Compositions and methods for treating nonalcoholic fatty liver disease

Abstract

Described are compositions and methods for inhibition of IRS1 gene expression. RNA interference (RNAi) agents for inhibiting the expression of IRS1 gene are described. The IRS1 RNAi agents disclosed herein may be targeted to cells, such as hepatocytes, for example, by using conjugated targeting ligands. Pharmaceutical compositions comprising one or more IRS RNAi agents optionally with one or more additional therapeutics are also described.

Description

Attorney Docket No: 208782001943COMPOSITIONS AND METHODS FOR TREATING NONALCOHOLIC FATTY LIVER DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. Provisional Application No. 63 / 685,369, filed on August 21, 2024, and International Application No. PCT / US2024 / 048960, filed on September 27, 2024, the contents of each of which are incorporated herein in its entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (208782001943 SEQLIST.xml; Size: 8,250,391 bytes; and Date of Creation: August 15, 2025) is herein incorporated by reference in its entirety.FIELD

[0003] The present disclosure relates to RNA interference (RNAi) agents to inhibit the expression of insulin receptor substrate-1 (IRS1). The disclosure also relates to compositions that include IRS 1 RNAi agents and methods of use thereof, including the use of such IRS 1 RNAi agents in the treatment of nonalcoholic fatty liver disease (NAFLD) and / or nonalcoholic steatohepatitis (NASH), also known as metabolic dysfunction-associated steatotic liver disease (MASLD) and / or metabolic dysfunction-associated steatohepatitis (MASH).BACKGROUND

[0004] Nonalcoholic fatty liver disease (NAFLD) is a broad term for a range of liver conditions affecting people who drink little to no alcohol. The main characteristic of NAFLD is too much fat stored in liver cells. It is currently unknown exactly why some individuals accumulate fat in the liver while others do not. Some individuals with NAFLD can develop nonalcoholic steatohepatitis (NASH), an aggressive form of fatty liver disease, which is marked by steatosis, fibrosis, and liver inflammation and may progress to advanced scarring (cirrhosis) and liver failure.1MOFO-359437731Attorney Docket No: 208782001943

[0005] NAFLD and NASH are both linked to being overweight or obese, insulin resistance, high blood sugar (hyperglycemia), and high levels of fats (particularly triglycerides) in the blood. NAFLD is also a risk factor for type 2 diabetes. Lifestyle modification remains the cornerstone of management of NAFLD and NASH including losing weight, keeping a healthy diet, limiting over the counter drugs, and avoiding alcohol. Additional treatment options include medications to reduce blood pressure or control diabetes. If NAFLD or NASH leads to cirrhosis, treatment of the complications of cirrhosis with medicines, minor medical procedures, and surgery may be necessary. Individuals with liver failure or liver cancer may need a liver transplant to restore health.

[0006] NAFLD is increasingly common around the world, especially in Western nations where it is the leading cause of liver disease. In the United States, it is the most common form of chronic liver disease, affecting about one-quarter of the population. It is a cause of endstage liver disease, with increased mortality secondary to cirrhosis and its complications. No drug treatment has been approved by the Food and Drug Administration for nonalcoholic fatty liver disease- either non-alcoholic fatty liver or NASH. Therefore, there continues to be a need to for safe and effective treatments for NAFLD and NASH.SUMMARY

[0007] Provided herein are RNA interference (RNAi) agents to inhibit the expression of insulin receptor substrate-1 (IRS1).

[0008] Described herein is an RNAi agent that inhibits expression of insulin receptor substrate-1 (IRS1) comprising an antisense strand and a sense strand that at least partially complements the antisense strand, wherein: (a) the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 1-96, 385-457, and 677-688; and / or (b) the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 97-192, 458-530, and 689-700.

[0009] In some implementations, one or more bases of the antisense stand and / or the sense strand are modified. In some implementations, the antisense strand has a modification pattern according to nsNfsnnnNfnnnnnnnNfnNfnnnnnsnsn. In some implementations, the sense strand has a modification pattern according to nsnsnnnnNfnNfNfNfnnnnnnnnsnsn. In some implementations, the sense strand has a modification pattern according to nsnsnnnnNfnNfNfNfnnnnnnnnnn. In some implementations, the antisense strand comprises2MOFO-359437731Attorney Docket No: 208782001943 at least 14 contiguous bases from any one of SEQ ID NOS: 193-288, 531-603, and 701-712. In some implementations, the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 289-384, 604-676, 713-724, and 726-731. In some implementations, (a) the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 193-288, 531-603, and 701-712; and (b) the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 289-384, 604-676, 713-724, and 726-731.

[0010] Also described herein is an RNAi agent that inhibits expression of insulin receptor substrate-1 (IRS1) comprising an antisense strand and a sense strand that at least partially complements the antisense strand, and a targeting ligand conjugated to the antisense strand or the sense strand, wherein the targeting ligand targets a hepatocyte.

[0011] In some implementations, the antisense strand comprises at least 14 contiguous bases that complement a sequence in an mRNA molecule that encodes IRS1 (SEQ ID NO: 725).

[0012] In some implementations, the antisense strand and the sense strand form a duplex of at least 14 bases in length. In some implementations, the antisense strand and the sense strand form a duplex of between 15 and 30 bases in length.

[0013] In some implementations, the antisense strand or a subsequence thereof differs by 0, 1, 2, 3, or 4 nucleotides from an equal length portion of any one of SEQ ID NOS: 1-96, 385- 457, 677-688, 193-288, 531-603, and 701-712, wherein the subsequence is at least 14, 15, 16, 17, 18, 19, 20, or 21 bases in length.

[0014] In some implementations, the antisense strand comprises, in order, nucleotides 2-23 of any one of SEQ ID NOS: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712. In some implementations, the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712. In some implementations, the antisense strand comprises, in order, nucleobases 1-14 of any one of SEQ ID NOS: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712. In some implementations, the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 449, 450, 457, 595, 596, 603, 677, 679, 680, 701, 703, and 704.

[0015] In some implementations, the sense strand or a subsequence thereof differs by 0, 1, 2, 3, or 4 nucleotides from an equal length portion of any one of SEQ ID NOS: 97-192, 458- 530, 689-700, 289-384, 604-676, 713-724, and 726-731, wherein the subsequence is at least 14, 15, 16, 17, 18, 19, 20, or 21 bases in length. In some implementations, the sense strand comprises, in order, nucleotides 1-22 of any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731. In some implementations, the sense strand3MOFO-359437731Attorney Docket No: 208782001943 comprises at least 14 contiguous bases from any one of SEQ ID NOS: 97-192, 458-530, 689- 700, 289-384, 604-676, 713-724, and 726-731. In some implementations, the sense strand comprises, in order, nucleobases 1-14 of any one of SEQ ID NOS: 97-192, 458-530, 689- 700, 289-384, 604-676, 713-724, and 726-731. In some implementations, the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 522, 523, 530, 689, 691, 692, 668, 669, 676, 713, 715, 716, and 726-731.

[0016] In some implementations, the antisense strand comprises at least 16 contiguous bases that complement a sequence in an mRNA molecule that encodes IRS1 (SEQ ID NO: 725).

[0017] In some implementations, the antisense strand and the sense strand form a duplex of at least 16 bases in length.

[0018] In some implementations, the antisense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712. In some implementations, the antisense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS: 449, 450, 457, 595, 596, 603, 677, 679, 680, 701, 703, and 704. In some implementations, the antisense strand comprises, in order, nucleobases 1-16, 1-17, 1- 18, 1-19, 1-20, 1-21, 1-22, 1-23, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 3-18, 4-19, 4-20, 4- 21, 4-22, 4-23, 5-21, 5-22, 5-23, 6-20, 6-21, 6-22, 6-23, 7-22, 7-23, or 8-23 of any one of SEQ ID NOS: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712. In some implementations, the antisense strand comprises a nucleotide sequence according to any one of SEQ ID NOS: 1-96, 385-457, and 677-688. In some implementations, one or more nucleotides are modified. In some implementations, the antisense strand comprises a nucleotide sequence according to any one of SEQ ID NOS: 449, 450, 457, 677, 679, and 680. In some implementations, one or more nucleotides are modified. In some implementations, the antisense strand has a modification pattern according to nsNfsnnnNfnnnnnnnNfnNfnnnnnsnsn. In some implementations, the antisense strand comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 193-288, 531-603, and 701-712. In some implementations, the antisense strand comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 595, 596, 603, 701, 703, and 704.

[0019] In some implementations, the sense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731. In some implementations, the sense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS: 522, 523, 530, 689, 691, 692, and 726-731. In some implementations, the sense strand comprises, in order, nucleobases 1-16, 1-17, 1-18, 1-19,4MOFO-359437731Attorney Docket No: 2087820019431-20, 1-21, 1-22, 1-23, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 3-18, 4-19, 4-20, 4-21, 4-22, 4-23, 5-21, 5-22, 5-23, 6-20, 6-21, 6-22, 6-23, 7-22, 7-23, or 8-23 of any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731. In some implementations, the sense strand comprises a nucleobase sequence according to any one of SEQ ID NOS: 97-192, 458-530, and 689-700. In some implementations, one or more nucleotides are modified. In some implementations, the sense strand comprises a nucleobase sequence according to any one of SEQ ID NOS: 522, 523, 530, 689, 691, and 692. In some implementations, one or more nucleotides are modified. In some implementations, the sense strand has a modification pattern according to nsnsnnnnNfnNfNfNfnnnnnnnnsnsn. In some implementations, the sense strand has a modification pattern according to nsnsnnnnNfnNfNfNfnnnnnnnnnn. In some implementations, the sense strand comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 289-384, 604-676, 713- 724, and 726-731. In some implementations, the sense strand comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 668, 669, 676, 713, 715, 716, and 726-731.

