 mC*mC*mUmUmCmUfCmCf mU*fC*mCmAmAfUmCfUfG siRNA GfGfGm AmCm AmGm AmU m mUmCmCmCfGmGfAmGmA-793 UmG*mG*mA(GalNAc-5) 1471 mAmGmG*mC *mA 1149 mC*mU*mUmCmUmCfCmGf mU*fU*mCmCmAfAmUfCfU siRNA GfGfAmCm AmGm AmU mU m mGmUmCmCfCmGfGmAmG-794 GmG*mA*mA(GalNAc-5) 1472 mAmAmG*mG*mC 1151 mU*mG*mGmAmUmUfUmGf mU*fG*mUmCmGfAmAfCfU siRNA AfAfGmGmAmGmUmUmCm mCmCmU mU fCm Af Am AmU -795 GmA*mC*mA(GalNAc-5) 1473 mCmCmA*mU*mU 1153 mG*mG*mAmUmUmUfGmAf mU*fA*mGmUmCfGmAfAfC siRNA AfGfGmAmGmUmUmCmGm mU mCmCmU fU mCf Am Am A -796 AmC*mU*mA(GalNAc-5) 1474 mUmCmC*mA*mU 1155 mG*mA*mUmUmUmGfAmAf mU*fA*mAmGmUfCmGfAfA siRNA GfGf AmGmU mU mCmGm Am mCmUmCmCfUmUfCmAmA-797 CmU*mU*mA(GalNAc-5) 1475 mAmUmC*mC*mA 1157 mU*mU*mGmGmAmUfGmCf mU*fA*mUmAmCfCmCfAfA siRNA CfCfUmGmUmUmGmGmGm mCmAmGmGfGmCfAmUmC -798 UmA*mU*mA(GalNAc-5) 1476 mCmAmA*mG*mU 1159 mU*mG*mGmAmUmGfCmCf mU*fU*mAmUmAfCmCfCfA siRNA CfUfGmUmUmGmGmGmUm mAmCmAmGfGmGfCmAmU -799 AmU*mA*mA(GalNAc-5) 1477 mCmCmA*mA*mG 1161 mG*mG*mAmUmGmCfCmCf mU*fC*mUmAmUfAmCfCfC siRNA UfGfUmUmGmGmGmUmAm mAmAmCmAfGmGfGmCmA -800 UmA*mG*mA(GalNAc-5) 1478 mUmCmC*mA*mA 1163 mG*mA*mUmGmCmCfCmUf mU*fU*mCmUmAfUmAfCfC siRNA GfUfUmGmGmGmUmAmUm mCmAmAmCfAmGfGmGmC -801 AmG*mA*mA(GalNAc-5) 1479 mAmUmC*mC*mA 1165 mU*mG*mCmCmCmUfGmUf mU*fC*mAmUmCfUmAfUfA siRNA U fGfGmGmU m AmU m AmGm mCmCmCmAfAmCfAmGmG-802 AmU*mG*mA(GalNAc-5) 1480 mGmCmA*mU*mC 1167 mG*mC*mCmCmUmGfUmUf mU*fU*mCmAmUfCmUfAfU siRNA GfGfGmU m AmU m AmGm Am mAmCmCmCfAmAfCmAmG-803 UmG*mA*mA(GalNAc-5) 1481 mGmGmC *mA*mU 1169 mC*mC*mCmUmGmUfUmGf mU*fG*mUmCmAfUmCfUfA siRNA GfGfUmAmUmAmGmAmUm mUmAmCmCfCmAfAmCmA-804 GmA*mC*mA(GalNAc-5) 1482 mGmGmG*mC*mA 1171 mC*mC*mUmGmUmUfGmGf mU*fG*mGmUmCfAmUfCfU siRNA GfU f AmU m AmGm AmU mGm mAmUmAmCfCmCfAmAmC-805 AmC*mC*mA(GalNAc-5) 1483 mAmGmG*mG*mC 1173 mC*mU*mGmUmUmGfGmGf mU*fA*mGmGmUfCmAfUfC siRNA UfAfUmAmGmAmUmGmAm mUmAmUmAfCmCfCmAmA-806 CmC*mU*mA(GalNAc-5) 1484 mCmAmG*mG*mG 1175Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mU*mG*mUmUmGmGfGmUf mU*fC*mAmGmGfUmCfAfU siRNA AfUfAmGmAmUmGmAmCm mCmUmAmUfAmCfCmCmA-807 CmU*mG*mA(GalNAc-5) 1485 mAmCmA*mG*mG 1177 mG*mU*mUmGmGmGfUmAf mU*fC*mCmAmGfGmUfCfA siRNA U f AfGm AmU mGm AmCmCm mUmCmUmAfUmAfCmCmC -808 UmG*mG*mA(GalNAc-5) 1486 mAmAmC *mA*mG 1179 mU*mU*mGmGmGmUfAmUf mU*fU*mCmCmAfGmGfUfC siRNA AfGf AmU mGm AmCmCmU m mAmUmCmUfAmUfAmCmC -809 GmG*mA*mA(GalNAc-5) 1487 mCmAmA*mC*mA 1181 mU*mG*mGmGmUmAfUmAf mU*fU*mUmCmCfAmGfGfU siRNA GfAfUmGmAmCmCmUmGm mCmAmUmCfUmAfUmAmC -810 GmA*mA*mA(GalNAc-5) 1488 mCmCmA*mA*mC 1183 mG*mG*mGmUmAmUfAmGf mU*fU*mUmUmCfCmAfGfG siRNA AfU fGm AmCmCmU mGmGm mUmCmAmUfCmUfAmUmA -811 AmA*mA*mA(GalNAc-5) 1489 mCmCmC *mA*mA 1185 mG*mG*mUmAmUmAfGmAf mU*fG*mUmUmUfCmCfAfG siRNA U fGf AmCmCmU mGmGm Am mGmUmCmAfUmCfUmAmU -812 AmA*mC*mA(GalNAc-5) 1490 mAmCmC*mC*mA 1187 mG*mU*mAmUmAmGfAmUf mU*fG*mGmUmUfUmCfCfA siRNA GfAfCmCmUmGmGmAmAm mGmGmU mCf AmU fCmU mA -813 AmC*mC*mA(GalNAc-5) 1491 mUmAmC*mC*mC 1189 mU*mA*mUmAmGmAfUmGf mU*fU*mGmGmUfUmUfCfC siRNA AfCfCmUmGmGmAmAmAm m AmGmGmU fCm AfU mCmU -814 CmC*mA*mA(GalNAc-5) 1492 mAmUmA*mC*mC 1191 mU*mG*mGmAmAmAfCmCf mU*fG*mUmCmAfUmCfUfG siRNA AfU fGmCmCm AmGm AmU m mGmCmAmUfGmGfUmUmU -815 GmA*mC*mA(GalNAc-5) 1493 mCmCmA*mG*mG 1193 mG*mG*mAmAmAmCfCmAf mU*fG*mGmUmCfAmUfCfU siRNA U fGfCmCm AmGm AmU mGm mGmGmCmAfUmGfGmUmU -816 AmC*mC*mA(GalNAc-5) 1494 mUmCmC*mA*mG 1195 mG*mA*mAmAmCmCfAmUf mU*fA*mGmGmUfCmAfUfC siRNA GfCfCmAmGmAmUmGmAm mUmGmGmCfAmUfGmGmU -817 CmC*mU*mA(GalNAc-5) 1495 mUmUmC*mC*mA 1197 mA*mA*mAmCmCmAfUmGf mU*fA*mAmGmGfUmCfAfU siRNA CfCfAmGmAmUmGmAmCm mCmUmGmGfCmAfUmGmG -818 CmU*mU*mA(GalNAc-5) 1496 mUmUmU*mC*mC 1199 mA*mG*mAmCmGmGfUmGf mU*fG*mCmCmAfAmUfUfG siRNA AfAfCmCmCmAmAmUmUm mGmGmU mU fCm AfCmCmG -819 GmG*mC*mA(GalNAc-5) 1497 mUmCmU*mG*mG 1201 mG*mA*mCmGmGmUfGmAf mU*fG*mGmCmCfAmAfUfU siRNA AfCfCmCmAmAmUmUmGm mGmGmGmU fU mCf AmCmC -820 GmC*mC*mA(GalNAc-5) 1498 mGmUmC*mU*mG 1203 mU*mU*mUmAmAmCfAmAf mU*fC*mCmUmGfGmUfCfG siRNA AfAfCmCmCmGmAmCmCmA mGmGmU mU fU mU fGmU mU-821 mG*mG*mA(GalNAc-5) 1499 mAmAmA*mC *mU 1205Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mU*mU*mAmAmCmAfAmAf mU*fA*mCmCmUfGmGfUfC siRNA AfCfCmCmGmAmCmCmAmG mGmGmGmUfUmUfUmGmU -822 mG*mU*mA(GalNAc-5) 1500 mUmAmA*mA*mC 1207 mG*mG*mGmUmCmCfUmGf mU*fU*mGmGmAfGmUfGfG siRNA UfCfCmUmCmCmAmCmUmC mAmGmGmAfCmAfGmGmA -823 mC*mA*mA(GalNAc-5) 1501 mCmCmC*mC*mU 1209 mC*mU*mGmUmCmCfUmCf mU*fU*mGmAmUfCmUfGfG siRNA CfAfCmUmCmCmAmGmAm m AmGmU mGfGm AfGmGm A -824 UmC*mA*mA(GalNAc-5) 1502 mCmAmG*mG*mA 1211 mU*mG*mUmCmCmUfCmCf mU*fA*mUmGmAfUmCfUfG siRNA AfCfUmCmCmAmGmAmUm mGm AmGmU fGmGf AmGmG -825 CmA*mU*mA(GalNAc-5) 1503 mAmCmA*mG*mG 1213 mG*mU*mCmCmUmCfCmAf mU*fA*mAmUmGfAmUfCfU siRNA CfUfCmCmAmGmAmUmCm mGmGm AmGfU mGfGm A mG -826 AmU*mU*mA(GalNAc-5) 1504 mGmAmC *mA*mG 1215 mC*mC*mUmUmUmAfGmUf mU*fG*mCmCmCfAmGfCfU siRNA U fU f AmGm AmGmCmU mGm mCmUmAmAfAmCfUmAmA -827 GmG*mC*mA(GalNAc-5) 1505 mAmGmG*mA*mA 1217 mC*mU*mUmUmAmGfUmUf mU*fU*mGmCmCfCmAfGfC siRNA U f AfGm AmGmCmU mGmGm mU mCmU m Af Am AfCmU mA -828 GmC*mA*mA(GalNAc-5) 1506 mAmAmG*mG*mA 1219 mU*mU*mUmAmGmUfUmUf mU*fC*mUmGmCfCmCfAfG siRNA AfGf AmGmCmU mGmGmGm mCmUmCmUfAmAfAmCmU -829 CmA*mG*mA(GalNAc-5) 1507 mAmAmA*mG*mG 1221 mU*mU*mAmGmUmUfUmAf mU*fA*mCmUmGfCmCfCfA siRNA GfAfGmCmUmGmGmGmCm