[0020] In some implementations, (a) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 97 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 1; (b) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 98 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 2; (c) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 99 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 3; (d) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 100 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 4; (e) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 101 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 5; (f) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 102 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 6; (g) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 103 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 7; (h) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 104 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 8; (i) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 105 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 9; (j) the sense strand comprises a nucleobase sequence5MOFO-359437731Attorney Docket No: 208782001943 according to SEQ ID NO: 106 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 10; (k) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 107 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 11; (1) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 108 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 12; (m) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 109 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 13; (n) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 110 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 14; (o) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 111 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 15; (p) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 112 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 16; (q) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 113 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 17; (r) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 114 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 18; (s) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 115 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 19; (t) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 116 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 20; (u) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 117 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 21; (v) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 118 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 22; (w) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 119 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 23; (x) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 120 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 24; (y) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 121 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 25; (z) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 122 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 26; (aa) the sense strand comprises a6MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 123 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 27; (bb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 124 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 28; (cc) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 125 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 29; (dd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 126 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 30; (ee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 127 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 31; (ff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 128 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 32; (gg) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 129 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 33; (hh) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 130 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 34; (ii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 131 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 35; (jj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 132 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 36; (kk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 133 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 37; (11) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 134 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 38; (mm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 135 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 39; (nn) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 136 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 40; (oo) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 137 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 41; (pp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 138 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 42; (qq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 139 and the antisense strand comprises a7MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 43; (rr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 140 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 44; (ss) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 141 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 45; (tt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 142 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 46; (uu) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 143 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 47; (vv) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 144 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 48; (ww) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 145 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 49; (xx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 146 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 50; (yy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 147 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 51; (zz) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 148 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 52; (aaa) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 149 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 53; (bbb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 150 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 54; (ccc) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 151 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 55; (ddd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 152 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 56; (eee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 153 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 57; (fff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 154 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 58; (ggg) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 155 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 59; (hhh) the sense strand comprises a8MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 156 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 60; (iii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 157 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 61; (jjj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 158 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 62; (kkk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 159 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 63; (111) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 160 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 64; (mmm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 161 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 65; (nnn) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 162 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 66; (ooo) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 163 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 67; (ppp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 164 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 68; (qqq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 165 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 69; (rrr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 166 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 70; (sss) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 167 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 71; (ttt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 168 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 72; (uuu) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 169 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 73; (vvv) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 170 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 74; (www) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 171 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 75; (xxx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 172 and the antisense strand comprises a9MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 76; (yyy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 173 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 77; (zzz) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 174 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 78; (aaaa) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 175 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 79; (bbbb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 176 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 80; (cccc) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 177 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 81; (dddd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 178 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 82; (eeee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 179 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 83; (ffff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 180 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 84; (gggg) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 181 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 85; (hhhh) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 182 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 86; (iiii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 183 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 87; (jjjj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 184 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 88; (kkkk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 185 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 89; (1111) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 186 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 90; (mmmm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 187 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 91; (nnnn) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 188 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 92; (oooo) the sense strand comprises a10MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 189 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 93; (pppp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 190 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 94; (qqqq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 191 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 95; (rrrr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 192 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 96; (ssss) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 458 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 385; (tttt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 459 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 386; (uuuu) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 460 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 387; (vvvv) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 461 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 388; (wwww) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 462 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 389; (xxxx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 463 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 390; (yyyy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 464 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 391; (zzzz) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 465 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 392; (aaaaa) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 466 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 393; (bbbbb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 467 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 394; (ccccc) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 468 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 395; (ddddd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 469 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 396; (eeeee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 470 and the antisense strand comprises a11MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 397; (fffff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 471 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 398; (ggggg) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 472 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 399; (hhhhh) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 473 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 400; (iiiii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 474 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 401; (jjjjj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 475 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 402; (kkkkk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 476 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 403; (11111) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 477 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 404; (mmmmm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 478 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 405; (nnnnn) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 479 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 406; (ooooo) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 480 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 407; (ppppp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 481 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 408; (qqqqq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 482 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 409; (rrrrr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 483 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 410; (sssss) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 484 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 411; (ttttt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 485 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 412; (uuuuu) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 486 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 413; (vvvw) the sense strand comprises a12MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 487 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 414; (wwwww) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 488 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 415; (xxxxx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 489 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 416; (yyyyy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 490 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 417; (zzzzz) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 491 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 418; (aaaaaa) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 492 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 419; (bbbbbb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 493 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 420; (cccccc) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 494 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 421; (dddddd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 495 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 422; (eeeeee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 496 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 423; (ffffff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 497 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 424; (gggggg) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 498 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 425; (hhhhhh) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 499 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 426; (iiiiii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 500 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 427; (jjjjjj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 501 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 428; (kkkkkk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 502 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 429; (111111) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 503 and the antisense strand comprises a13MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 430; (mmmmmm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 504 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 431; (nnnnnn) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 505 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 432; (oooooo) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 506 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 433; (pppppp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 507 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 434; (qqqqqq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 508 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 435; (rrrrrr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 509 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 436; (ssssss) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 510 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 437; (tttttt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 511 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 438; (uuuuuu) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 512 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 439; (vvvwv) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 513 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 440; (wwwwww) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 514 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 441; (xxxxxx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 515 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 442; (yyyyyy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 516 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 443; (zzzzzz) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 517 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 444; (aaaaaaa) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 518 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 445; (bbbbbbb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 519 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 446; (ccccccc) the sense strand comprises a14MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 520 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 447; (ddddddd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 521 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 448; (eeeeeee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 522 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 449; (fffffff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 523 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 450; (ggggggg) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 524 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 451; (hhhhhhh) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 525 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 452; (iiiiiii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 526 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 453; (jjjjjjj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 527 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 454; (kkkkkkk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 528 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 455; (1111111) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 529 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 456; (mmmmmmm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 530 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 457; (nnnnnnn) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 689 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 677; (ooooooo) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 690 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 678; (ppppppp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 691 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 679; (qqqqqqq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 692 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 680; (rrrrrrr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 693 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 681; (sssssss) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 694 and the antisense strand15MOFO-359437731Attorney Docket No: 208782001943 comprises a nucleobase sequence according to SEQ ID NO: 682; (ttttttt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 695 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 683; (uuuuuuu) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 696 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 684; (vvvvvvv) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 697 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 685; (wwwwwww) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 698 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 686; (xxxxxxx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 699 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 687; or (yyyyyyy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 700 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 688.

[0021] In some implementations, (a) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 530 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 457; (b) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 523 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 450; (c) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 691 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 679; (d) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 689 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 677; (e) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 522 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 449; or (f) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 692 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 680.

[0022] In some implementations, (a) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 289 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 193; (b) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 290 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 194; (c) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 291 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 195; (d) the sense strand16MOFO-359437731Attorney Docket No: 208782001943 comprises a modified nucleotide sequence according to SEQ ID NO: 292 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 196; (e) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 293 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 197; (f) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 294 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 198; (g) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 295 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 199; (h) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 296 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 200; (i) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 297 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 201; (j) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 298 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 202; (k) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 299 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 203; (1) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 300 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 204; (m) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 301 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 205; (n) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 302 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 206; (o) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 303 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 207; (p) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 304 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 208; (q) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 305 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 209; (r) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 306 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 210; (s) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 307 and the antisense strand comprises a modified nucleotide sequence17MOFO-359437731Attorney Docket No: 208782001943 according to SEQ ID NO: 211; (t) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 308 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 212; (u) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 309 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 213; (v) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 310 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 214; (w) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 311 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 215; (x) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 312 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 216; (y) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 313 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 217; (z) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 314 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 218; (aa) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 315 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 219; (bb) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 316 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 220; (cc) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 317 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 221; (dd) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 318 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 222; (ee) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 319 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 223;(ff) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 320 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 224; (gg) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 321 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 225; (hh) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 322 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 226; (ii) the sense strand comprises a modified nucleotide18MOFO-359437731Attorney Docket No: 208782001943 sequence according to SEQ ID NO: 323 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 227; (jj) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 324 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 228; (kk) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 325 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 229;(11) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 326 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 230; (mm) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 327 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 231; (nn) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 328 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 232; (oo) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 329 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 233; (pp) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 330 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 234; (qq) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 331 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 235;(rr) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 332 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 236; (ss) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 333 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 237; (tt) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 334 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 238; (uu) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 335 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 239; (vv) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 336 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 240; (ww) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 337 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 241; (xx) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO:19MOFO-359437731Attorney Docket No: 208782001943338 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 242; (yy) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 339 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 243; (zz) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 340 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 244; (aaa) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 341 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 245; (bbb) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 342 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 246; (ccc) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 343 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 247; (ddd) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 344 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 248; (eee) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 345 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 249; (fff) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 346 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 250; (ggg) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 347 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 251; (hhh) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 348 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 252; (iii) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 349 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 253; (jjj) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 350 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 254; (kkk) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 351 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 255; (111) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 352 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 256; (mmm) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 353 and the antisense strand comprises a modified20MOFO-359437731Attorney Docket No: 208782001943 nucleotide sequence according to SEQ ID NO: 257; (nnn) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 354 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 258; (ooo) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 355 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 259; (ppp) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 356 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 260; (qqq) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 357 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 261; (rrr) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 358 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 262; (sss) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 359 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 263; (ttt) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 360 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 264; (uuu) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 361 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 265; (vvv) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 362 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 266; (www) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 363 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 267; (xxx) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 364 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 268; (yyy) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 365 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 269; (zzz) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 366 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 270; (aaaa) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 367 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 271; (bbbb) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 368 and the antisense strand comprises a modified nucleotide sequence21MOFO-359437731Attorney Docket No: 208782001943 according to SEQ ID NO: 272; (cccc) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 369 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 273; (dddd) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 370 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 274; (eeee) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 371 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 275; (ffff) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 372 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 276; (gggg) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 373 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 277; (hhhh) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 374 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 278; (iiii) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 375 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 279; (jjjj) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 376 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 280; (kkkk) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 377 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 281; (1111) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 378 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 282; (mmmm) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 379 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 283; (nnnn) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 380 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 284; (oooo) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 381 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 285; (pppp) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 382 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 286; (qqqq) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 383 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID22MOFO-359437731Attorney Docket No: 208782001943NO: 287; (rrrr) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 384 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 288;(ssss) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 604 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 531; (tttt) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 605 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 532; (uuuu) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 606 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 533; (vvvv) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 607 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 534; (wwww) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 608 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 535; (xxxx) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 609 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 536; (yyyy) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 610 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 537; (zzzz) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 611 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 538; (aaaaa) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 612 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 539; (bbbbb) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 613 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 540; (ccccc) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 614 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 541; (ddddd) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 615 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 542; (eeeee) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 616 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 543; (fffff) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 617 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO:23MOFO-359437731Attorney Docket No: 208782001943544; (ggggg) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 618 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 545; (hhhhh) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 619 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 546; (iiiii) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 620 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 547; (jjjjj) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 621 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 548; (kkkkk) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 622 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 549; (11111) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 623 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 550; (mmmmm) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 624 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 551; (nnnnn) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 625 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 552; (ooooo) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 626 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 553; (ppppp) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 627 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 554; (qqqqq) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 628 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 555; (rrrrr) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 629 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 556; (sssss) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 630 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 557; (ttttt) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 631 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 558; (uuuuu) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 632 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO:24MOFO-359437731Attorney Docket No: 208782001943559; (vvvvv) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 633 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 560; (wwwww) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 634 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 561; (xxxxx) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 635 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 562; (yyyyy) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 636 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 563; (zzzzz) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 637 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 564; (aaaaaa) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 638 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 565; (bbbbbb) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 639 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 566; (cccccc) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 640 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 567; (dddddd) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 641 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 568; (eeeeee) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 642 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 569; (ffffff) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 643 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 570; (gggggg) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 644 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 571; (hhhhhh) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 645 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 572; (iiiiii) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 646 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 573; (jjjjjj) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 647 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID25MOFO-359437731Attorney Docket No: 208782001943NO: 574; (kkkkkk) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 648 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 575; (111111) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 649 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 576; (mmmmmm) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 650 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 577; (nnnnnn) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 651 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 578; (oooooo) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 652 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 579; (pppppp) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 653 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 580; (qqqqqq) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 654 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 581; (rrrrrr) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 655 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 582; (ssssss) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 656 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 583; (tttttt) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 657 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 584; (uuuuuu) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 658 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 585; (vvvvvv) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 659 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 586; (wwwwww) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 660 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 587; (xxxxxx) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 661 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 588; (yyyyyy) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 662 and the antisense strand comprises a modified nucleobase sequence26MOFO-359437731Attorney Docket No: 208782001943 according to SEQ ID NO: 589; (zzzzzz) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 663 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 590; (aaaaaaa) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 664 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 591; (bbbbbbb) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 665 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 592; (ccccccc) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 666 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 593; (ddddddd) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 667 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 594; (eeeeeee) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 668 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 595; (fffffff) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 669 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 596; (ggggggg) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 670 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 597; (hhhhhhh) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 671 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 598; (iiiiiii) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 672 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 599; (jjjjjjj) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 673 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 600; (kkkkkkk) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 674 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 601; (1111111) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 675 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 602; (mmmmmmm) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 676 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 603; (nnnnnnn) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 713 and the antisense strand27MOFO-359437731Attorney Docket No: 208782001943 comprises a modified nucleobase sequence according to SEQ ID NO: 701; (ooooooo) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 714 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 702; (ppppppp) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 715 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 703; (qqqqqqq) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 716 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 704; (rrrrrrr) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 717 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 705; (sssssss) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 718 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 706; (ttttttt) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 719 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 707; (uuuuuuu) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 720 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 708; (vvvvvvv) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 721 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 709; (wwwwwww) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 722 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 710; (xxxxxxx) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 723 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 711; (yyyyyyy) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 724 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 712; (aaaaaaaa) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 726 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 603; (bbbbbbbb) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 727 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 596; (cccccccc) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 728 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 703;(dddddddd) the sense strand comprises a modified nucleobase sequence according to SEQ ID28MOFO-359437731Attorney Docket No: 208782001943NO: 729 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 701; (eeeeeeee) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 730 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 595; or (ffffffff) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 731 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 704.

[0023] In some implementations, (a) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 676 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 603; (b) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 669 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 596; (c) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 715 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 703;(d) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 713 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 701; (e) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 668 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 595; (f) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 716 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 704; (g) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 726 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 603; (h) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 727 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 596; (i) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 728 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 703;(j) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 729 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 701; (k) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 730 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 595; or (1) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 731 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 704.29MOFO-359437731Attorney Docket No: 208782001943

[0024] In some implementations, the RNAi agent comprises a targeting ligand comprising a structure according to Formula I:wherein R is a linker conjugated to the wherein the targeting ligand is conjugated to the 3' end of the sense strand, wherein R comprises a structure according to Formula III:Formula III and wherein connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to the 3' end of the sense strand.

[0025] In some implementations, the sense strand comprises a 3' overhang of 1-5 nucleotides in length. In some implementations, the sense strand comprises a 5' overhang of 1-5 nucleotides in length.

[0026] In some implementations, the antisense strand comprises a 3' overhang of 1-5 nucleotides in length. In some implementations, the antisense strand comprises a 5' overhang of 1-5 nucleotides in length.

[0027] In some implementations, the sense strand or the antisense strand comprises at least one modified nucleotide or at least one modified intemucleoside linkage. In some implementations, the sense strand and or the antisense strand comprises a modified intemucleoside linkage at a first, second, penultimate, or final intemucleoside linkage position. In some implementations, the at least one modified nucleotide or at least one modified intemucleoside linkage comprises a 2'-O-methyl modified nucleotide, a nucleotide comprising a 5'-phosphorothioate group, a 2'-deoxy-2'-fluoro modified nucleotide, a 2'-30MOFO-359437731Attorney Docket No: 208782001943 deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, deoxythymidine, an inverted deoxythymidine, a 2'-amino-modified nucleotide, a 2'-alkyl-modified nucleotide, a morpholino nucleotide, a phosphorami date, or a non-natural base comprising nucleotide.

[0028] In some implementations, the targeting ligand is conjugated to the sense strand. In some implementations, the targeting ligand is conjugated to the 3' end of the sense strand. In some implementations, the targeting ligand is conjugated to the 5' end of the sense strand.

[0029] In some implementations, the targeting ligand is conjugated to the antisense strand. In some implementations, the targeting ligand is conjugated to the 3' end of the antisense strand. In some implementations, the targeting ligand is conjugated to the 5' end of the antisense strand.

[0030] In some implementations, the targeting ligand comprises a galactose trimer. In some implementations, the targeting ligand comprises N-acetylgalactosamine (GalNac).

[0031] In some implementations, the targeting ligand comprises a structure according to Formula I:wherein R is: (i) the sense strand or the antisense strand; or (ii) a linker conjugated to the sense strand or the antisense strand. In some implementations, R is a linker conjugated to the sense strand or the antisense strand having a structure according to Formula III:wherein: (i) connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to the sense strand or the antisense strand; or (ii)31MOFO-359437731Attorney Docket No: 208782001943 connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to a phosphate group which is conjugated to the sense strand or the antisense strand. In some implementations, Formula III or the phosphate group is conjugated to the 3' end or the 5' end of the sense strand or the antisense strand. In some implementations, Formula III or the phosphate group is conjugated to an internal nucleotide or nucleoside base of the sense strand or the antisense strand.

[0032] In some implementations, the RNAi agent comprises a targeting ligand and linker according to Formula V:

[0033] In some implementations, the RNAi agent is an siRNA molecule. In some implementations, the RNAi agent is an shRNA molecule.

[0034] Also described herein is a modified oligonucleotide consisting of 12 to 30 or 12 to 50 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence comprising 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 21, at least 22, at least 23, at least 24, or at least 25 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 725, and wherein the modified oligonucleotide comprises at least one synthetically modified internucleoside linkage or at least one synthetically modified sugar-phosphate backbone.

[0035] In some implementations, the modified oligonucleotide comprises a synthetically modified intemucleoside linkage at a first, second, penultimate, or final internucleoside linkage position.

[0036] In some implementations, the modified oligonucleotide comprises a 2'-O-methyl modified nucleotide, a nucleotide comprising a 5'-phosphorothioate group, a 2'-deoxy-2'- fluoro modified nucleotide, a 2'-deoxy -modified nucleotide, a locked nucleotide, an abasic nucleotide, deoxythymidine, an inverted deoxythymidine, a 2'-amino-modified nucleotide, a32MOFO-359437731Attorney Docket No: 2087820019432'-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, or a non-natural base comprising nucleotide.

[0037] In some implementations, the modified oligonucleotide or a subsequence thereof differs by 0, 1, 2, 3, or 4 nucleotides from an equal length portion of any one of SEQ ID NOS: 193-288, 531-603, and 701-712, wherein the subsequence is at least 14, 15, 16, 17, 18, 19, 20, or 21 bases in length.

[0038] In some implementations, the modified oligonucleotide comprises, in order, nucleotides 2-23 of any one of SEQ ID NOS: 193-288, 531-603, and 701-712.

[0039] In some implementations, the modified oligonucleotide comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 193-288, 531-603, and 701-712.

[0040] In some implementations, the modified oligonucleotide is conjugated to a targeting ligand that targets a hepatocyte. In some implementations, the modified oligonucleotide is conjugated to the targeting ligand conjugated to its 3' end. In some implementations, the modified oligonucleotide is conjugated to the targeting ligand conjugated to its 5' end. In some implementations, the targeting ligand comprises a galactose trimer. In some implementations, the targeting ligand comprises N-acetylgalactosamine (GalNac).

[0041] In some implementations, the targeting ligand comprises a structure according to Formula I:wherein R is:(i) the modified oligonucleotide; or33MOFO-359437731Attorney Docket No: 208782001943(ii) a linker conjugated to the modified oligonucleotide. In some implementations, R is a linker conjugated to the modified oligonucleotide having a structure according to Formula III:Formula III wherein:(i) connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to the modified oligonucleotide; or(ii) connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to a phosphate group which is conjugated to the modified oligonucleotide.

[0042] In some implementations, Formula III or the phosphate group is conjugated to the 3' end or the 5' end of the modified oligonucleotide. In some implementations, Formula III or the phosphate group is conjugated to an internal nucleotide or nucleoside base of the modified oligonucleotide.

[0043] In some implementations, the modified oligonucleotide comprises a targeting ligand and linker according to Formula V:

[0044] In some implementations, the modified oligonucleotide is an siRNA molecule. In some implementations, the modified oligonucleotide is an shRNA molecule.

[0045] Further described herein is an oligomeric duplex comprising (a) a first modified oligonucleotide consisting of 12 to 30 or 12 to 50 linked nucleosides, wherein a nucleobase34MOFO-359437731Attorney Docket No: 208782001943 sequence of the first modified oligonucleotide comprises 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 21, at least 22, at least 23, at least 24, or at least 25 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 725; and (b) a second modified oligonucleotide consisting of 12 to 30 or 12 to 50 linked nucleosides, wherein a nucleobase sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleobases that is at least 90% complementary to the nucleobase sequence of an equal length portion of the first modified oligonucleotide. In some implementations, the first modified oligonucleotide and / or second modified oligonucleotide comprises at least one synthetically modified intemucleoside linkage or at least one synthetically modified sugar-phosphate backbone.

[0046] In some implementations, the first modified oligonucleotide and / or the second comprises a 2'-O-methyl modified nucleotide, a nucleotide comprising a 5'-phosphorothioate group, a 2'-deoxy-2'-fluoro modified nucleotide, a 2 '-deoxy -modified nucleotide, a locked nucleotide, an abasic nucleotide, deoxythymidine, an inverted deoxythymidine, a 2'-amino- modified nucleotide, a 2'-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, or a non-natural base comprising nucleotide.

[0047] In some implementations, the first modified oligonucleotide or a subsequence thereof differs by 0, 1, 2, 3, or 4 nucleotides from an equal length portion of any one of SEQ ID NOS: 193-288, 531-603, and 701-712, wherein the subsequence is at least 14, 15, 16, 17, 18, 19, 20, or 21 bases in length. In some implementations, the first modified oligonucleotide comprises, in order, nucleotides 2-23 of any one of SEQ ID NOS: 193-288, 531-603, and 701-712. In some implementations, the first modified oligonucleotide comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 193-288, 531-603, and 701-712. In some implementations, the first modified oligonucleotide comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 595, 596, 603, 701, 703, and 704.

[0048] In some implementations, the second modified oligonucleotide or a subsequence thereof differs by 0, 1, 2, 3, or 4 nucleotides from an equal length portion of any one of SEQ ID NOS: 289-384, 604-676, 713-724, and 726-731, wherein the subsequence is at least 14, 15, 16, 17, 18, 19, 20, or 21 bases in length. In some implementations, the second modified oligonucleotide comprises, in order, nucleotides 1-22 of any one of SEQ ID NOS: 289-384, 604-676, 713-724, and 726-731. In some implementations, the second modified oligonucleotide comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 289-384, 604-676, 713-724, and 726-731. In some implementations, the second35MOFO-359437731Attorney Docket No: 208782001943 modified oligonucleotide comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 522, 523, 530, 689, 691, 692, and 726-731.