mGmCmUmCfUmAfAmAmC -830 AmG*mU*mA(GalNAc-5) 1508 mUmAmA*mA*mG 1223 mU*mA*mGmUmUmUfAmGf mU*fC*mAmCmUfGmCfCfC siRNA AfGfCmUmGmGmGmCmAm mAmGmCmUfCmUfAmAmA -831 GmU*mG*mA(GalNAc-5) 1509 mCmUmA*mA*mA 1225 mA*mG*mUmUmUmAfGmAf mU*fU*mCmAmCfUmGfCfC siRNA GfCfUmGmGmGmCmAmGm mCm AmGmCfU mCfU mAm A -832 UmG*mA*mA(GalNAc-5) 1510 mAmCmU*mA*mA 1227 mG*mU*mUmUmAmGfAmGf mU*fU*mUmCmAfCmUfGfC siRNA CfUfGmGmGmCmAmGmUm mCmCm AmGfCmU fCmU mA-833 GmA*mA*mA(GalNAc-5) 1511 mAmAmC *mU*mA 1229 mU*mU*mUmAmGmAfGmCf mU*fC*mUmUmCfAmCfUfG siRNA U fGfGmGmCm AmGmU mGm mCmCmCmAfGmCfUmCmU-834 AmA*mG*mA(GalNAc-5) 1512 mAmAmA*mC *mU 1231 mU*mU*mAmGmAmGfCmUf mU*fA*mCmUmUfCmAfCfU siRNA GfGfGmCm AmGmU mGm Am mGmCmCmCfAmGfCmUmC-835 AmG*mU*mA(GalNAc-5) 1513 mUmAmA*mA*mC 1233 mU*mA*mGmAmGmCfUmGf mU*fC*mAmCmUfUmCfAfC siRNA GfGfCm AmGmU mGm Am Am mUmGmCmCfCmAfGmCmU-836 GmU*mG*mA(GalNAc-5) 1514 mCmUmA*mA*mA 1235Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mA*mG*mAmGmCmUfGmGf mU*fC*mCmAmCfUmUfCfA siRNA GfCfAmGmUmGmAmAmGm mCmUmGmCfCmCfAmGmC-837 UmG*mG*mA(GalNAc-5) 1515 mUmCmU*mA*mA 1237 mG*mA*mGmCmUmGfGmGf mU*fU*mCmCmAfCmUfUfC siRNA CfAfGmUmGmAmAmGmUm mAmCmUmGfCmCfCmAmG-838 GmG*mA*mA(GalNAc-5) 1516 mCmUmC*mU*mA 1239 mA*mG*mCmUmGmGfGmCf mU*fA*mUmCmCfAmCfUfU siRNA AfGfUmGmAmAmGmUmGm mCmAmCmUfGmCfCmCmA-839 GmA*mU*mA(GalNAc-5) 1517 mGmCmU*mC*mU 1241 mG*mC*mUmGmGmGfCmAf mU*fU*mAmUmCfCmAfCfU siRNA GfU fGm Am AmGmU mGmGm mUmCmAmCfUmGfCmCmC-840 AmU*mA*mA(GalNAc-5) 1518 mAmGmC *mU*mC 1243 mC*mU*mGmGmGmCfAmGf mU*fA*mUmAmUfCmCfAfC siRNA U fGf Am AmGmU mGmGm Am mUmUmCmAfCmUfGmCmC -841 UmA*mU*mA(GalNAc-5) 1519 mCmAmG*mC*mU 1245 mU*mG*mGmGmCmAfGmUf mU*fG*mAmUmAfUmCfCfA siRNA Gf Af AmGmU mGmGm AmU m mCmU mU mCf AmCfU mGmC -842 AmU*mC*mA(GalNAc-5) 1520 mCmCmA*mG*mC 1247 mG*mG*mCmAmGmUfGmAf mU*fG*mUmGmAfUmAfUfC siRNA AfGfUmGmGmAmUmAmUm mCmAmCmUfUmCfAmCmU-843 CmA*mC*mA(GalNAc-5) 1521 mGmCmC*mC*mA 1249 mG*mC*mAmGmUmGfAmAf mU*fA*mGmUmGfAmUfAfU siRNA GfUfGmGmAmUmAmUmCm mCmCmAmCfUmUfCmAmC-844 AmC*mU*mA(GalNAc-5) 1522 mUmGmC*mC*mC 1251 mC*mA*mGmUmGmAfAmGf mU*fC*mAmGmUfGmAfUfA siRNA UfGfGmAmUmAmUmCmAm mUmCmCmAfCmUfUmCmA-845 CmU*mG*mA(GalNAc-5) 1523 mCmUmG*mC*mC 1253 mA*mG*mUmGmAmAfGmUf mU*fU*mCmAmGfUmGfAfU siRNA GfGf AmU m AmU mCm AmCm m AmU mCmCf AmCfU mU mC -846 UmG*mA*mA(GalNAc-5) 1524 mAmCmU*mG*mC 1255 mG*mU*mGmAmAmGfUmGf mU*fU*mUmCmAfGmUfGfA siRNA GfAfUmAmUmCmAmCmUm mUmAmUmCfCmAfCmUmU-847 GmA*mA*mA(GalNAc-5) 1525 mCmAmC*mU*mG 1257 mU*mG*mAmAmGmUfGmGf mU*fC*mUmUmCfAmGfUfG siRNA AfU f AmU mCm AmCmU mGm mAmUmAmUfCmCfAmCmU -848 AmA*mG*mA(GalNAc-5) 1526 mUmCmA*mC*mU 1259 mG*mA*mAmGmUmGfGmAf mU*fC*mCmUmUfCmAfGfU siRNA UfAfUmCmAmCmUmGmAm mGm AmU m AfU mCfCm AmC -849 AmG*mG*mA(GalNAc-5) 1527 mUmUmC*mA*mC 1261 mA*mA*mGmUmGmGfAmUf mU*fU*mCmCmUfUmCfAfG siRNA AfU fCm AmCmU mGm Am Am mUmGmAmUfAmUfCmCmA -850 GmG*mA*mA(GalNAc-5) 1528 mCmUmU*mC*mA 1263 mA*mG*mUmGmGmAfUmAf mU*fC*mUmCmCfUmUfCfA siRNA UfCfAmCmUmGmAmAmGm mGmU mGm AfU m AfU mCmC-851 GmA*mG*mA(GalNAc-5) 1529 mAmCmU*mU*mC 1265Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mG*mU*mGmGmAmUfAmUf mU*fU*mCmUmCfCmUfUfC siRNA CfAfCmUmGmAmAmGmGm m AmGmU mGf AmU f AmU mC -852 AmG*mA*mA(GalNAc-5) 1530 mCmAmC*mU*mU 1267 mU*mU*mCmAmGmAfUmAf mU*fU*mGmCmCfAmCfUfA siRNA AfU fGm AmU m AmGmU mGm mUmCmAmUfUmAfUmCmU -853 GmC*mA*mA(GalNAc-5) 1531 mGmAmA*mG*mG 1269 mU*mC*mAmGmAmUfAmAf mU*fA*mUmGmCfCmAfCfU siRNA U fGf AmU m AmGmU mGmGm mAmUmCmAfUmUfAmUmC -854 CmA*mU*mA(GalNAc-5) 1532 mUmGmA*mA*mG 1271 mC*mA*mGmAmUmAfAmUf mU*fG*mAmUmGfCmCfAfC siRNA GfAfUmAmGmUmGmGmCm mUmAmUmCfAmUfUmAmU -855 AmU*mC*mA(GalNAc-5) 1533 mCmUmG*mA*mA 1273 mA*mG*mAmUmAmAfUmGf mU*fA*mGmAmUfGmCfCfA siRNA AfUfAmGmUmGmGmCmAm mCmUmAmUfCmAfUmUmA -856 UmC*mU*mA(GalNAc-5) 1534 mUmCmU*mG*mA 1275 mG*mA*mUmAmAmUfGmAf mU*fC*mAmGmAfUmGfCfC siRNA U f AfGmU mGmGmCm AmU m mAmCmUmAfUmCfAmUmU -857 CmU*mG*mA(GalNAc-5) 1535 mAmUmC*mU*mG 1277 mU*mA*mAmUmGmAfUmAf mU*fU*mAmCmAfGmAfUfG siRNA GfU fGmGmCm AmU mCmU m mCmCmAmCfUmAfUmCmA-858 GmU*mA*mA(GalNAc-5) 1536 mUmUmA*mU*mC 1279 mA*mA*mUmGmAmUfAmGf mU*fA*mUmAmCfAmGfAfU siRNA U fGfGmCm AmU mCmU mGm mGmCmCm AfCmU f AmU mC-859 UmA*mU*mA(GalNAc-5) 1537 mAmUmU*mA*mU 1281 mA*mU*mGmAmUmAfGmUf mU*fC*mAmUmAfCmAfGfA siRNA GfGfCm AmU mCmU mGmU m mU mGmCmCf AmCfU mAmU-860 AmU*mG*mA(GalNAc-5) 1538 mCmAmU*mU*mA 1283 mA*mA*mAmAmGmUfAmAf mU*fG*mUmUmUfCmUfCfA siRNA AfGfGmGmU mGm AmGm Am mCmCmCmUfUmUfAmCmU -861 AmA*mC*mA(GalNAc-5) 1539 mUmUmU*mG*mC 1285 mA*mA*mAmGmUmAfAmAf mU*fA*mGmUmUfUmCfUfC siRNA GfGfGmU mGm AmGm Am Am mAmCmCmCfUmUfUmAmC -862 AmC*mU*mA(GalNAc-5) 1540 mUmUmU*mU*mG 1287 mA*mA*mGmUmAmAfAmGf mU*fC*mAmGmUfUmUfCfU siRNA GfGfUmGmAmGmAmAmAm mCmAmCmCfCmUfUmUmA-863 CmU*mG*mA(GalNAc-5) 1541 mCmUmU*mU*mU 1289 mA*mG*mUmAmAmAfGmGf mU*fC*mCmAmGfUmUfUfC siRNA GfUfGmAmGmAmAmAmCm mUmCmAmCfCmCfUmUmU-864 UmG*mG*mA(GalNAc-5) 1542 mAmCmU*mU*mU 1291 mG*mA*mGmAmAmAfCmUf mU*fA*mGmCmUfUmCfUfU siRNA GfGf AmU m Am AmGm Am Am m AmU mCmCf AmGfU mU mU -865 GmC*mU*mA(GalNAc-5) 1543 mCmUmC*mA*mC 1293 mA*mG*mAmAmAmCfUmGf mU*fC*mAmGmCfUmUfCfU siRNA GfAfUmAmAmGmAmAmGm mUmAmUmCfCmAfGmUmU-866 CmU*mG*mA(GalNAc-5) 1544 mUmCmU*mC*mA 1295Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mG*mA*mAmAmCmUfGmGf mU*fU*mCmAmGfCmUfUfC siRNA AfUfAmAmGmAmAmGmCm mU mU m AmU fCmCf AmGmU -867 UmG*mA*mA(GalNAc-5) 1545 mUmUmC*mU*mC 1297 mA*mA*mAmCmUmGfGmAf mU*fU*mUmCmAfGmCfUfU siRNA UfAfAmGmAmAmGmCmUm mCmUmUmAfUmCfCmAmG -868 GmA*mA*mA(GalNAc-5) 1546 mUmUmU*mC*mU 1299 mU*mG*mGmCmCmAfAmGf mU*fG*mUmAmCfUmGfGfA siRNA GfAfGmAmUmCmCmAmGm mU mCmU mCfCmU fU mGmG-869 UmA*mC*mA(GalNAc-5) 1547 mCmCmA*mG*mG 1301 mC*mC*mAmAmGmGfAmGf mU*fC*mAmGmGfUmAfCfU siRNA AfU fCmCm AmGmU m AmCm mGmGm AmU fCmU fCmCmU -870 CmU*mG*mA(GalNAc-5) 1548 mUmGmG*mC*mC 1303 mC *mA*mAmGmGmAfGmAf mU*fU*mCmAmGfGmUfAfC siRNA UfCfCmAmGmUmAmCmCm mUmGmGmAfUmCfUmCmC -871 UmG*mA*mA(GalNAc-5) 1549 mUmUmG*mG*mC 1305 mA*mA*mGmGmAmGfAmUf mU*fU*mUmCmAfGmGfUfA siRNA CfCfAmGmUmAmCmCmUm mCmU mGmGf AmU fCmU mC -872 GmA*mA*mA(GalNAc-5) 1550 mCmUmU*mG*mG 1307 mA*mG*mGmAmGmAfUmCf mU*fU*mUmUmCfAmGfGfU siRNA CfAfGmUmAmCmCmUmGm mAmCmUmGfGmAfUmCmU -873 AmA*mA*mA(GalNAc-5) 1551 mCmCmU*mU*mG 1309 mG*mG*mAmGmAmUfCmCf mU*fC*mUmUmUfCmAfGfG siRNA AfGfUmAmCmCmUmGmAm mUmAmCmUfGmGfAmUmC -874 AmA*mG*mA(GalNAc-5) 1552 mUmCmC*mU*mU 1311 mG*mA*mGmAmUmCfCmAf mU*fU*mCmUmUfUmCfAfG siRNA GfU f AmCmCmU mGm Am Am mGmUmAmCfUmGfGmAmU -875 AmG*mA*mA(GalNAc-5) 1553 mCmUmC*mC*mU 1313 mA*mG*mAmUmCmCfAmGf mU*fA*mUmCmUfUmUfCfA siRNA U f AfCmCmU mGm Am Am Am mGmGmU m AfCmU fGmGm A -876 GmA*mU*mA(GalNAc-5) 1554 mUmCmU*mC*mC 1315 mG*mA*mUmCmCmAfGmUf mU*fA*mAmUmCfUmUfUfC siRNA AfCfCmUmGmAmAmAmGm m AmGmGmU f AmCfU mGmG -877 AmU*mU*mA(GalNAc-5) 1555 mAmUmC*mU*mC 1317 mA*mU*mCmCmAmGfUmAf mU*fA*mAmAmUfCmUfUfU siRNA CfCfUmGmAmAmAmGmAm mCm AmGmGfU m AfCmU mG -878 UmU*mU*mA(GalNAc-5) 1556 mGmAmU*mC *mU 1319 mC*mC*mAmGmUmAfCmCf mU*fU*mCmAmAfAmUfCfU siRNA U fGf Am Am AmGm AmU mU m mUmUmCmAfGmGfUmAmC -879 UmG*mA*mA(GalNAc-5) 1557 mUmGmG*mA*mU 1321 mC*mA*mGmUmAmCfCmUf mU*fA*mUmCmAfAmAfUfC siRNA Gf Af Am AmGm AmU mU mU m mUmUmUmCfAmGfGmUmA -880 GmA*mU*mA(GalNAc-5) 1558 mCmUmG*mG*mA 1323 mA*mG*mUmAmCmCfUmGf mU*fU*mAmUmCfAmAfAfU siRNA Af Af AmGm AmU mU mU mGm mCmUmUmUfCmAfGmGmU-881 AmU*mA*mA(GalNAc-5) 1559 mAmCmU*mG*mG 1325Attorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO:mG*mU*mAmCmCmUfGmAf mU*fC*mUmAmUfCmAfAfA siRNA Af AfGm AmU mU mU mGm Am mUmCmUmUfUmCfAmGmG -882 UmA*mG*mA(GalNAc-5) 1560 mUmAmC*mU*mG 1327 mU*mA*mCmCmUmGfAmAf mU*fU*mCmUmAfUmCfAfA siRNA AfGf AmU mU mU mGm AmU m m AmU mCmU fU mU fCm A mG -883 AmG*mA*mA(GalNAc-5) 1561 mGmUmA*mC*mU 1329 mA*mC*mCmUmGmAfAmAf mU*fU*mUmCmUfAmUfCfA siRNA GfAfUmUmUmGmAmUmAm mAmAmUmCfUmUfUmCmA -884 GmA*mA*mA(GalNAc-5) 1562 mGmGmU*mA*mC 1331 mG*mA*mUmAmGmAfAmGf mU*fC*mCmUmUfGmCfGfG siRNA AfGfGmUmCmCmGmCmAm mAmCmCmUfCmUfUmCmU-885 AmG*mG*mA(GalNAc-5) 1563 mAmUmC*mA*mA 1333 mA*mU*mAmGmAmAfGmAf mU*fG*mCmCmUfUmGfCfG siRNA GfGfUmCmCmGmCmAmAm mGm AmCmCfU mCfU mU mC -886 GmG*mC*mA(GalNAc-5) 1564 mUmAmU*mC*mA 1335 mU*mA*mGmAmAmGfAmGf mU*fU*mGmCmCfUmUfGfC siRNA GfUfCmCmGmCmAmAmGm mGmGmAmCfCmUfCmUmU-887 GmC*mA*mA(GalNAc-5) 1565 mCmUmA*mU*mC 1337 mA*mG*mAmAmGmAfGmGf mU*fU*mUmGmCfCmUfUfG siRNA UfCfCmGmCmAmAmGmGm mCmGmGmAfCmCfUmCmU-888 CmA*mA*mA(GalNAc-5) 1566 mUmCmU*mA*mU 1339 mG*mA*mAmGmAmGfGmUf mU*fC*mUmUmGfCmCfUfU siRNA CfCfGmCmAmAmGmGmCm mGmCmGmGfAmCfCmUmC-889 AmA*mG*mA(GalNAc-5) 1567 mUmUmC*mU*mA 1341 mA*mA*mGmAmGmGfUmCf mU*fC*mCmUmUfGmCfCfU siRNA CfGfCmAmAmGmGmCmAm mUmGmCmGfGmAfCmCmU -890 AmG*mG*mA(GalNAc-5) 1568 mCmUmU*mC*mU 1343 mC*mA*mAmUmGmUfGmCf mU*fC*mUmCmUfAmUfGfU siRNA U fU fGmU m AmCm AmU m Am mAmCmAmAfGmCfAmCmA -891 GmA*mG*mA(GalNAc-5) 1569 mUmUmG*mA*mC 1345 mA*mA*mUmGmUmGfCmUf mU*fA*mCmUmCfUmAfUfG siRNA U fGfU m AmCm AmU m AmGm mUmAmCmAfAmGfCmAmC -892 AmG*mU*mA(GalNAc-5) 1570 mAmUmU*mG*mA 1347 siRN mC*mA*mAmCmAmUfGmAf 1450 mU*fA*mGmCmUfCmAfUfU 1450 A- CfCfGmAmAmAmUmGmAm 0 mUmCmGmGfUmCfAmUmG 1 1131 GmC*mU*mA(GalNAc-5) mUmUmG*mC*mGsiRN mC*mA*mGmAmCmGfGmUf 1450 mU*fC*mCmAmAfUmUfGfG 1450 A- GfAfAmCmCmCmAmAmUm 2 mGmUmUmCfAmCfCmGmU 3 1132 UmG*mG*mA(GalNAc-5) mCmUmG*mG*mGsiRN mG*mA*mAmAmGmUfUmUf 1450 mU*fU*mCmGmGfGmUfUfU 1450 A- AfAfCmAmAmAmAmCmCm 4 mU mGmU mU f Am Af AmCmU 5 1133 CmG*mA*mA(GalNAc-5) mUmUmC*mU*mGsiRN mG*mA*mUmUmUmGfAmUf 1450 mU*fC*mGmGmAfCmCfUfC 1450 A- AfGf Am AmGm AmGmGmU m 6 mU mU mCmU f AmU fCm Am A 71134 CmC*mG*mA(GalNAc-5) mAmUmC*mU*mUAttorney Docket Number: J0365.70001WO00SEQ SEQ ID ID siRNA Sense Sequence* NO: Antisense SequenceANO: siRN mA*mU*mUmUmGmAfUmAf 1450 mU*fG*mCmGmGfAmCfCfU 1450 A- GfAfAmGmAmGmGmUmCm 8 mCmUmUmCfUmAfUmCmA 9 1135 CmG*mC*mA(GalNAc-5) mAmAmU*mC *mUsiRN mG*mA*mUmUmUmGfAmAf 1452 mU*fA*mAmGmUfCmGfAfA 1157 A- GfGf AmGmU mU mCmGm Am 0 mCmUmCmCfUmUfCmAmA1141 CmUmUmA(GalNAc-5) mAmUmC*mC*mAsiRN mG*mA*mAmAmCmCfAmUf 1452 mU*fA*mGmGmUfCmAfUfC 1197 A- GfCfCmAmGmAmUmGmAm 1 mUmGmGmCfAmUfGmGmU1142 CmCmUmA(GalNAc-5) mUmUmC*mC*mAsiRN mG*mA*mUmUmUmGfAmUf 1452 mU*fC*mGmGmAfCmCfUfC 1450 A- AfGf Am AmGm AmGmGmU m 2 mU mU mCmU f AmU fCm Am A 7 1143 CmCmGmA(GalNAc-5) mAmUmC*mU*mUsiRN mC*mA*mGmUmAmCfCmUf 1452 mU*fA*mUmCmAfAmAfUfC 1323 A- Gf Af Am AmGm AmU mU mU m 3 mUmUmUmCfAmGfGmUmA1144 GmAmUmA(GalNAc-5) mCmUmG*mG*mAsiRN mA*mA*mAmCmCmAfUmGf 1452 mU*fA*mAmGmGfUmCfAfU 1199 A- CfCfAmGmAmUmGmAmCm 4 mCmUmGmGfCmAfUmGmG1145 CmUmUmA(GalNAc-5) mUmUmU*mC*mCsiRN mG*mA*mAmAmGmUfUmUf 1452 mU*fU*mCmGmGfGmUfUfU 1450 A- AfAfCmAmAmAmAmCmCm 5 mU mGmU mU f Am Af AmCmU 51146 CmGmAmA(GalNAc-5) mUmUmC*mU*mG* The last two internucleoside