[0049] In some implementations, (a) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 289 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 193; (b) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 290 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 194; (c) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 291 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 195; (d) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 292 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 196; (e) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 293 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 197; (f) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 294 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 198; (g) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 295 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 199;(h) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 296 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 200; (i) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 297 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 201; (j) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 298 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 202; (k) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 299 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 203; (1) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 300 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 204; (m) the second modified oligonucleotide comprises36MOFO-359437731Attorney Docket No: 208782001943 a modified nucleotide sequence according to SEQ ID NO: 301 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 205; (n) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 302 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 206; (o) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 303 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 207; (p) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 304 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 208; (q) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 305 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 209; (r) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 306 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 210; (s) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 307 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 211; (t) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 308 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 212; (u) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 309 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 213; (v) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 310 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 214; (w) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 311 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 215; (x) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 312 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 216; (y) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 313 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 217; (z) the second modified oligonucleotide comprises a modified nucleotide sequence according to37MOFO-359437731Attorney Docket No: 208782001943SEQ ID NO: 314 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 218; (aa) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 315 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 219; (bb) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 316 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 220; (cc) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 317 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 221; (dd) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 318 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 222; (ee) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 319 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 223; (ff) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 320 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 224; (gg) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 321 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 225; (hh) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 322 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 226; (ii) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 323 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 227; (jj) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 324 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 228; (kk) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 325 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 229; (11) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 326 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 230; (mm) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 327 and38MOFO-359437731Attorney Docket No: 208782001943 the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 231; (nn) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 328 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 232; (oo) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 329 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 233; (pp) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 330 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 234; (qq) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 331 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 235; (rr) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 332 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 236; (ss) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 333 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 237; (tt) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 334 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 238; (uu) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 335 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 239; (vv) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 336 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 240; (ww) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 337 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 241 ; (xx) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 338 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 242; (yy) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 339 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 243; (zz) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 340 and the first modified oligonucleotide comprises a39MOFO-359437731Attorney Docket No: 208782001943 modified nucleotide sequence according to SEQ ID NO: 244; (aaa) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 341 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 245; (bbb) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 342 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 246; (ccc) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 343 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 247; (ddd) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 344 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 248; (eee) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 345 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 249; (fff) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 346 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 250; (ggg) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 347 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 251; (hhh) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 348 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 252; (iii) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 349 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 253; (jjj) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 350 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 254; (kkk) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 351 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 255; (111) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 352 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 256; (mmm) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 353 and the first modified40MOFO-359437731Attorney Docket No: 208782001943 oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 257; (nnn) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 354 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 258; (ooo) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 355 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 259; (ppp) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 356 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 260; (qqq) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 357 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 261; (rrr) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 358 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 262; (sss) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 359 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 263; (ttt) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 360 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 264; (uuu) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 361 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 265; (vvv) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 362 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 266; (www) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 363 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 267; (xxx) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 364 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 268; (yyy) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 365 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 269; (zzz) the second modified oligonucleotide comprises a modified nucleotide sequence41MOFO-359437731Attorney Docket No: 208782001943 according to SEQ ID NO: 366 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 270; (aaaa) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 367 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 271; (bbbb) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 368 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 272; (cccc) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 369 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 273; (dddd) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 370 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 274; (eeee) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 371 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 275; (ffff) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 372 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 276; (gggg) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 373 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 277; (hhhh) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 374 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 278; (iiii) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 375 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 279; (jjjj) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 376 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 280; (kkkk) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 377 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 281; (1111) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 378 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 282; (mmmm) the second modified42MOFO-359437731Attorney Docket No: 208782001943 oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 379 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 283; (nnnn) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 380 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 284; (oooo) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 381 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 285; (pppp) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 382 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 286; (qqqq) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 383 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 287; (rrrr) the second modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 384 and the first modified oligonucleotide comprises a modified nucleotide sequence according to SEQ ID NO: 288;(ssss) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 604 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 531; (tttt) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 605 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 532; (uuuu) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 606 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 533; (vvvv) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 607 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 534; (wwww) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 608 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 535;(xxxx) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 609 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 536; (yyyy) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 610 and the first modified oligonucleotide comprises a modified nucleobase sequence43MOFO-359437731Attorney Docket No: 208782001943 according to SEQ ID NO: 537; (zzzz) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 611 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 538; (aaaaa) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 612 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 539; (bbbbb) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 613 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 540; (ccccc) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 614 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 541; (ddddd) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 615 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 542; (eeeee) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 616 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 543; (fffff) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 617 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 544; (ggggg) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 618 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 545; (hhhhh) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 619 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 546; (iiiii) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 620 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 547; (jjjjj) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 621 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 548; (kkkkk) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 622 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 549; (11111) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 62344MOFO-359437731Attorney Docket No: 208782001943 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 550; (mmmmm) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 624 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 551; (nnnnn) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 625 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 552; (ooooo) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 626 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 553; (ppppp) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 627 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 554; (qqqqq) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 628 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 555; (rrrrr) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 629 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 556; (sssss) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 630 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 557; (ttttt) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 631 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 558; (uuuuu) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 632 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 559; (vvvw) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 633 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 560; (wwwww) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 634 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 561; (xxxxx) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 635 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 562; (yyyyy) the second modified oligonucleotide45MOFO-359437731Attorney Docket No: 208782001943 comprises a modified nucleobase sequence according to SEQ ID NO: 636 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 563; (zzzzz) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 637 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 564; (aaaaaa) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 638 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 565; (bbbbbb) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 639 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 566; (cccccc) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 640 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 567; (dddddd) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 641 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 568; (eeeeee) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 642 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 569; (ffffff) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 643 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 570; (gggggg) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 644 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 571; (hhhhhh) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 645 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 572; (iiiiii) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 646 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 573; (jjjjjj) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 647 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 574; (kkkkkk) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 648 and the first modified oligonucleotide comprises a modified nucleobase sequence according46MOFO-359437731Attorney Docket No: 208782001943 to SEQ ID NO: 575; (111111) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 649 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 576; (mmmmmm) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 650 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 577; (nnnnnn) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 651 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 578; (oooooo) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 652 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 579; (pppppp) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 653 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 580; (qqqqqq) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 654 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 581; (rrrrrr) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 655 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 582; (ssssss) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 656 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 583; (tttttt) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 657 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 584; (uuuuuu) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 658 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 585; (vvvvvv) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 659 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 586; (wwwwww) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 660 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 587; (xxxxxx) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 661 and the first47MOFO-359437731Attorney Docket No: 208782001943 modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 588; (yyyyyy) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 662 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 589; (zzzzzz) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 663 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 590; (aaaaaaa) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 664 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 591; (bbbbbbb) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 665 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 592; (ccccccc) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 666 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 593; (ddddddd) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 667 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 594; (eeeeeee) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 668 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 595; (fffffff) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 669 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 596; (ggggggg) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 670 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 597; (hhhhhhh) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 671 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 598; (iiiiiii) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 672 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 599; (jjjjjjj) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 673 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 600; (kkkkkkk) the second modified oligonucleotide comprises a modified48MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 674 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 601; (1111111) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 675 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 602; (mmmmmmm) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 676 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 603; (nnnnnnn) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 713 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 701; (ooooooo) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 714 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 702; (ppppppp) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 715 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 703; (qqqqqqq) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 716 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 704; (rrrrrrr) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 717 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 705; (sssssss) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 718 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 706; (ttttttt) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 719 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 707; (uuuuuuu) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 720 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 708; (vvvvvvv) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 721 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 709; (wwwwwww) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 722 and the first modified oligonucleotide comprises a modified nucleobase sequence according49MOFO-359437731Attorney Docket No: 208782001943 to SEQ ID NO: 710; (xxxxxxx) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 723 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 711; (yyyyyyy) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 724 and the antisecond modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 712; (aaaaaaaa) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 726 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 603; (bbbbbbbb) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 727 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 596; (cccccccc) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 728 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 703; (dddddddd) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 729 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 701; (eeeeeeee) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 730 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 595; or (ffffffff) the second modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 731 and the first modified oligonucleotide comprises a modified nucleobase sequence according to SEQ ID NO: 704.

[0050] In some implementations, the first modified oligonucleotide and / or second modified oligonucleotide comprises a targeting ligand. In some implementations, the first modified oligonucleotide comprises a targeting ligand conjugated to its 3' end. In some implementations, the first modified oligonucleotide comprises a targeting ligand conjugated to its 5' end. In some implementations, the second modified oligonucleotide comprises a targeting ligand conjugated to its 3' end. In some implementations, the second modified oligonucleotide comprises a targeting ligand conjugated to its 5' end. In some implementations, the targeting ligand targets a hepatocyte, and optionally wherein the targeting ligand comprises a galactose trimer. In some implementations, the targeting ligand comprises N-acetylgalactosamine (GalNac).50MOFO-359437731Attorney Docket No: 208782001943

[0051] In some implementations, the targeting ligand comprises a structure according toFormula I:wherein R is:(i) the first modified oligonucleotide or the second modified oligonucleotide; or(ii) a linker conjugated to the first modified oligonucleotide or the second modified oligonucleotide. In some implementations, R is a linker conjugated to the first modified oligonucleotide or the second modified oligonucleotide having a structure according to Formula III:Formula III wherein:(i) connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to the first modified oligonucleotide or the second modified oligonucleotide; or(ii) connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to a phosphate group which is conjugated to the first modified oligonucleotide or the second modified oligonucleotide. In some implementations, Formula III or the phosphate group is conjugated to the 3' end or the 5' end of the first modified oligonucleotide or the second modified oligonucleotide. In some implementations, Formula III or the phosphate group is conjugated to an internal nucleotide or nucleoside base of the first modified oligonucleotide or the second modified oligonucleotide.51MOFO-359437731Attorney Docket No: 208782001943

[0052] In some implementations, the first modified oligonucleotide or the second modified oligonucleotide comprises a targeting ligand and linker according to Formula V:

[0053] In some implementations, the oligomeric duplex is an siRNA molecule. In some implementations, the oligomeric duplex is an shRNA molecule.

[0054] Also described herein is a pharmaceutical composition comprising the RNAi agent described herein, the modified oligonucleotide described herein, or the oligomeric duplex described herein, and a pharmaceutically acceptable carrier.

[0055] Further described herein is a lipid nanoparticle comprising the RNAi agent described herein, the modified oligonucleotide described herein, the oligomeric duplex described herein, or the pharmaceutical composition described herein.

[0056] Also described herein is a method of making a pharmaceutical composition, comprising combining the RNAi agent described herein, the modified described herein, or the oligomeric duplex described herein, with a delivery vehicle selected from the group consisting of a phosphate-buffered saline (PBS), lipid, a nanoparticle, a polymer, a liposome, a micelle, a dynamic polyconjugate (DPC), and antibody-oligo conjugate.

[0057] Further described is a method of treating nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) in a subject, comprising administering to the subject an effective amount of a liver-targeted modified oligonucleotide, a liver-targeted oligomeric duplex, or a liver-targeted RNAi agent that inhibits expression of insulin receptor substrate- 1 (IRS1).

[0058] Also described herein is a use of a liver-targeted modified oligonucleotide, a liver- targeted oligomeric duplex, or a liver-targeted RNAi agent that inhibits expression of insulin receptor substrate-1 (IRS1) for the manufacture of a medicament for the treatment of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) in a subject.52MOFO-359437731Attorney Docket No: 208782001943

[0059] Further described herein is a method of inhibiting expression of insulin receptor substrate-1 (IRS1) in a subject, comprising administering to the subject an effective amount of a liver-targeted modified oligonucleotide, a liver-targeted oligomeric duplex, or a liver- targeted RNAi agent that inhibits expression of IRS 1.

[0060] Also described herein is a use of a liver-targeted modified oligonucleotide, a liver- targeted oligomeric duplex, or a liver-targeted RNAi agent in the manufacture of a medicament for inhibiting expression of insulin receptor substrate 1 (IRS1) in a hepatocyte of a subject.

[0061] Further described herein is a method of controlling or reducing liver fat accumulation in a subject, comprising administering to the subject an effective amount of a liver-targeted modified oligonucleotide, a liver-targeted oligomeric duplex, or a liver-targeted RNAi agent that inhibits expression of IRS 1.

[0062] Also described herein is a use of a liver-targeted modified oligonucleotide, a liver- targeted oligomeric duplex, or a liver-targeted RNAi agent that inhibits expression of insulin receptor substrate-1 (IRS1) in the manufacture of a medicament for controlling or reducing liver fat accumulation in a subject.

[0063] In some implementations of the method or use, the method treats metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH) in the subject.

[0064] In some implementations of the method or use, the method treats nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) in the subject.

[0065] In some implementations of the method or use, the liver-targeted modified oligonucleotide is the modified oligonucleotide as described herein.

[0066] In some implementations of the method or use, the liver-targeted oligomeric duplex is the oligomeric duplex as described herein.

[0067] In some implementations of the method or use, the RNAi agent comprises an antisense strand and a sense strand that at least partially complements the antisense strand, wherein (a) the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 1-96, 385-457, and 677-688; and / or (b) the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 97-192, 458-530, and 689-700.

[0068] In some implementations of the method or use, one or more bases of the antisense stand and / or the sense strand are modified. In some implementations, (a) the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 193-288, 531-603, and53MOFO-359437731Attorney Docket No: 208782001943701-712; and / or (b) the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 289-384, 604-676, 713-724, and 726-731.

[0069] In some implementations of the method or use, the RNAi agent comprises an antisense strand and a sense strand that at least partially complements the antisense strand, and a targeting ligand conjugated to the antisense strand or the sense strand, wherein the targeting ligand targets a hepatocyte.

[0070] In some implementations of the method or use, the antisense strand comprises at least 14 contiguous bases that complement a sequence in an mRNA molecule that encodes IRS1 (SEQ ID NO: 725).

[0071] In some implementations of the method or use, the antisense strand and the sense strand form a duplex of at least 14 bases in length. In some implementations, the antisense strand and the sense strand form a duplex of between 15 and 30 bases in length. In some implementations, the antisense strand or a subsequence thereof differs by 0, 1, 2, 3, or 4 nucleotides from an equal length portion of any one of SEQ ID NOS: 1-96, 385-457, 677- 688, 193-288, 531-603, and 701-712, wherein the subsequence is at least 14, 15, 16, 17, 18, 19, 20, or 21 bases in length. In some implementations, the antisense strand comprises, in order, nucleotides 2-23 of any one of SEQ ID NOS: 1-96, 385-457, 677-688, 193-288, 531- 603, and 701-712. In some implementations, the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712. In some implementations, the antisense strand comprises, in order, nucleobases 1-14 of any one of SEQ ID NOS: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712. In some implementations, the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 449, 450, 457, 595, 596, 603, 677, 679, 680, 701, 703, and 704.

[0072] In some implementations of the method or use, the sense strand or a subsequence thereof differs by 0, 1, 2, 3, or 4 nucleotides from an equal length portion of any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731, wherein the subsequence is at least 14, 15, 16, 17, 18, 19, 20, or 21 bases in length. In some implementations, the sense strand comprises, in order, nucleotides 1-22 of any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731. In some implementations, the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731. In some implementations, the sense strand comprises, in order, nucleobases 1-14 of any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731. In some54MOFO-359437731Attorney Docket No: 208782001943 implementations, the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 522, 523, 530, 689, 691, 692, 668, 669, 676, 713, 715, 716, and 726-731.

[0073] In some implementations of the method or use, the antisense strand comprises at least 16 contiguous bases that complement a sequence in an mRNA molecule that encodes IRS1 (SEQ ID NO: 725). In some implementations, the antisense strand and the sense strand form a duplex of at least 16 bases in length. In some implementations, the antisense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS: 1-96, 385-457, 677- 688, 193-288, 531-603, and 701-712. In some implementations, the antisense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS: 449, 450, 457, 595, 596, 603, 677, 679, 680, 701, 703, and 704. In some implementations, the antisense strand comprises, in order, nucleobases 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 2-17, 2-18, 2- 19, 2-20, 2-21, 2-22, 2-23, 3-18, 4-19, 4-20, 4-21, 4-22, 4-23, 5-21, 5-22, 5-23, 6-20, 6-21, 6- 22, 6-23, 7-22, 7-23, or 8-23 of any one of SEQ ID NOS: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712. In some implementations, the antisense strand comprises a nucleotide sequence according to any one of SEQ ID NOS: 1-96, 385-457, and 677-688. In some implementations, one or more nucleotides of the antisense strand are modified. In some implementations, the antisense strand comprises a nucleotide sequence according to any one of SEQ ID NOS: 449, 450, 457, 677, 679, and 680. In some implementations, one or more nucleotides of the antisense strand are modified. In some implementations, the antisense strand has a modification pattern according to nsNfsnnnNfnnnnnnnNfnNfnnnnnsnsn. In some implementations, the antisense strand comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 193-288, 531-603, and 701-712. In some implementations, the antisense strand comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 595, 596, 603, 701, 703, and 704.

[0074] In some implementations of the method or use, the sense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604- 676, 713-724, and 726-731. In some implementations, the sense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS: 522, 523, 530, 689, 691, 692, and 726-731. In some implementations, the sense strand comprises, in order, nucleobases 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 3-18, 4-19, 4-20, 4-21, 4-22, 4-23, 5-21, 5-22, 5-23, 6-20, 6-21, 6-22, 6-23, 7-22, 7-23, or 8-23 of any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731. In some implementations, the sense strand comprises a nucleobase sequence according to any one of55MOFO-359437731Attorney Docket No: 208782001943SEQ ID NOS: 97-192, 458-530, and 689-700. In some implementations, one or more nucleotides of the sense strand are modified. In some implementations, the sense strand comprises a nucleobase sequence according to any one of SEQ ID NOS: 522, 523, 530, 689, 691, and 692. In some implementations, one or more nucleotides of the sense strand are modified. In some implementations, the sense strand has a modification pattern according to nsnsnnnnNfnNfNfNfnnnnnnnnsnsn. In some implementations, the sense strand has a modification pattern according to nsnsnnnnNfnNfNfNfnnnnnnnnnn. In some implementations, the sense strand comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 289-384, 604-676, 713-724, and 726-731. In some implementations, the sense strand comprises a modified nucleotide sequence according to any one of SEQ ID NOS: 668, 669, 676, 713, 715, 716, and 726-731.

[0075] In some implementations of the method or use, (a) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 97 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 1; (b) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 98 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 2; (c) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 99 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 3; (d) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 100 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 4; (e) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 101 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 5; (f) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 102 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 6; (g) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 103 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 7; (h) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 104 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 8; (i) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 105 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 9; (j) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 106 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 10; (k) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 107 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 11; (1) the sense56MOFO-359437731Attorney Docket No: 208782001943 strand comprises a nucleobase sequence according to SEQ ID NO: 108 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 12; (m) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 109 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 13; (n) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 110 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 14; (o) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 111 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 15; (p) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 112 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 16; (q) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 113 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 17; (r) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 114 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 18; (s) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 115 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 19; (t) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 116 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 20; (u) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 117 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 21; (v) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 118 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 22; (w) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 119 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 23; (x) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 120 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 24; (y) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 121 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 25; (z) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 122 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 26; (aa) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 123 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 27; (bb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 124 and the antisense strand comprises a57MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 28; (cc) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 125 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 29; (dd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 126 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 30; (ee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 127 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 31; (ff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 128 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 32; (gg) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 129 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 33; (hh) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 130 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 34; (ii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 131 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 35; (jj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 132 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 36; (kk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 133 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 37; (11) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 134 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 38; (mm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 135 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 39; (nn) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 136 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 40; (oo) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 137 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 41; (pp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 138 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 42; (qq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 139 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 43; (rr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 140 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 44; (ss) the sense strand comprises a58MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 141 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 45; (tt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 142 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 46; (uu) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 143 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 47; (vv) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 144 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 48; (ww) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 145 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 49; (xx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 146 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 50; (yy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 147 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 51; (zz) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 148 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 52; (aaa) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 149 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 53; (bbb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 150 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 54; (ccc) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 151 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 55; (ddd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 152 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 56; (eee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 153 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 57; (fff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 154 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 58; (ggg) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 155 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 59; (hhh) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 156 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 60; (iii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 157 and the antisense strand comprises a59MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 61; (jjj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 158 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 62; (kkk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 159 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 63; (111) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 160 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 64; (mmm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 161 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 65; (nnn) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 162 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 66; (ooo) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 163 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 67; (ppp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 164 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 68; (qqq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 165 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 69; (rrr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 166 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 70; (sss) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 167 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 71; (ttt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 168 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 72; (uuu) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 169 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 73; (vvv) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 170 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 74; (www) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 171 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 75; (xxx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 172 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 76; (yyy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 173 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 77; (zzz) the sense strand comprises a60MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 174 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 78; (aaaa) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 175 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 79; (bbbb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 176 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 80; (cccc) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 177 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 81; (dddd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 178 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 82; (eeee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 179 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 83; (ffff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 180 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 84; (gggg) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 181 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 85; (hhhh) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 182 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 86; (iiii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 183 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 87; (jjjj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 184 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 88; (kkkk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 185 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 89; (1111) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 186 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 90; (mmmm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 187 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 91; (nnnn) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 188 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 92; (oooo) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 189 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 93; (pppp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 190 and the antisense strand comprises a61MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 94; (qqqq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 191 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 95; (rrrr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 192 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 96; (ssss) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 458 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 385; (tttt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 459 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 386; (uuuu) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 460 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 387; (vvvv) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 461 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 388; (wwww) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 462 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 389; (xxxx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 463 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 390; (yyyy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 464 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 391; (zzzz) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 465 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 392; (aaaaa) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 466 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 393; (bbbbb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 467 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 394; (ccccc) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 468 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 395; (ddddd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 469 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 396; (eeeee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 470 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 397; (fffff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 471 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 398; (ggggg) the sense strand comprises a62MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 472 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 399; (hhhhh) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 473 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 400; (iiiii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 474 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 401; (jjjjj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 475 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 402; (kkkkk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 476 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 403; (11111) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 477 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 404; (mmmmm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 478 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 405; (nnnnn) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 479 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 406; (ooooo) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 480 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 407; (ppppp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 481 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 408; (qqqqq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 482 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 409; (rrrrr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 483 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 410; (sssss) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 484 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 411; (ttttt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 485 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 412; (uuuuu) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 486 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 413; (vvvw) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 487 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 414; (wwwww) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 488 and the antisense strand comprises a63MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 415; (xxxxx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 489 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 416; (yyyyy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 490 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 417; (zzzzz) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 491 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 418; (aaaaaa) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 492 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 419; (bbbbbb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 493 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 420; (cccccc) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 494 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 421; (dddddd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 495 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 422; (eeeeee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 496 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 423; (ffffff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 497 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 424; (gggggg) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 498 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 425; (hhhhhh) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 499 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 426; (iiiiii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 500 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 427; (jjjjjj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 501 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 428; (kkkkkk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 502 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 429; (111111) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 503 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 430; (mmmmmm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 504 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 431; (nnnnnn) the sense strand comprises a64MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 505 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 432; (oooooo) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 506 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 433; (pppppp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 507 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 434; (qqqqqq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 508 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 435; (rrrrrr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 509 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 436; (ssssss) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 510 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 437; (tttttt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 511 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 438; (uuuuuu) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 512 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 439; (vvvwv) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 513 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 440; (wwwwww) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 514 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 441; (xxxxxx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 515 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 442; (yyyyyy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 516 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 443; (zzzzzz) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 517 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 444; (aaaaaaa) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 518 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 445; (bbbbbbb) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 519 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 446; (ccccccc) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 520 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 447; (ddddddd) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 521 and the antisense strand comprises a65MOFO-359437731Attorney Docket No: 208782001943 nucleobase sequence according to SEQ ID NO: 448; (eeeeeee) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 522 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 449; (fffffff) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 523 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 450; (ggggggg) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 524 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 451; (hhhhhhh) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 525 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 452; (iiiiiii) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 526 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 453; (jjjjjjj) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 527 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 454; (kkkkkkk) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 528 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 455; (1111111) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 529 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 456; (mmmmmmm) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 530 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 457; (nnnnnnn) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 689 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 677; (ooooooo) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 690 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 678; (ppppppp) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 691 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 679; (qqqqqqq) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 692 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 680; (rrrrrrr) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 693 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 681; (sssssss) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 694 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 682; (ttttttt) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 695 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 683; (uuuuuuu) the sense strand66MOFO-359437731Attorney Docket No: 208782001943 comprises a nucleobase sequence according to SEQ ID NO: 696 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 684; (vvvvvvv) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 697 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 685; (wwwwwww) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 698 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 686; (xxxxxxx) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 699 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 687; or (yyyyyyy) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 700 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 688.

[0076] In some implementations of the method or use, (a) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 530 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 457; (b) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 523 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 450; (c) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 691 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 679; (d) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 689 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 677; (e) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 522 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 449; or (f) the sense strand comprises a nucleobase sequence according to SEQ ID NO: 692 and the antisense strand comprises a nucleobase sequence according to SEQ ID NO: 680.