linkages at the 3’ end of the sense strand may be phosphorothioate intemucleoside linkages or phosphodiester intemucleoside linkages. For all siRNAs disclosed in Table 4, the sense strand may be either version. The version that is not specifically provided in Table 4 is contemplated and encompassed by the present disclosure.The antisense strand of any one of the siRNAs disclosed in Table 4 may optionally contain a vinylphosphonate at the 5’ end.Table 5. Lipid Modified siRNAs (2’-O- C22-N = 2’-O- docosanoxyl (C22) nucleotide; VP= V inylpho sphonate)SE SEQ Q ID IDsiRNA Sense Sequence NO: Antisense Sequence NO:mG*mA*mAmGmA(2'-O-C22- (VPmU) *f A*mAmGmAfGmAf siRNA A)fAmGfCfCfUmAmGmGmU CfCmU m AmGmGfCmU fU mU 157 -893 mCmUmCmU*mU*mA 1571 mCmUmUmC*mA*mG 2 mA*mA*mGmAmA(2'-O-C22- (VPmU)*fU*mAmAmGfAmGf siRNA A)fGmCfCfUfAmGmGmUmC AfCmCmU m AmGfGmCfU mU 157 -894 mUmCmUmU*mA*mA 1573 mUmCmUmU*mC*mA 4 mA*mA*mGmCmC(2'-O-C22- (VPmU)*fC*mAmUmCfUmAf siRNA U)fAmGfGfUfCmUmCmUmU AfGmAmGmAmCfCmUfAmG 157-895 mAmGmAmU*mG*mA 1575 mGmCmUmU*mU*mC 6Attorney Docket Number: J0365.70001WO00SE SEQ Q ID IDsiRNA Sense Sequence NO: Antisense Sequence NO:mA*mG*mCmCmU(2'-O-C22- (VPmU)*fU*mCmAmUfCmUf siRNA A)fGmGfU fCfU mCmU mU mA AfAmGmAmGmAfCmCfUmA 157 -896 mGmAmUmG*mA*mA 1577 mGmGmCmU*mU*mU 8 mU*mA*mCmCmU (2'-O-C22- (VPmU)*fU*mGmCmUfUmGf siRNA G)fGmAfGfGfUmGmGmCmC GfCmCmAmCmCfUmCfCmA 158 -897 mAmAmGmC *mA*mA 1579 mGmGmUmA*mA*mU 0 mA*mC*mCmUmG(2'-O-C22- (VPmU)*fG*mUmGmCfUmUf siRNA G)fAmGfGfUfGmGmCmCmA GfGmCmCmAmCfCmUfCmC 158 -898 mAmGmCmA*mC *mA 1581 mAmGmGmU*mA*mA 2 mC*mC*mUmGmG(2'-O-C22- (VPmU)*fA*mGmUmGfCmUf siRNA A)fGmGfUfGfGmCmCmAmA UfGmGmCmCmAfCmCfUmC 158 -899 mGmCmAmC *mU*mA 1583 mCmAmGmG*mU*mA 4 mU*mC*mAmAmA(2'-O-C22- (VPmU) *fG*mGmAmGf AmAf siRNA C)fCmUfCfAfUmGmGmGmU CfCmCmAmUmGfAmGfGmU 158 -900 mUmCmUmC*mC*mA 1585 mUmUmGmA*mA*mG 6 mC*mA*mAmAmC(2'-O-C22- (VPmU)*fU*mGmGmAfGmAf siRNA C )fU mCf AfU fGmGmGmU mU AfCmCmCmAmUfGmAfGmG 158 -901 mCmUmCmC*mA*mA 1587 mUmUmUmG*mA*mA 8 mA*mA*mAmCmC(2'-O-C22- (VPmU)*fC*mUmGmGfAmGf siRNA U)fCmAfUfGfGmGmUmUmC AfAmCmCmCmAfUmGfAmG 159 -902 mUmCmCmA*mG*mA 1589 mGmUmUmU*mG*mA 0 mC*mC*mUmCmA(2'-O-C22- (VPmU)*fU*mCmGmCfUmGf siRNA U)fGmGfGfUfUmCmUmCmC GfAmGmAmAmCfCmCfAmU 159 -903 mAmGmCmG*mA*mA 1591 mGmAmGmG*mU*mU 2 mC*mU*mCmAmU(2'-O-C22- (VPmU)*fG*mUmCmGfCmUf siRNA G)fGmGfUfUfCmUmCmCmA GfGmAmGmAmAfCmCfCmA 159 -904 mGmCmGmA*mC *mA 1593 mUmGmAmG*mG*mU 4 mU*mC*mAmUmG(2'-O-C22- (VPmU)*fU*mGmUmCfGmCf siRNA G)fGmUfUfCfUmCmCmAmG UfGmGmAmGmAfAmCfCmC 159 -905 mCmGmAmC *mA*mA 1595 mAmUmGmA*mG*mG 6 mC*mA*mUmGmG(2'-O-C22- (VPmU)*fU*mUmGmUfCmGf siRNA G)fUmUfCfUfCmCmAmGmC CfUmGmGmAmGfAmAfCmC 159 -906 mGmAmCmA*mA*mA 1597 mCmAmUmG*mA*mG 8 mA*mU*mGmGmG(2'-O-C22- (VPmU)*fC*mUmUmGfUmCf siRNA U)fUmCfUfCfCmAmGmCmG GfCmUmGmGmAfGmAfAmC 160 -907 mAmCmAmA*mG*mA 1599 mCmCmAmU*mG*mA 0 mU*mG*mGmGmU(2'-O-C22- (VPmU)*fC*mCmUmUfGmUf siRNA U)fCmUfCfCfAmGmCmGmA CfGmCmUmGmGfAmGfAmA 160 -908 mCmAmAmG*mG*mA 1601 mCmCmCmA*mU *mG 2 mG*mG*mGmUmU(2'-O-C22- (VPmU)*fG*mCmCmUfUmGf siRNA C)fUmCfCfAfGmCmGmAmC UfCmGmCmUmGfGmAfGmA 160 -909 mAmAmGmG*mC *mA 1603 mAmCmCmC*mA*mU 4 mU*mU*mCmUmC(2'-O-C22- (VPmU)*fA*mUmCmCfAmAf siRNA C)fGmGfGfAfCmAmGmAmU UfCmUmGmUmCfCmCfGmG 160-910 mUmGmGmA*mU*mA 1605 mAmGmAmA*mG*mG 6Attorney Docket Number: J0365.70001WO00SE SEQ Q ID IDsiRNA Sense Sequence NO: Antisense Sequence NO:mU*mC*mUmCmC(2'-O-C22- (VPmU)*fC*mAmUmCfCmAf siRNA G)fGmGfAfCfAmGmAmUmU AfUmCmUmGmUfCmCfCmG 160 -911 mGmGmAmU*mG*mA 1607 mGmAmGmA*mA*mG 8 mC*mU*mCmCmG(2'-O-C22- (VPmU)*fA*mCmAmUfCmCf siRNA G)fGmAfCfAfGmAmUmUmG AfAmUmCmUmGfUmCfCmC 161 -912 mGmAmUmG*mU*mA 1609 mGmGmAmG*mA*mA 0 mC*mC*mGmGmG(2'-O-C22- (VPmU)*fC*mAmAmCfAmUf siRNA A)fCmAfGfAfUmUmGmGmA CfCm Am AmU mCfUmGfU mC 161 -913 mUmGmUmU*mG*mA 1611 mCmCmGmG*mA*mG 2 mC*mG*mGmGmA(2'-O-C22- (VPmU) *fC *mCmAmAfCmAf siRNA C )f AmGf AfU fU mGmGm AmU U fCmCm Am AmU fCmU fGmU 161 -914 mGmUmUmG*mG*mA 1613 mCmCmCmG*mG*mA 4 mG*mG*mGmAmC(2'-O-C22- (VPmU)*fU*mCmCmAfAmCf siRNA A)fGm AfU fU fGmGm AmU mG AfU mCmCm Am AfU mCfU mG 161 -915 mUmUmGmG*mA*mA 1615 mUmCmCmC*mG*mG 6 mG*mG*mAmCmA(2'-O-C22- (VPmU)*fC*mUmCmCfAmAf siRNA G)f AmU fU fGfGm AmU mGmU Cf AmU mCmCm Af AmU fCmU 161 -916 mUmGmGmA*mG*mA 1617 mGmUmCmC*mC*mG 8 mA*mC*mAmGmA(2'-O-C22- (VPmU)*fU*mUmCmUfCmCf siRNA U)fUmGfGf AfU mGmU mU mG AfAmCmAmUmCfCmAfAmU 162 -917 mGmAmGmA*mA*mA 1619 mCmUmGmU*mC*mC 0 mU*mA*mGmAmU(2'-O-C22- (VPmU)*fC*mAmUmGfGmUf siRNA G)fAmCfCfUfGmGmAmAmA UfUmCmCmAmGfGmUfCmA 162 -918 mCmCmAmU*mG*mA 1621 mUmCmUmA*mU*mA 2 mA*mG*mAmUmG(2'-O-C22- (VPmU)*fG*mCmAmUfGmGf siRNA A)fCmCfUfGfGmAmAmAmC U fU mU mCmCm AfGmGfU mC 162 -919 mCmAmUmG*mC*mA 1623 mAmUmCmU*mA*mU 4 mG*mA*mUmGmA(2'-O-C22- (VPmU)*fG*mGmCmAfUmGf siRNA C)fCmUfGfGfAmAmAmCmC GfU mU mU mCmCf AmGfGmU 162 -920 mAmUmGmC*mC*mA 1625 mCmAmUmC*mU*mA 6 mA*mU*mGmAmC(2'-O-C22- (VPmU)*fU*mGmGmCfAmUf siRNA C)fUmGfGfAfAmAmCmCmA GfGmUmUmUmCfCmAfGmG 162 -921 mUmGmCmC*mA*mA 1627 mUmCmAmU*mC*mU 8 mG*mA*mCmCmU(2'-O-C22- (VPmU)*fU*mCmUmGfGmCf siRNA G)fGmAfAfAfCmCmAmUmG AfUmGmGmUmUfUmCfCmA 163 -922 mCmCmAmG*mA*mA 1629 mGmGmUmC*mA*mU 0 mC*mC*mUmGmG(2'-O-C22- (VPmU)*fC*mAmUmCfUmGf siRNA A)fAmAfCfCfAmUmGmCmC GfCmAmUmGmGfUmUfUmC 163 -923 mAmGmAmU*mG*mA 1631 mCmAmGmG*mU *mC 2 mC*mU*mGmGmA(2'-O-C22- (VPmU)*fU*mCmAmUfCmUf