[0077] In some implementations of the method or use, (a) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 289 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 193; (b) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 290 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 194;(c) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 291 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 195; (d) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 292 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 196; (e) the sense strand comprises a modified nucleotide sequence according to SEQ ID67MOFO-359437731Attorney Docket No: 208782001943NO: 293 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 197; (f) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 294 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 198; (g) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 295 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 199; (h) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 296 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 200; (i) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 297 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 201; (j) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 298 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 202; (k) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 299 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 203; (1) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 300 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 204; (m) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 301 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 205; (n) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 302 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 206; (o) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 303 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 207; (p) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 304 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 208; (q) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 305 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 209; (r) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 306 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 210; (s) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 307 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 211; (t) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 308 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 212; (u) the sense strand68MOFO-359437731Attorney Docket No: 208782001943 comprises a modified nucleotide sequence according to SEQ ID NO: 309 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 213; (v) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 310 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 214;(w) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 311 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 215; (x) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 312 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 216; (y) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 313 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 217; (z) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 314 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 218; (aa) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 315 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 219; (bb) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 316 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 220; (cc) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 317 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 221; (dd) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 318 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 222; (ee) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 319 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 223; (ff) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 320 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 224; (gg) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 321 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 225; (hh) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 322 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 226; (ii) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 323 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 227;(jj) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 32469MOFO-359437731Attorney Docket No: 208782001943 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 228; (kk) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 325 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 229; (11) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 326 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 230; (mm) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 327 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 231; (nn) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 328 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 232; (oo) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 329 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 233; (pp) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 330 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 234; (qq) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 331 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 235; (rr) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 332 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 236; (ss) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 333 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 237; (tt) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 334 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 238; (uu) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 335 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 239; (vv) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 336 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 240; (ww) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 337 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 241 ; (xx) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 338 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 242; (yy) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 339 and the antisense strand comprises a modified70MOFO-359437731Attorney Docket No: 208782001943 nucleotide sequence according to SEQ ID NO: 243; (zz) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 340 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 244; (aaa) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 341 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 245; (bbb) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 342 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 246; (ccc) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 343 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 247; (ddd) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 344 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 248; (eee) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 345 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 249; (fff) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 346 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 250; (ggg) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 347 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 251; (hhh) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 348 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 252; (iii) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 349 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 253; (jjj) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 350 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 254; (kkk) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 351 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 255; (111) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 352 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 256; (mmm) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 353 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 257; (nnn) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 354 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID71MOFO-359437731Attorney Docket No: 208782001943NO: 258; (poo) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 355 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 259; (ppp) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 356 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 260; (qqq) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 357 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 261; (rrr) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 358 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 262; (sss) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 359 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 263; (ttt) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 360 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 264; (uuu) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 361 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 265; (vvv) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 362 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 266; (www) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 363 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 267; (xxx) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 364 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 268; (yyy) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 365 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 269; (zzz) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 366 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 270; (aaaa) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 367 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 271; (bbbb) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 368 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 272; (cccc) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 369 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 273; (dddd) the sense strand72MOFO-359437731Attorney Docket No: 208782001943 comprises a modified nucleotide sequence according to SEQ ID NO: 370 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 274; (eeee) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 371 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 275; (ffff) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 372 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 276; (gggg) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 373 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 277; (hhhh) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 374 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 278; (iiii) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 375 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 279; (jjjj) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 376 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 280; (kkkk) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 377 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 281; (1111) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 378 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 282; (mmmm) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 379 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 283; (nnnn) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 380 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 284; (oooo) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 381 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 285; (pppp) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 382 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 286; (qqqq) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 383 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 287; (rrrr) the sense strand comprises a modified nucleotide sequence according to SEQ ID NO: 384 and the antisense strand comprises a modified nucleotide sequence according to SEQ ID NO: 288; (ssss) the sense strand comprises a modified nucleobase sequence73MOFO-359437731Attorney Docket No: 208782001943 according to SEQ ID NO: 604 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 531; (tttt) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 605 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 532;(uuuu) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 606 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 533; (vvvv) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 607 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 534; (wwww) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 608 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 535; (xxxx) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 609 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 536; (yyyy) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 610 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 537; (zzzz) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 611 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 538; (aaaaa) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 612 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 539; (bbbbb) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 613 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 540; (ccccc) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 614 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 541; (ddddd) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 615 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 542; (eeeee) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 616 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 543; (fffff) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 617 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 544; (ggggg) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 618 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 545; (hhhhh) the sense strand comprises a modified nucleobase sequence74MOFO-359437731Attorney Docket No: 208782001943 according to SEQ ID NO: 619 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 546; (iiiii) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 620 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 547; (jjjjj) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 621 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 548; (kkkkk) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 622 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 549; (11111) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 623 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 550; (mmmmm) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 624 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 551; (nnnnn) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 625 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 552; (ooooo) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 626 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 553; (ppppp) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 627 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 554; (qqqqq) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 628 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 555; (rrrrr) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 629 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 556; (sssss) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 630 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 557; (ttttt) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 631 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 558; (uuuuu) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 632 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 559; (vvvvv) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 633 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 560; (wwwww) the sense strand comprises a modified nucleobase sequence75MOFO-359437731Attorney Docket No: 208782001943 according to SEQ ID NO: 634 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 561 (xxxxx) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 635 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 562; (yyyyy) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 636 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 563; (zzzzz) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 637 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 564; (aaaaaa) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 638 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 565; (bbbbbb) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 639 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 566; (cccccc) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 640 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 567; (dddddd) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 641 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 568; (eeeeee) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 642 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 569; (ffffff) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 643 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 570; (gggggg) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 644 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 571; (hhhhhh) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 645 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 572; (iiiiii) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 646 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 573; (jjjjjj) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 647 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 574; (kkkkkk) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 648 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 575; (111111) the sense strand comprises a modified nucleobase76MOFO-359437731Attorney Docket No: 208782001943 sequence according to SEQ ID NO: 649 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 576; (mmmmmm) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 650 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 577; (nnnnnn) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 651 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 578; (oooooo) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 652 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 579; (pppppp) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 653 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 580; (qqqqqq) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 654 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 581; (rrrrrr) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 655 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 582; (ssssss) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 656 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 583; (tttttt) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 657 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 584; (uuuuuu) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 658 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 585; (vvvvvv) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 659 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 586; (wwwwww) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 660 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 587; (xxxxxx) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 661 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 588; (yyyyyy) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 662 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 589; (zzzzzz) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 663 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 590; (aaaaaaa) the sense strand comprises a77MOFO-359437731Attorney Docket No: 208782001943 modified nucleobase sequence according to SEQ ID NO: 664 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 591; (bbbbbbb) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 665 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 592; (ccccccc) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 666 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 593; (ddddddd) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 667 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 594; (eeeeeee) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 668 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 595; (fffffff) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 669 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 596; (ggggggg) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 670 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 597; (hhhhhhh) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 671 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 598; (iiiiiii) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 672 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 599; (jjjjjjj) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 673 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 600; (kkkkkkk) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 674 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 601; (1111111) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 675 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 602; (mmmmmmm) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 676 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 603; (nnnnnnn) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 713 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 701; (ooooooo) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 714 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO:78MOFO-359437731Attorney Docket No: 208782001943702; (ppppppp) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 715 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 703; (qqqqqqq) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 716 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 704; (rrrrrrr) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 717 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 705; (sssssss) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 718 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 706; (ttttttt) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 719 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 707; (uuuuuuu) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 720 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 708; (vvvvvvv) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 721 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 709; (wwwwwww) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 722 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 710; (xxxxxxx) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 723 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 711; (yyyyyyy) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 724 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 712; (aaaaaaaa) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 726 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 603; (bbbbbbbb) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 727 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 596; (cccccccc) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 728 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 703;(dddddddd) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 729 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 701; (eeeeeeee) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 730 and the antisense strand comprises a modified nucleobase79MOFO-359437731Attorney Docket No: 208782001943 sequence according to SEQ ID NO: 595; or (ffffffff) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 731 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 704.

[0078] In some implementations of the method or use, (a) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 676 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 603; (b) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 669 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 596;(c) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 715 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 703; (d) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 713 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 701; (e) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 668 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 595; (f) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 716 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 704; (g) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 726 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 603; (h) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 727 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 596;(i) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 728 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 703; (j) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 729 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 701; (k) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 730 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 595; or (1) the sense strand comprises a modified nucleobase sequence according to SEQ ID NO: 731 and the antisense strand comprises a modified nucleobase sequence according to SEQ ID NO: 704. In some implementations, the RNAi agent comprises a targeting ligand comprising a structure according to Formula I:80MOFO-359437731Attorney Docket No: 208782001943wherein R is a linker conjugated to the wherein the targeting ligand is conjugated to the 3' end of the sense strand, wherein R comprises a structure according to Formula III:Formula III and wherein connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to the 3' end of the sense strand.

[0079] In some implementations of the method or use, the sense strand comprises a 3' overhang of 1-5 nucleotides in length. In some implementations of the method or use, the sense strand comprises a 5' overhang of 1-5 nucleotides in length. In some implementations of the method or use, the antisense strand comprises a 3' overhang of 1-5 nucleotides in length. In some implementations of the method or use, the antisense strand comprises a 5' overhang of 1-5 nucleotides in length.

[0080] In some implementations of the method or use, the sense strand or the antisense strand comprises at least one modified nucleotide or at least one modified intemucleoside linkage. In some implementations of the method or use, the sense strand and or the antisense strand comprises a modified internucleoside linkage at a first, second, penultimate, or final intemucleoside linkage position. In some implementations of the method or use, the at least one modified nucleotide or at least one modified intemucleoside linkage comprises a 2'-O- methyl modified nucleotide, a nucleotide comprising a 5'-phosphorothioate group, a 2'- deoxy -2 '-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, deoxythymidine, an inverted deoxythymidine, a 2'-amino-modified81MOFO-359437731Attorney Docket No: 208782001943 nucleotide, a 2'-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, or a non-natural base comprising nucleotide.

[0081] In some implementations of the method or use, the targeting ligand is conjugated to the sense strand.

[0082] In some implementations of the method or use, the targeting ligand is conjugated to the 3' end of the sense strand. In some implementations of the method or use, the targeting ligand is conjugated to the 5' end of the sense strand. In some implementations of the method or use, the targeting ligand is conjugated to the antisense strand. In some implementations of the method or use, the targeting ligand is conjugated to the 3' end of the antisense strand. In some implementations of the method or use, the targeting ligand is conjugated to the 5' end of the antisense strand. In some implementations of the method or use, the targeting ligand comprises a galactose trimer. In some implementations of the method or use, the targeting ligand comprises N-acetylgalactosamine (GalNac). In some implementations of the method or use, the targeting ligand comprises a structure according to Formula I:wherein R is:(i) the sense strand or the antisense strand; or(ii) a linker conjugated to the sense strand or the antisense strand. In some implementations of the method or use, R is a linker conjugated to the sense strand or the antisense strand having a structure according to Formula III:Formula III82MOFO-359437731Attorney Docket No: 208782001943 wherein:(i) connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to the sense strand or the antisense strand; or(ii) connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to a phosphate group which is conjugated to the sense strand or the antisense strand. In some implementations of the method or use, Formula III or the phosphate group is conjugated to the 3' end or the 5' end of the sense strand or the antisense strand. In some implementations of the method or use, Formula III or the phosphate group is conjugated to an internal nucleotide or nucleoside base of the sense strand or the antisense strand.

[0083] In some implementations of the method or use, RNAi agent comprises a targeting ligand and linker according to Formula V:

[0084] In some implementations of the method or use, the RNAi agent is an siRNA molecule. In some implementations of the method or use, the RNAi agent is an shRNA molecule.

[0085] Further described herein is a method of producing the RNAi agent as described herein, comprising annealing together the sense strand and the antisense strand. In some implementations, the method further comprises synthesizing the antisense strand and / or the sense strand.BRIEF DESCRIPTION OF THE DRAWINGS

[0086] FIG. 1 depicts a schematic illustrating the modifications of an exemplary modified sequence relative to an unmodified sequence.83MOFO-359437731Attorney Docket No: 208782001943

[0087] FIG. 2A shows dose dependent response curves in primary human hepatocytes (pHHs) for exemplary IRS1 siRNA agents conjugated to a targeting ligand according to Formula V.