siRNA A)fAmCfCfAfUmGmCmCmA GfGmCmAmUmGfGmUfUmU 163 -924 mGmAmUmG*mA*mA 1633 mCmCmAmG*mG*mU 4 mA*mC*mGmGmU(2'-O-C22- (VPmU)*fU*mGmGmCfCmAf siRNA G)fAmAfCfCfCmAmAmUmU AfU mU mGmGmGfU mU fCm A 163-925 mGmGmCmC *mA*mA 1635 mCmCmGmU *mC *mU 6Attorney Docket Number: J0365.70001WO00SE SEQ Q ID IDsiRNA Sense Sequence NO: Antisense Sequence NO:mG*mU*mGmAmA(2'-O-C22- (VPmU)*fA*mGmAmUfGmGf siRNA C)fCmCfAfAfUmUmGmGmC CfCm Am AmU mU fGmGfGmU 163 -926 mCmAmUmC*mU*mA 1637 mUmCmAmC*mC*mG 8 mU*mG*mAmAmC(2'-O-C22- (VPmU)*fG*mAmGmAfUmGf siRNA C)fCmAfAfUfUmGmGmCmC GfCmCmAmAmUfUmGfGmG 164 -927 mAmUmCmU*mC*mA 1639 mUmUmCmA*mC*mC 0 mA*mA*mUmUmG(2'-O-C22- (VPmU)*fU*mUmUmCfUmGf siRNA G)fCmCfAfUfCmUmCmCmC GfGmAmGmAmUfGmGfCmC 164 -928 mAmGmAmA*mA*mA 1641 mAmAmUmU*mG*mG 2 mA*mU*mUmGmG(2'-O-C22- (VPmU)*fC*mUmUmUfCmUf siRNA C)fCmAfUfCfUmCmCmCmA GfGmGmAmGmAfUmGfGmC 164 -929 mGmAmAmA*mG*mA 1643 mCmAmAmU*mU*mG 4 mG*mA*mUmCmA(2'-O-C22- (VPmU)*fU*mCmUmAfAmAf siRNA U)fUmCfCfUfUmUmAmGmU CfU m Am Am AmGfGm Af AmU 164 -930 mUmUmAmG*mA*mA 1645 mGmAmUmC*mU*mG 6 mA*mU*mCmAmU(2'-O-C22- (VPmU)*fC*mUmCmUfAmAf siRNA U)fCmCfUfUfUmAmGmUmU AfCmUmAmAmAfGmGfAmA 164 -931 mUmAmGmA*mG*mA 1647 mUmGmAmU*mC*mU 8 mU*mC*mAmUmU(2'-O-C22- (VPmU)*fG*mCmUmCfUmAf siRNA C )fCmU fU fU f AmGmU mU mU AfAmCmUmAmAfAmGfGmA 165 -932 mAmGmAmG*mC *mA 1649 mAmUmGmA*mU*mC 0 mC*mA*mUmUmC(2'-O-C22- (VPmU)*fA*mGmCmUfCmUf siRNA C )fU mU fU f AfGmU mU mU mA AfAmAmCmUmAfAmAfGmG 165 -933 mGmAmGmC *mU*mA 1651 mAmAmUmG*mA*mU 2 mG*mA*mUmAmG(2'-O-C22- (VPmU)*fC*mUmCmAfUmAf siRNA U)fGmGfCf AfU mCmU mGmU CfAmGmAmUmGfCmCfAmC 165 -934 mAmUmGmA*mG*mA 1653 mUmAmUmC*mA*mU 4 mA*mU*mAmGmU(2'-O-C22- (VPmU)*fG*mCmUmCfAmUf siRNA G)fGmCfAfUfCmUmGmUmA AfCmAmGmAmUfGmCfCmA 165 -935 mUmGmAmG*mC*mA 1655 mCmUmAmU*mC*mA 6 mU*mA*mGmUmG(2'-O-C22- (VPmU)*fG*mGmCmUfCmAf siRNA G)fCmAfUfCfUmGmUmAmU UfAmCmAmGmAfUmGfCmC 165 -936 mGmAmGmC *mC *mA 1657 mAmCmUmA*mU*mC 8 mA*mG*mUmGmG(2'-O-C22- (VPmU)*fG*mGmGmCfUmCf siRNA C )f AmU fCfUfGmU m AmU mG AfUmAmCmAmGfAmUfGmC 166 -937 mAmGmCmC*mC*mA 1659 mCmAmCmU*mA*mU 0 mG*mC*mCmAmC(2'-O-C22- (VPmU)*fU*mUmCmUfGmGf siRNA U)fAmGfGfUfAmCmCmGmC CfGmGmUmAmCfCmUfAmG 166 -938 mCmAmGmA*mA*mA 1661 mUmGmGmC*mU*mG 2 mC*mC*mAmCmU(2'-O-C22- (VPmU)*fC*mUmUmCfUmGf siRNA A)fGmGfUfAfCmCmGmCmC GfCmGmGmUmAfCmCfUmA 166 -939 mAmGmAmA*mG*mA 1663 mGmUmGmG*mC*mU 4 mC*mA*mCmUmA(2'-O-C22- (VPmU)*fU*mCmUmUfCmUf siRNA G)fGmUfAfCfCmGmCmCmA GfGmCmGmGmUfAmCfCmU 166-940 mGmAmAmG*mA*mA 1665 mAmGmUmG*mG*mC 6Attorney Docket Number: J0365.70001WO00SE SEQ Q ID IDsiRNA Sense Sequence NO: Antisense Sequence NO:mU*mU*mCmUmG(2'-O-C22- (VPmU)*fG*mUmCmAfUmCf siRNA A)fCmCfAfCfGmUmUmGmG CfAmAmCmGmUfGmGfUmC 166 -941 mAmUmGmA*mC*mA 1667 mAmGmAmA*mG*mG 8 mU*mC*mUmGmA(2'-O-C22- (VPmU)*fU*mGmUmCfAmUf siRNA C)fCmAfCfGfUmUmGmGmA CfCmAmAmCmGfUmGfGmU 167 -942 mUmGmAmC*mA*mA 1669 mCmAmGmA*mA*mG 0 mC*mU*mGmAmC(2'-O-C22- (VPmU)*fG*mUmGmUfCmAf siRNA C)fAmCfGfUfUmGmGmAmU UfCmCmAmAmCfGmUfGmG 167 -943 mGmAmCmA*mC *mA 1671 mUmCmAmG*mA*mA 2 mU*mG*mGmCmC(2'-O-C22- (VPmU)*fA*mAmCmUfUmUf siRNA A)fUmCfUfCfCmCmAmGmA CfUmGmGmGmAfGmAfUmG 167 -944 mAmAmGmU*mU*mA 1673 mGmCmCmA*mA*mU 4 mC*mA*mAmGmA(2'-O-C22- (VPmU)*fA*mCmCmUfAmGf siRNA C)fAmGfCfAfGmCmCmAmC UfGmGmCmUmGfCmUfGmU 167 -945 mUmAmGmG*mU*mA 1675 mCmUmUmG*mU*mU 6 mA*mA*mGmAmC(2'-O-C22- (VPmU)*fU*mAmCmCfUmAf siRNA A)fGmCfAfGfCmCmAmCmU GfUmGmGmCmUfGmCfUmG 167 -946 mAmGmGmU*mA*mA 1677 mUmCmUmU*mG*mU 8 mA*mG*mAmCmA(2'-O-C22- (VPmU)*fG*mUmAmCfCmUf siRNA G)fCmAfGfCfCmAmCmUmA AfGmUmGmGmCfUmGfCmU 168 -947 mGmGmUmA*mC*mA 1679 mGmUmCmU*mU*mG 0 mA*mC*mAmGmC(2'-O-C22- (VPmU)*fC*mGmGmUfAmCf siRNA A)fGmCfCfAfCmUmAmGmG CfUmAmGmUmGfGmCfUmG 168 -948 mUmAmCmC*mG*mA 1681 mCmUmGmU*mC*mU 2 mA*mG*mCmCmA(2'-O-C22- (VPmU)*fU*mCmUmGfGmCf siRNA C)fUmAfGfGfUmAmCmCmG GfGmUmAmCmCfUmAfGmU 168 -949 mCmCmAmG*mA*mA 1683 mGmGmCmU *mG*mC 4 mU*mG*mGmAmG(2'-O-C22- (VPmU)*fG*mAmAmGfUmGf siRNA G)fUmGfGfCfCmAmAmGmC CfUmUmGmGmCfCmAfCmC 168 -950 mAmCmUmU*mC*mA 1685 mUmCmCmA*mG*mG 6 mG*mG*mAmGmG(2'-O-C22- (VPmU)*fU*mGmAmAfGmUf siRNA U)fGmGfCfCfAmAmGmCmA GfCmUmUmGmGfCmCfAmC 168 -951 mCmUmUmC*mA*mA 1687 mCmUmCmC*mA*mG 8 mG*mA*mGmGmU(2'-O-C22- (VPmU)*fU*mUmGmAfAmGf siRNA G)fGmCfCfAfAmGmCmAmC UfGmCmUmUmGfGmCfCmA 169 -952 mUmUmCmA*mA*mA 1689 mCmCmUmC*mC*mA 0 mA*mG*mGmUmG(2'-O-C22- (VPmU)*fU*mUmUmGfAmAf siRNA G)fCmCfAfAfGmCmAmCmU GfUmGmCmUmUfGmGfCmC 169 -953 mUmCmAmA*mA*mA 1691 mAmCmCmU *mC *mC 2 mG*mG*mUmGmG(2'-O-C22- (VPmU)*fG*mUmUmUfGmAf siRNA C)fCmAfAfGfCmAmCmUmU AfGmUmGmCmUfUmGfGmC 169 -954 mCmAmAmA*mC *mA 1693 mCmAmCmC*mU*mC 4 mG*mU*mGmGmC(2'-O-C22- (VPmU)*fG*mGmUmUfUmGf siRNA C)fAmAfGfCfAmCmUmUmC AfAmGmUmGmCfUmUfGmG 169-955 mAmAmAmC *mC *mA 1695 mCmCmAmC*mC*mU 6Attorney Docket Number: J0365.70001WO00SE SEQ Q ID IDsiRNA Sense Sequence NO: Antisense Sequence NO:mG*mC*mCmAmA(2'-O-C22- (VPmU)*fU*mGmAmGfGmUf siRNA G)fCmAfCfUfUmCmAmAmA U fU mGm Am AmGfU mGfCmU 169 -956 mCmCmUmC*mA*mA 1697 mUmGmGmC*mC*mA 8 mA*mG*mCmAmC(2'-O-C22- (VPmU)*fC*mCmCmAfUmGf siRNA U)fUmCfAfAfAmCmCmUmC AfGmGmU mU mU fGm Af A mG 170 -957 mAmUmGmG*mG*mA 1699 mUmGmCmU*mU*mG 0 mG*mC*mAmCmU(2'-O-C22- (VPmU)*fA*mCmCmCfAmUf siRNA U)fCmAfAfAfCmCmUmCmA Gf AmGmGmU mU fU mGf Am A 170 -958 mUmGmGmG*mU*mA 1701 mGmUmGmC*mU*mU 2 mA*mC*mUmUmC(2'-O-C22- (VPmU)*fG*mA...