[0088] FIG. 2B shows dose dependent response curves in primary human hepatocytes (pHHs) for exemplary IRS1 siRNA agents conjugated to a targeting ligand according to Formula IV.

[0089] FIG. 3 depicts a schematic of an in vivo study schedule for mice treated with exemplary RNAi agents, as described in Example 6.

[0090] FIG. 4A shows a percent IRS1 mRNA expression compared to control vehicle in harvested liver tissue from mice on a high fat diet treated with exemplary IRS1 siRNA agents, as described in Example 6.

[0091] FIG. 4B shows a percent IRS1 polypeptide level compared to control vehicle in harvested liver tissue from mice on a high fat diet treated with exemplary IRS1 siRNA agents, as described in Example 6.

[0092] FIG. 5 shows a percent change in hepatic triglycerides compared to a control vehicle in mice on a high fat diet treated with exemplary IRS1 siRNA agents, as described in Example 6.DETAILED DESCRIPTION

[0093] Provided herein are inhibitory nucleic acids (e.g. RNAi agents) to block gene expression in a highly conserved regulatory mechanism known as RNA interference. RNAi agents comprise short interfering RNA (siRNA) and short hairpin RNA (shRNA). The interfering RNA can be assembled from two separate oligonucleotides, where one strand is the sense strand and the other is the antisense strand, wherein the antisense and sense strands are self-complementary; the antisense strand comprises nucleotide sequence that is complementary to a nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense strand comprises nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. In some embodiments, the nucleic acid targeted by the RNAi may produce an unwanted protein wherein its inhibition would result in a therapeutic benefit.

[0094] Insulin receptor substrate-1 (IRS1) encodes a protein which is phosphorylated by insulin receptor tyrosine kinase and appears to have a central role in the insulin-stimulated84MOFO-359437731Attorney Docket No: 208782001943 signal transduction pathway. The IRS proteins transmit signals from the insulin and IGF-1 receptors to elicit a cellular response.

[0095] Mutations in the IRS1 gene are associated with type II diabetes and susceptibility to insulin resistance. Additionally, the IRS1 gene may be associated with nonalcoholic fatty liver disease (NAFLD) and / or nonalcoholic steatohepatitis (NASH). In addition to a variety of other disorders, insulin resistance and hyperinsulinemia are primary abnormalities in NAFLD and NASH (Neuschwander-Tetri, B. A. and S. H. Caldwell (2003) Hepatology 37(5): 1202-1209; Sanyal, A. J. (2001) Am. J. Gastroenterol. 96(2):274-276). A common feature in these disorders is abnormal fat metabolism and / or mitochondrial injury or dysfunction. Previously, the major mechanism of insulin resistance was thought to be the downregulation of IRS 1 signaling by excess free fatty acids which impair the tyrosine phosphorylation of IRS1 (see e.g., US20090304704A1). Accordingly, the downregulation of IRS1 signaling was expected to result in NAFLD and NASH disorders.

[0096] The present invention is based, in part, on the inventor’s surprising finding that inhibition of IRS 1 mRNA expression by RNAi agents targeting the IRS1 gene results in a reduction of liver fat in mice. Such control and reduction of liver fat is unexpected in view of the prior literature teachings that IRS1 inhibition causes NAFLD and NASH disorders, which are characterized by abnormal fat metabolism.

[0097] Provided herein are RNAi agents and compositions designed to target the IRS1 gene and inhibit the production of IRS 1 mRNA expression. Also described herein are methods of using the RNAi agents or compositions thereof in treating or ameliorating nonalcoholic fatty liver disease (NAFLD). Also described herein are methods of using the RNAi agents or compositions thereof in treating or ameliorating nonalcoholic steatohepatitis (NASH).I. DEFINITIONS

[0098] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0099] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. For example, “a” or “an” means “at least one” or “one85MOFO-359437731Attorney Docket No: 208782001943 or more.” It is understood that aspects, embodiments, and variations described herein include “comprising,” “consisting,” and / or “consisting essentially of’ aspects, embodiments and variations.

[0100] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0101] The term “controlling” as used herein, in reference to a liver fat accumulation in a subject, is understood to mean reducing an increase in an amount of liver fat accumulation compared to an untreated subject. Controlling can include preventing an increase in an amount of liver fat.

[0102] As used herein, the term “nucleic acid” refers to a polymer or oligomer of nucleotides. Nucleic acids are also referred as “ribonucleic acids” when the sugar moiety of the nucleotides is D-ribose and as “deoxyribonucleic acids” when the sugar moiety is 2-deoxy-D- ribose.

[0103] As used herein, the term “nucleotide” usually refers to a compound consisting of a nucleoside esterified to a monophosphate, polyphosphate, or phosphate-derivative group via the hydroxyl group of the 5-carbon of the sugar moiety. Nucleotides are also referred as “ribonucleotides” when the sugar moiety is D-ribose and as “deoxyribonucleotides” when the sugar moiety is 2-deoxy-D-ribose.

[0104] As used herein, the term “nucleoside” refers to a glycosylamine consisting of a nucleobase, such as a purine or pyrimidine, usually linked to a 5-carbon sugar (e.g. D-ribose or 2-deoxy-D-ribose) via a P-glycosidic linkage. Nucleosides are also referred as “ribonucleosides” when the sugar moiety is D-ribose and as “deoxyribonucleosides” when the sugar moiety is 2-deoxy-D-ribose.

[0105] As used herein, the term “nucleobase”, refers to a compound containing a nitrogen atom that has the chemical properties of a base. Non-limiting examples of nucleobases are compounds comprising pyridine, purine, or pyrimidine moieties, including, but not limited to adenine, guanine, hypoxanthine, thymine, cytosine, and uracil.

[0106] As used herein, the term “nucleotide sequences” encompasses nucleotide sequences with no modified nucleotides and nucleotide sequences with modified nucleotides. The latter are referred to as “modified nucleotide sequences” or simply “modified sequences.”86MOFO-359437731Attorney Docket No: 208782001943

[0107] As used herein, the term “modified nucleotide” is a nucleotide other than a ribonucleotide (2'-hydroxyl nucleotide).

[0108] As used herein, the following notations are used to indicate modified nucleotides, targeting groups, and linking groups. As the person of ordinary skill in the art would readily understand, unless otherwise indicated by the sequence, that when present in an oligonucleotide, the monomers are mutually linked by 5 '-3 '-phosphodiester bonds:A = adenosine-3 '-phosphate;C = cytidine-3 '-phosphate;G = guanosine-3 '-phosphate;U = uridine-3 '-phosphate n = any 2'-0Me modified nucleotide a = 2'-O-methyladenosine-3 '-phosphate as = 2'-O-methyladenosine-3'-phosphorothioate c = 2'-O-methylcytidine-3 '-phosphate cs = 2'-O-methylcytidine-3'-phosphorothioate g = 2'-O-methylguanosine-3 '-phosphate gs = 2'-O-methylguanosine-3'-phosphorothioate t = 2'-O-methyl-5-methyluridine-3 '-phosphate ts = 2'-O-methyl-5-methyluridine-3'-phosphorothioate u = 2'-O-methyluridine-3 '-phosphate us = 2'-O-methyluridine-3'-phosphorothioateNf = any 2'-fluoro modified nucleotideNfs = any 2'-fluoro modified nucleotide with 3 '-phosporothioateAf= 2'-fluoroadenosine-3 '-phosphateAfs = 2'-fluoroadenosine-3 '-phosporothioateCf = 2'-fluorocytidine-3 '-phosphateCfs = 2'-fluorocytidine-3'-phosphorothioateGf= 2'-fluoroguanosine-3 '-phosphateGfs = 2'-fluoroguanosine-3'-phosphorothioateTf= 2'-fluoro-5'-methyluridine-3 '-phosphateTfs = 2'-fluoro-5'-methyluridine-3'-phosphorothioateUf= 2 '-fluorouridine-3 '-phosphateUfs = 2'-fluorouridine-3'-phosphorothioate87MOFO-359437731Attorney Docket No: 208782001943 dN = any 2'-deoxyribonucleotide dT= 2'-deoxythymidine-3 '-phosphateNUNA = 2', 3 '-seco nucleotide mimics (unlocked nucleobase analogs)NLNA = locked nucleotideNfANA = 2'-F-Arabino nucleotideNM = 2'-methoxyethyl nucleotideAM = 2'-methoxyethyladenosine-3 '-phosphateAMs = 2'-methoxyethyladenosine-3'-phosphorothioateTM = 2'-methoxyethylthymidine-3 '-phosphateTMs = 2'-methoxyethylthymidine-3'-phosphorothioateR = ribitol(invdN)= any inverted deoxyribonucleotide (3 '-3' linked nucleotide)(invAb)= inverted (3 '-3' linked) abasic deoxyribonucleotide, see Table 4 (invAb)s= inverted (3 '-3' linked) abasic deoxyribonucleotide-5 '- phosphorothioate, see Table 4(invn) = any inverted 2'-0Me nucleotide (3 '-3 ' linked nucleotide) s = phosphorothioate linkage vpdN = vinyl phosphonate deoxyribonucleotide(5Me-Nf) = 5'-Me, 2'-fluoro nucleotide cPrp = cyclopropyl phosphonate, see Table 4 epTcPr = see Table 4 epTM = see Table 4

[0109] As used herein, an “RNAi 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. RNAi agents disclosed herein are comprised of a sense strand and an antisense strand, and include, but are not limited to: short interfering RNAs (siRNAs),88MOFO-359437731Attorney Docket No: 208782001943 double-stranded RNAs (dsRNA), micro RNAs (miRNAs), short, hairpin RNAs (shRNA), and dicer substrates. The antisense strand of the RNAi agents described herein is at least partially complementary to the mRNA being targeted.

[0110] As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence (e.g., RNAi agent sense strand or targeted mRNA) in relation to a second nucleotide sequence (e.g., RNAi agent antisense strand or a singlestranded antisense oligonucleotide), means the ability of an oligonucleotide or polynucleotide including the first nucleotide sequence to hybridize (form base pair hydrogen bonds under mammalian physiological conditions (or similar conditions in vitro)') and form a duplex or double helical structure under certain conditions with an oligonucleotide or polynucleotide including the second nucleotide sequence. Complementary sequences include Watson-Crick base pairs or non -Watson-Crick base pairs and include natural or modified nucleotides or nucleotide mimics, at least to the extent that the above hybridization requirements are fulfilled. Sequence identity or complementarity is independent of modification. For example, a and Af are complementary to U (or T) and identical to A for the purposes of determining identity or complementarity.[OHl] As used herein, “partially complementary” means that in a hybridized pair of nucleobase sequences, at least 70%, but not all, of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide.

[0112] As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to complete or partial amelioration or reduction of a disease or condition or disorder, or a symptom, adverse effect or outcome, or phenotype associated therewith. Desirable effects of treatment include, but are not limited to, preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. The terms do not require complete curing of a disease or complete elimination of any symptom or effect(s) on all symptoms or outcomes.

[0113] As used herein, “delaying development of a disease” means to defer, hinder, slow, retard, stabilize, suppress and / or postpone development of the disease (such as nonalcoholic fatty liver disease (NAFLD) and / or nonalcoholic steatohepatitis (NASH)). This delay can be of varying lengths of time, depending on the history of the disease and / or subject being89MOFO-359437731Attorney Docket No: 208782001943 treated. As sufficient or significant delay can, in effect, encompass prevention, in that the subject does not develop the disease.