Claims

Attorney Docket Number: J0365.70001WO00CLAIMSWhat is claimed is:

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 an ATF4 pathway.

2. The method of claim 1, wherein the disease or condition is a metabolism-related disease or condition.

3. The method of claim 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, skeletal muscle atrophy, sarcopenia, or a neurodegenerative disorder.

4. The method of claim 3, wherein the liver disease is a non-alcoholic fatty liver disease (NAFLD).

5. The method of claim 3, wherein the diabetes is Type II diabetes.

6. The method of claim 3, wherein the cancer comprises colon cancer, breast cancer, or endometrium cancer.

7. The method of claim 3, wherein the neurodegenerative disorder comprises dementia, depression, or anxiety.

8. The method of any one of claims 1-7, wherein the therapeutic agent is capable of lowering an mRNA level or a protein level of an ATF4 gene.

9. The method of any one of claims 1-8, wherein the therapeutic agent is capable of inhibiting DNA binding to an ATF4 protein.

10. The method of any one of claims 1-9, wherein the therapeutic agent is an siRNA molecule.

11. The method of claim 10, wherein the siRNA molecule is an siRNA molecule targeting an mRNA of an ATF4 gene.

12. The method of claim 10 or claim 11, wherein the siRNA molecule comprises an antisense strand comprising a region of complementarity of at least 8 nucleosides to an ATF4 RNA sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 3, and a sense strand that is at least substantially complementary to the antisense strand.

13. The method of claim 12, wherein the sense strand is 15-35 nucleosides in length, and / or the antisense strand is 15-35 nucleosides in length, wherein the antisense strand and the sense strand hybridize to form a duplex region of 15-25 base pairs in length.Attorney Docket Number: J0365.70001WO0014. The method of claim 12 or claim 13, wherein the antisense strand comprises a region of complementarity of at least 8 nucleosides to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942, optionally wherein the antisense strand comprises a region of complementary 15-21 nucleobases to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942.

15. The method of any one of claims 12-14, wherein the antisense strand comprises at least 8 consecutive nucleobases of the antisense strand of any one of the siRNAs listed in Tables 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469, optionally wherein the antisense strand comprises the nucleobase sequences of the antisense strand of any one of the siRNAs listed in Tables 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469.

16. The method of any one of claims 12-15, wherein the sense strand comprises at least 8 consecutive nucleobases of the sense strand of any one of the siRNAs listed in Tables 1-5 or the sense strand sequence as set forth in any one of SEQ ID NOs: 3416-8942, optionally wherein the sense strand comprises the nucleobase sequences of the sense strand of any one of the siRNAs listed in Tables 1-5 or the sense strand sequence as set forth in any one of SEQ ID NOs: 3416-8942.

17. The method of any one of claim 12-16, wherein the antisense strand comprises at least 8 consecutive nucleobases of any one of SEQ ID NOs: 69, 159, 177, 265, 283, 305, 307, 323, 355, 415, 421, 427, 431, 433, 437, 439, 515, 605, 623, 711, 729, 751, 753, 769, 801, 861, 867, 873, 877, 879, 883, 885, 14471, 14473, 14475, 14477, 14479, 14481, 14483, 14485, 14487, and 14489, optionally wherein the antisense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 69, 159, 177, 265, 283, 305, 307, 323, 355, 415, 421, 427, 431, 433, 437, 439, 515, 605, 623, 711, 729, 751, 753, 769, 801, 861, 867, 873, 877, 879, 883, 885, 14471, 14473, 14475, 14477, 14479, 14481, 14483, 14485, 14487, and 14489.

18. The method of any one of claims 12-17, wherein the sense strand comprises least 8 consecutive nucleobases of any one of SEQ ID NOs: 68, 158, 176, 264, 282, 304, 306, 322, 354, 414, 420, 426, 430, 432, 436, 438, 514, 604, 622, 710, 728, 750, 752, 768, 800, 860, 866, 872, 876, 878, 882, 884, 14470, 14472, 14474, 14476, 14478, 14480, 14482, 14484, 14486, and 14488, optionally wherein the sense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 68, 158, 176, 264, 282, 304, 306, 322, 354, 414, 420, 426, 430, 432,Attorney Docket Number: J0365.70001WO00436, 438, 514, 604, 622, 710, 728, 750, 752, 768, 800, 860, 866, 872, 876, 878, 882, 884, 14470, 14472, 14474, 14476, 14478, 14480, 14482, 14484, 14486, and 14488.

19. The method of any one of claims 12-17, wherein the antisense strand comprises 15-23 consecutive nucleobases of any one of SEQ ID NOs: 265, 305, 421, 427, 431, 711, 751, 867, 873, 877, 14477, and 14487, and the sense strand comprises 15-21 nucleobases of any one of SEQ ID NOs: 264, 304, 420, 426, 430, 710, 750, 866, 872, 876, 14476, and 14486.

20. The method of any one of claims 10-19, wherein the siRNA molecule comprises the nucleobase sequences of any one of siRNA-30, siRNA-75, siRNA-84, siRNA- 128, siRNA-137, siRNA-148, siRNA-149, siRNA-157, siRNA-173, siRNA-203, siRNA-206, siRNA-209, siRNA-211, siRNA-212, siRNA-214, siRNA-215, siRNA-253, siRNA-298, siRNA-307, siRNA-351, siRNA-360, siRNA-371, siRNA-372, siRNA-380, siRNA-396, siRNA-426, siRNA-429, siRNA-432, siRNA-434, siRNA-435, siRNA-437, siRNA-438, siRNA-1116, siRNA-1117, siRNA-1118, siRNA-1119, siRNA-1120, siRNA-1121, siRNA-1122, siRNA- 1123, siRNA- 1124, siRNA- 1125, optionally wherein the siRNA molecule comprises the nucleobase sequences of any one of siRNA- 128, siRNA- 148, siRNA-206, siRNA-209, siRNA-211, siRNA-351, siRNA-429, siRNA-432, siRNA-434, siRNA-1119, and siRNA- 1124.

21. The method of any one of claims 12-20, wherein the siRNA molecule comprises one or more modified nucleosides, optionally wherein each nucleoside of the antisense strand is a modified nucleoside and each nucleoside of the sense strand is a modified nucleoside.

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

23. The method of claim 22, wherein the 2’ -modified nucleoside is selected from 2’-deoxyribonucleoside (DNA), 2’-fluoro (2’-F), 2’-O-methyl (2’-O-Me), 2’-0-methoxyethyl (2’-MOE), 2’-0-aminopropyl (2’-O-AP), 2’-0-dimethylaminoethyl (2’-O-DMAOE), 2’-O-dimethylaminopropyl (2’-O-DMAP), 2’-0-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-0-N-methylacetamido (2’-O-NMA) modified nucleoside and combinations thereof.

24. The method of any one of claims 21-23, 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.

25. The method of any one of claims 12-24, 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,Attorney Docket Number: J0365.70001WO00optionally wherein the nucleosides at positions 9, 10, and 11 (counting 5’ to 3’) of the sense strand are 2’-F modified nucleosides.

26. The method of claim 25, wherein the nucleoside at position 7 (counting 5’ to 3’) of the sense strand is a 2’-F modified nucleoside.

27. The method of any one of claims 12-26, where 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.

28. The method of claim 27, 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.

29. The method of any one of claims 12-28, wherein the siRNA molecule comprises one or more modified intemucleoside linkages, optionally wherein the siRNA molecule comprises one or more phosphorothioate intemucleoside linkages in at least one strand.

30. The method of any one of claims 12-29, wherein the sense strand comprises two to four phosphorothioate intemucleoside linkages, optionally wherein the first two and / or the last two intemucleoside linkages in the sense strand (from 5’ to 3’) are phosphorothioate intemucleoside linkages.

31. The method of any one of claims 12-29, wherein the antisense strand comprises four phosphorothioate intemucleoside linkages, optionally wherein the first two and / or the last two intemucleoside linkages in the antisense strand (from 5’ to 3’) are phosphorothioate intemucleoside linkages.

32. The method of any one of claims 21-23, wherein the nucleosides at positions 7, 9, 10, and 11 (counting 5’to 3’) of the sense strand are 2’-F modified nucleosides, the nucleosides at 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 and the last 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.

33. The method of any one of claims 21-23, wherein the siRNA molecule is selected from any one of the siRNAs listed in Table 3.

34. The method of any one of claims 21-23, wherein the siRNA molecule is selected from: siRNA-476, siRNA-521, siRNA-530, siRNA-574, siRNA-583, siRNA-594, siRNA-595, siRNA-603, siRNA-619, siRNA-649, siRNA-652, siRNA-655, siRNA-657, siRNA-658,Attorney Docket Number: J0365.70001WO00siRNA-660, siRNA-661, siRNA-1126, siRNA-1127, siRNA-1128, siRNA-1129, and siRNA-1130.35 The method of any one of claims 1-9, wherein the therapeutic agent is a small molecule.

36. The method of any one of claims 1-35, wherein the subject is a human.

37. The method of any one of claims 1-36, wherein the therapeutic agent specifically targets liver cells, kidney cells, muscle cells, or adipose cells.

38. The method of claim 37, wherein the therapeutic agent comprises a targeting agent.

39. The method of claim 38, wherein the targeting agent is a peptide.

40. The method of claim 39, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 9.

41. The method of claim 39 or 40, wherein the peptide is covalently linked to the therapeutic agent.

42. The method of claim 41, wherein the therapeutic agent is an siRNA and the peptide is covalently linked to the 3’ end of the sense strand of the siRNA.

43. The method of claim 32, wherein the targeting agent is N-acetylgalactosamine (GalNAc).

44. The method of claim 43, wherein the GalNAc is covalently linked to the therapeutic agent.

45. The method of claim 44, wherein the therapeutic agent is an siRNA and the GalNAc is covalently linked to the 3’ end of the sense strand of the siRNA.

46. The method of any one of claims 43-45, wherein the GalNAc comprises a structure of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d).

47. The method of any one of claims 43-46, wherein the siRNA is selected from the siRNAs listed in Table 4.

48. The method of any one of claims 43-46, wherein the siRNA is selected from: siRNA-699, siRNA-744, siRNA-753, siRNA-797, siRNA-806, siRNA-817, siRNA-818, siRNA-826, siRNA-842, siRNA-872, siRNA-875, siRNA-878, siRNA-880, siRNA-881, siRNA-883, siRNA-884, siRNA-1131, siRNA-1132, siRNA-1133, siRNA-1134, siRNA-1135, siRNA-1141, siRNA-1142, siRNA-1143, siRNA-1144, siRNA-1145, and siRNA-1146.

49. The method of any one of claims 1-34, wherein the therapeutic agent is an siRNA and the siRNA is conjugated to a lipid.

50. The method of claim 49, wherein the lipid is conjugated to an internal nucleotide of a sense strand or an antisense strand of the siRNA.Attorney Docket Number: J0365.70001WO0051. The method of claim 50, wherein the lipid-conjugated internal nucleotide comprises a 2’-O- docosanoxyl (C22) nucleotide base-3 ’-phosphate.

52. The method of claim 50, wherein the lipid-conjugated internal nucleotide comprises a 2’-O- hexadecyl (C16) nucleotide base-3 ’-phosphate.

53. The method of claim 51 or claim 52, wherein the nucleotide base is selected from the group consisting of adenine, guanine, cytosine, thymine, uracil and analogs thereof.

54. The method of claim 49, wherein the lipid is conjugated to a terminus of a sense strand or an antisense strand of the siRNA.

55. The method of claim 54, wherein the lipid comprises a C22 lipid monomer or a C16 lipid monomer.

56. The method of any one of claims 1-55, wherein the therapeutic agent is an siRNA, and the siRNA further comprises a vinylphosphonate, optionally wherein thevinylpho sphonate is at the 5’ end of the sense strand.

57. The method of any one of claims 49-56, wherein the siRNA is selected from the siRNAs listed in Table 5.

58. The method of any one of claims 49-56, wherein the siRNA is selected from: siRNA-922, siRNA-967, siRNA-976, siRNA-1020, siRNA-1029, siRNA-1040, siRNA-1041, siRNA-1049, siRNA-1065, siRNA-1095, siRNA-1098, siRNA-1101, siRNA-1103, siRNA-1104, siRNA-1106, siRNA-1107, siRNA-1136, siRNA-1137, siRNA-1138, siRNA-1139, and siRNA- 1140.

59. An siRNA molecule targeting an mRNA of the ATF4 gene.

60. The siRNA molecule of claim 59, wherein the siRNA molecule comprises an antisense strand comprising a region of complementarity of at least 8 nucleosides to an ATF4 RNA sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 3, and a sense strand that is at least substantially complementary to the antisense strand.

61. The siRNA molecule of claim 60, wherein the sense strand is 15-35 nucleosides in length, and / or the antisense strand is 15-35 nucleosides in length, wherein the antisense strand and the sense strand hybridize to form a duplex region of 15-25 base pairs in length.

62. The siRNA molecule of claim 60 or claim 61, wherein the antisense strand comprises a region of complementarity of at least 8 nucleosides to the sense strand sequence of any one of the siRNAs listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942, optionally wherein the antisense strand comprises a region of complementary 15-21 nucleobases to the sense strand sequence of any one of the siRNAsAttorney Docket Number: J0365.70001WO00listed in Tables 1-5 or to an ATF4 RNA sequence as set forth in any one of SEQ ID NOs: 2017-8942.

63. The siRNA molecule of any one of claims 60-62, wherein the antisense strand comprises at least 8 consecutive nucleobases of the antisense strand of any one of the siRNAs listed in Tables 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469, optionally wherein the antisense strand comprises the nucleobase sequences of the antisense strand of any one of the siRNAs listed in Tables 1-5 or the antisense strand sequence as set forth in any one of SEQ ID NOs: 8943-14469.

64. The siRNA molecule of any one of claims 60-63, wherein the sense strand comprises at least 8 consecutive nucleobases of the sense strand of any one of the siRNAs listed in Tables 1-5 or the sense strand sequence as set forth in any one of SEQ ID NOs: 3416-8942, optionally wherein the sense strand comprises the nucleobase sequences of the sense strand of any one of the siRNAs listed in Tables 1-5 or the sense strand sequence as set forth in any one of SEQ ID NOs: 3416-8942.

65. The siRNA molecule of any one of claim 60-64, wherein the antisense strand comprises at least 8 consecutive nucleobases of any one of SEQ ID NOs: 69, 159, 177, 265, 283, 305, 307, 323, 355, 415, 421, 427, 431, 433, 437, 439, 515, 605, 623, 711, 729, 751, 753, 769, 801, 861, 867, 873, 877, 879, 883, 885, 14471, 14473, 14475, 14477, 14479, 14481, 14483, 14485, 14487, and 14489, optionally wherein the antisense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 69, 159, 177, 265, 283, 305, 307, 323, 355, 415, 421, 427, 431, 433, 437, 439, 515, 605, 623, 711, 729, 751, 753, 769, 801, 861, 867, 873, 877, 879, 883, 885, 14471, 14473, 14475, 14477, 14479, 14481, 14483, 14485, 14487, and 14489.

66. The siRNA molecule of any one of claims 60-65, wherein the sense strand comprises least 8 consecutive nucleobases of any one of SEQ ID NOs: 68, 158, 176, 264, 282, 304, 306, 322, 354, 414, 420, 426, 430, 432, 436, 438, 514, 604, 622, 710, 728, 750, 752, 768, 800, 860, 866, 872, 876, 878, 882, 884, 14470, 14472, 14474, 14476, 14478, 14480, 14482, 14484, 14486, and 14488, optionally wherein the sense strand comprises the nucleobase sequence of any one of SEQ ID NOs: 68, 158, 176, 264, 282, 304, 306, 322, 354, 414, 420, 426, 430, 432, 436, 438, 514, 604, 622, 710, 728, 750, 752, 768, 800, 860, 866, 872, 876, 878, 882, 884, 14470, 14472, 14474, 14476, 14478, 14480, 14482, 14484, 14486, and 14488.

67. The siRNA molecule of any one of claims 60-66, wherein the antisense strand comprises 15-23 consecutive nucleobases of any one of SEQ ID NOs: 265, 305, 421, 427, 431, 711, 751, 867, 873, 877, 14477, and 14487, and the sense strand comprises 15-21Attorney Docket Number: J0365.70001WO00nucleobases of any one of SEQ ID NOs: 264, 304, 420, 426, 430, 710, 750, 866, 872, 876, 14476, and 14486.

68. The siRNA molecule of any one of claims 59-67, wherein the siRNA molecule comprises the nucleobase sequences of any one of siRNA-30, siRNA-75, siRNA-84, siRNA-128, siRNA-137, siRNA-148, siRNA-149, siRNA-157, siRNA-173, siRNA-203, siRNA-206, siRNA-209, siRNA-211, siRNA-212, siRNA-214, siRNA-215, siRNA-253, siRNA-298, siRNA-307, siRNA-351, siRNA-360, siRNA-371, siRNA-372, siRNA-380, siRNA-396, siRNA-426, siRNA-429, siRNA-432, siRNA-434, siRNA-435, siRNA-437, siRNA-438, siRNA-1116, siRNA-1117, siRNA-1118, siRNA-1119, siRNA-1120, siRNA-1121, siRNA-1122, siRNA-1123, siRNA-1124, and siRNA-1125, optionally wherein the siRNA molecule comprises the nucleobase sequences of any one of siRNA-128, siRNA-148, siRNA-206, siRNA-209, siRNA-211, siRNA-351, siRNA-429, siRNA-432, siRNA-434, siRNA-1119, and siRNA- 1124.

69. The siRNA molecule of any one of claims 59-68, wherein the siRNA molecule comprises one or more modified nucleosides, optionally wherein each nucleoside of the antisense strand is a modified nucleoside and each nucleoside of the sense strand is a modified nucleoside.

70. The siRNA molecule of claim 69, wherein the one or more modified nucleosides are 2’ modified nucleosides.

71. The siRNA molecule of claim 70, wherein 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’-0-aminopropyl (2’-O-AP), 2’-0-dimethylaminoethyl (2’-O-DMAOE), 2’-0-dimethylaminopropyl (2’-O-DMAP), 2’-0-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-0-N-methylacetamido (2’-O-NMA) modified nucleoside and combinations thereof.

72. The siRNA molecule of any one of claims 69-71, 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.

73. The siRNA molecule of any one of claims 60-72, 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, optionally wherein the nucleosides at positions 9, 10, and 11 (counting 5’ to 3’) of the sense strand are 2’-F modified nucleosides.Attorney Docket Number: J0365.70001WO0074. The siRNA molecule of claim 73, wherein the nucleoside at position 7 (counting 5’ to 3’) of the sense strand is a 2’-F modified nucleoside.

75. The siRNA molecule of any one of claims 60-74, where 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.

76. The siRNA molecule of claim 75, 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.

77. The siRNA molecule of any one of claims 60-76, wherein the siRNA molecule comprises one or more modified intemucleoside linkages, optionally wherein the siRNA molecule comprises one or more phosphorothioate internucleoside linkages in at least one strand.

78. The siRNA molecule of any one of claims 60-77 wherein the sense strand comprises two to four phosphorothioate intemucleoside linkages, optionally wherein the first two and / or the last two intemucleoside linkages in the sense strand (from 5’ to 3’) are phosphorothioate intemucleoside linkages.

79. The siRNA molecule of any one of claims 60-78, wherein the antisense strand comprises four phosphorothioate intemucleoside linkages, optionally wherein the first two and / or the last two intemucleoside linkages in the antisense strand (from 5’ to 3’) are phosphorothioate intemucleoside linkages.

80. The siRNA molecule of any one of claims 60-79, wherein the nucleosides at positions 7, 9, 10, and 11 (counting 5’ to 3’) of the sense strand are 2’-F modified nucleosides, the nucleosides at 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 and the last 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.

81. The siRNA molecule of any one of claims 69-80, wherein the siRNA molecule is selected from any one of the siRNAs listed in Table 3.

82. The siRNA molecule of any one of claims 69-80, wherein the siRNA molecule is selected from: siRNA-476, siRNA-521, siRNA-530, siRNA-574, siRNA-583, siRNA-594, siRNA-595, siRNA-603, siRNA-619, siRNA-649, siRNA-652, siRNA-655, siRNA-657,Attorney Docket Number: J0365.70001WO00siRNA-658, siRNA-660, siRNA-661, siRNA-1126, siRNA-1127, siRNA-1128, siRNA-1129, and siRNA- 1130.

83. The siRNA molecule of any one of claims 59-82, further comprising a targeting agent, optionally wherein the targeting agent is covalently linked to the siRNAmolecule.

84. The siRNA molecule of claim 83, wherein the targeting agent targets liver cells, kidney cells, muscle cells, or adipose cells.

85. The siRNA molecule of claim 82 or claim 83, wherein the targeting agent comprises a peptide.

86. The siRNA molecule of claim 85, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 9.

87. The siRNA molecule of any one of claims 83-86, wherein the peptide is covalently linked to the 3’ end of the sense strand of the siRNA.

88. The siRNA molecule of claim 83 or claim 84, wherein the targeting agent comprises a N-acetylgalactosamine (GalNAc).

89. The siRNA molecule of claim 88, wherein the GalNAc is covalently linked to the 3’ end of the sense strand of the siRNA.

90. The siRNA molecule of claim 88 or claim 89, wherein the GalNAc comprises a structure of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d).

91. The siRNA molecule of any one of claims 88-90, wherein the siRNA molecule is selected from the siRNAs listed in Table 4.

92. The siRNA molecule of any one of claims 88-90, wherein the siRNA molecule is selected from: siRNA-699, siRNA-744, siRNA-753, siRNA-797, siRNA-806, siRNA-817, siRNA-818, siRNA-826, siRNA-842, siRNA-872, siRNA-875, siRNA-878, siRNA-880, siRNA-881, siRNA-883, siRNA-884, siRNA-1131, siRNA-1132, siRNA-1133, siRNA-1134, siRNA-1135, siRNA-1141, siRNA-1142, siRNA-1143, siRNA-1144, siRNA-1145, and siRNA- 1146,.

93. The siRNA molecule of claim 83 or claim 84, wherein the targeting agent comprises a lipid.

94. The siRNA molecule of claim 93, wherein the lipid is conjugated to an internal nucleotide of a sense strand or an antisense strand of the siRNAmolecule.

95. The siRNA molecule of claim 94, wherein the lipid-conjugated internal nucleotide comprises a 2’-O- docosanoxyl (C22) nucleotide base-3 ’-phosphate.

96. The siRNA molecule of claim 94, wherein the lipid-conjugated internal nucleotide comprises a 2’-O- hexadecyl (C16) nucleotide base-3 ’-phosphate.Attorney Docket Number: J0365.70001WO0097. The siRNA molecule of any one of claims 94-96, wherein the nucleobase of the nucleotide is selected from the group consisting of adenine, guanine, cytosine, thymine, uracil and analogs thereof.

98. The siRNA molecule of claim 93, wherein the lipid is conjugated to a terminus of a sense strand or an antisense strand of the siRNAmolecule.

99. The siRNA molecule of claim 98, wherein the lipid comprises a C22 lipid monomer or a C16 lipid monomer.

100. The siRNA molecule of any one of claims 59-99, wherein the siRNA molecule further comprises a vinylphosphonate, optionally wherein the vinylpho sphonate is at the 5’ end of the sense strand.

101. The siRNA molecule of any one of claims 93-100, wherein the siRNA molecule is selected from the siRNAs listed in Table 5.

102. The siRNA molecule of any one of claims 93-100, wherein the siRNA molecule is selected from: siRNA-922, siRNA-967, siRNA-976, siRNA-1020, siRNA-1029, siRNA-1040, siRNA-1041, siRNA-1049, siRNA-1065, siRNA-1095, siRNA-1098, siRNA-1101, siRNA-1103, siRNA-1104, siRNA-1106, siRNA-1107, siRNA-1136, siRNA-1137, siRNA-1138, siRNA-1139, and siRNA-1140.

103. A composition comprising the siRNA of any one of claims 59-102.

104. A nanoparticle composition comprising the siRNA of any one of claims 59-102 or the composition of claim 103.

105. The nanoparticle composition of claim 104, wherein the composition comprises an adipose targeting peptide having a sequence set forth in SEQ ID NO: 9.

106. The nanoparticle composition of claim 105, 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.

107. The nanoparticle composition of claim 106, wherein the at least one positive charged amino acid comprises arginine, lysine, or histidine.

108. The nanoparticle composition of claim 107, wherein the at least one positive charged amino acid is arginine.

109. The nanoparticle composition of any one of claims 104-108, wherein the ratio of the peptide to the siRNA is at least 10:1, 20:1, 30:1, or 40:1.

110. The nanoparticle composition of any one of claims 104-109, wherein the pH of the nanoparticle composition is from about 5.5 to about 7.5.Attorney Docket Number: J0365.70001WO00111. The nanoparticle composition of claim 110, wherein the pH is from about 6 to about 6.5.

112. The nanoparticle composition of claim 110, wherein the pH is about 6.

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