[0114] “Preventing,” as used herein, includes providing prophylaxis with respect to the occurrence or recurrence of a disease in a subject that may be predisposed to the disease but has not yet been diagnosed with the disease. In some embodiments, the provided RNAi agent and compositions are used to delay development of a disease or to slow the progression of a disease.

[0115] An “effective amount” of an agent, e.g., a pharmaceutical formulation, RNAi agent, or composition, in the context of administration, refers to an amount effective, at dosages / amounts and for periods of time necessary, to achieve a desired result, such as a therapeutic or prophylactic result.

[0116] A “therapeutically effective amount” of an agent, e.g., a pharmaceutical formulation, RNAi agent, or composition refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result, such as for treatment of a disease, condition, or disorder, and / or pharmacokinetic or pharmacodynamic effect of the treatment. The therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the subject. In some embodiments, the provided methods involve administering the RNAi agent and / or compositions at effective amounts, e.g., therapeutically effective amounts.

[0117] As used herein, a “subject” or an “individual” is a mammal. In some embodiments, a “mammal” includes humans, non-human primates, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats, cats, monkeys, etc. In some embodiments, the subject is human.

[0118] Throughout this disclosure, various aspects of the claimed subject matter are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the claimed subject matter. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, where a range of values is provided, it is understood that each intervening value, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the claimed subject matter. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the claimed subject matter,90MOFO-359437731Attorney Docket No: 208782001943 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 claimed subject matter. This applies regardless of the breadth of the range.

[0119] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0120] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.II. RNAi AGENTS

[0121] Provided herein are inhibitory' nucleic acids produced to inhibit the expression of insulin receptor substrate-1 (IRS 1). In some embodiments, the inhibitory nucleic acids described herein include modified oligonucleotides, oligomeric duplexes, antisense oligonucleotides (ASOs), ribozymes, external guide sequence (EGS) oligonucleotides, siRNA compounds, single- or double-stranded RNA interference (RNAi) compounds such as siRNA compounds, modified bases / locked nucleic acids (LNAs), antagomirs, peptide nucleic acids (PNAs), and other oligomeric compounds or oligonucleotide mimetics which hybridize to at least a portion of insulin receptor substrate- 1 (IRS1) and modulate its function. In some embodiments, the inhibitory nucleic acids include antisense RNA, antisense DNA, chimeric antisense oligonucleotides, antisense oligonucleotides comprising modified linkages, interference RNA (RNAi), short interfering RNA (siRNA); a micro, interfering RNA (miRNA); a small, temporal RNA (stRNA); or a short, hairpin RNA (shRNA); small RNA- induced gene activation (RNAa); small activating RNAs (saRNAs), or combinations thereof. In a specific embodiment, the inhibitory nucleic acid is an interference RNA (RNAi).

[0122] In some embodiments, the inhibitory agent is a modified oligonucleotide. In some embodiments, the modified oligonucleotide consists of 10 to 50 linked nucleosides, 10 to 30 linked nucleosides, 12 to 30 linked nucleosides, 15 to 50 linked nucleosides, 20 to 50 linked nucleosides, or 12 to 50 linked nucleosides. In an exemplary embodiments, the modified91MOFO-359437731Attorney Docket No: 208782001943 oligonucleotide consi sts of between 12 to 30 or 12 to 50 linked nucleosides. In some embodiments, the modified oligonucleotide includes at least one synthetically modified intemucleoside linkage. In some embodiments, the modified oligonucleotide includes at least one synthetically modified sugar-phosphate backbone. In some embodiments, the modified oligonucleotide comprises a nucleobase sequence including 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 21, at least 22, at least 23, at least 24, or at least 25 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 725 (IRS1). In some embodiments, the modified oligonucleotide is a modified antisense strand. In some embodiments, the modified oligonucleotide is conjugated to a targeting ligand that targets a hepatocyte.

[0123] In some embodiments, the inhibitory agent is an oligomeric duplex. In some embodiments, the oligomeric duplex comprises a first modified oligonucleotide and a second modified oligonucleotide. In some embodiments, the first modified oligonucleotide consists of 10 to 50 linked nucleosides, 10 to 30 linked nucleosides, 12 to 30 linked nucleosides, 15 to 50 linked nucleosides, 20 to 50 linked nucleosides, or 12 to 50 linked nucleosides. In an exemplary embodiments, the first modified oligonucleotide consists of between 12 to 30 or 12 to 50 linked nucleosides. In some embodiments, the first modified oligonucleotide comprises a nucleobase sequence including 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 21, at least 22, at least 23, at least 24, or at least 25 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 725 (IRS1). In some embodiments, the first modified oligonucleotide is a modified antisense strand. In some embodiments, the second modified oligonucleotide consists of 10 to 50 linked nucleosides, 10 to 30 linked nucleosides, 12 to 30 linked nucleosides, 15 to 50 linked nucleosides, 20 to 50 linked nucleosides, or 12 to 50 linked nucleosides. In an exemplary embodiments, the second modified oligonucleotide consists of between 12 to 30 or 12 to 50 linked nucleosides. In some embodiments, the second modified oligonucleotide comprises a complementary region of at least 8 nucleobases that is at least 90% complementary (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary) to the nucleobase sequence of an equal length portion of the first modified oligonucleotide. In some embodiments, the second modified oligonucleotide is a modified sense strand. In some embodiments, the first and / or second modified oligonucleotide is conjugated to a targeting ligand that targets a hepatocyte.

[0124] In some embodiments, the inhibitory agent is an RNAi agent. In some embodiments, the RNAi agent comprises an antisense strand and a sense strand. In some embodiments, the92MOFO-359437731Attorney Docket No: 208782001943 antisense strand of the RNAi agent is 10 to 40, 10 to 30, 13 to 30, or 13 to 26 nucleotides in length. In some embodiments, the antisense strand of the RNAi agent is 10, 11, 12, 13, 14, 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 nucleotides in length. In some embodiments, the antisense strand of the RNAi agent is between 1 to 10 nucleotides, 5 to 15 nucleotides, 10 to 20 nucleotides, 15-25 nucleotides, 20- 30 nucleotides, 25-35 nucleotides, or 30 to 40 nucleotides in length. In a specific embodiment, the antisense strand of the RNAi agent is between 20-25 nucleotides in length.

[0125] In some embodiments, the sense strand of the RN Ai agent is 10 to 40, 10 to 30, 13 to 30, or 13 to 26 nucleotides in length. In some embodiments, the sense strand of the RNAi agent is 10, 11, 12, 13, 14, 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 nucleotides in length. In some embodiments, the sense strand of the RN Ai agent is between 1 to 10 nucleotides, 5 to 15 nucleoti des, 10 to 20 nucleotides, 15-25 nucleotides, 20-30 nucleotides, 25-35 nucleotides, or 30 to 40 nucleotides in length. In a specific embodiment, the antisense strand of the RNAi agent is between 20-25 nucleotides in length.

[0126] In some embodiments, the RNAi agent comprises an antisense strand with a 3' overhang of nucleotides. In some embodiments, the antisense strand 3' overhang is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length. In some embodiments, the antisense strand comprises a 3' overhang of 1-10 nucleotides in length, 1-9 nucleotides in length, 1-8 nucleotides in length, 1-7 nucleotides in length, 1-6 nucleotides in length, 1-5 nucleotides in length, 1-4 nucleotides in length, 1-3 nucleotides in length,! or 2 nucleotides in length, or 1 nucleotide in length. In a specific embodiment, the RNAi agent comprises an antisense strand comprising a 3' overhang of 1-5 nucleotides in length.

[0127] In some embodiments, the RNAi agent comprises an antisense strand with a 5' overhang of nucleotides. In some embodiments, the antisense strand 5' overhang is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length. In some embodiments, the antisense strand comprises a 5' overhang of 1-10 nucleotides in length, 1-9 nucleotides in length, 1-8 nucleotides in length, 1-7 nucleotides in length, 1-6 nucleotides in length, 1-5 nucleotides in length, 1-4 nucleotides in length, 1-3 nucleotides in length,! or 2 nucleotides in length, or 1 nucleotide in length. In a specific embodiment, the RNAi agent comprises an antisense strand comprising a 5' overhang of 1-5 nucleotides in length.

[0128] In some embodiments, the RNAi agent comprises a sense strand with a 3' overhang of nucleotides. In some embodiments, the sense strand 3' overhang is 1, 2, 3, 4, 5, 6, 7, 8, 9, or93MOFO-359437731Attorney Docket No: 20878200194310 nucleotides in length. In some embodiments, the sense strand comprises a 3' overhang of 1-10 nucleotides in length, 1-9 nucleotides in length, 1-8 nucleotides in length, 1-7 nucleotides in length, 1-6 nucleotides in length, 1 -5 nucleotides in length, 1-4 nucleotides in length, 1-3 nucleotides in length, ! or 2 nucleotides in length, or 1 nucleotide in length. In a specific embodiment, the RNAi agent comprises a sense strand comprising a 3' overhang of 1-5 nucleotides in length.

[0129] In some embodiments, the RNAi agent comprises a sense strand with a 5' overhang of nucleotides. In some embodiments, the sense strand 5' overhang is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length. In some embodiments, the sense strand comprises a 5' overhang of 1-10 nucleotides in length, 1-9 nucleotides in length, 1-8 nucleotides in length, 1-7 nucleotides in length, 1-6 nucleotides in length, 1-5 nucleotides in length, 1-4 nucleotides in length, 1-3 nucleotides in length,! or 2 nucleotides in length, or 1 nucleotide in length. In a specific embodiment, the RNAi agent comprises a sense strand comprising a 5' overhang of 1-5 nucleotides in length.

[0130] In some embodiments, the 3' overhang of the sense and / or the antisense strand comprises uracil and / or comprises nucleotides complementary to a sequence in a pregenomic RNA and / or mRNA molecule that encodes insulin receptor substrate-1 (IRS1). In some embodiments, the 5' overhang of the sense and / or the antisense strand comprises uracil and / or comprises nucleotides complementary to a sequence in a pregenomic RNA and / or mRNA molecule that encodes insulin receptor substrate- 1 (IRS1).

[0131] In some embodiments, the 3' overhang of the sense and / or the antisense strand comprises uracil and / or comprises nucleotides partially complementary’ to a sequence in a pregenomic RNA and / or mRNA molecule that encodes insulin receptor substrate-1 (IRS1). In some embodiments, the 5' overhang of the sense and / or the antisense strand comprises uracil and / or comprises nucleotides partially complementary to a sequence in a pregenomic RNA and / or mRNA molecule that encodes insulin receptor substrate-1 (IRS1).

[0132] In some embodiments, the antisense strand of the RNAi agent comprises nucleobases that complement a sequence in an mRNA molecule that encodes insulin receptor substrate-1 (IRS1). In some embodiments, the mRNA molecule that encodes IRS1 comprises a nucleobase sequence according to SEQ ID NO: 725. In some embodiments, the antisense strand comprises at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 contiguous bases that complement a sequence in an IRS1 mRNA molecule. In some embodiments, the antisense strand comprises at least 14 contiguous bases94MOFO-359437731Attorney Docket No: 208782001943 that complement a sequence in an IRS1 mRNA molecule. In some embodiments, the antisense strand comprises at least 15 contiguous bases that complement a sequence in an IRS1 mRNA molecule. In some embodiments, the antisense strand comprises at least 16 contiguous bases that complement a sequence in an IRS1 mRNA molecule. In some embodiments, the antisense strand comprises at least 17 contiguous bases that complement a sequence in an 1RS1 mRNA molecule.

[0133] In some embodiments, the antisense strand of the RNAi agent comprises a uracil nucleobase at the 5' terminus or the sense strand of the RNAi agent comprises an adenine nucleobase at the 3' terminus. In some embodiments, the antisense strand of the RNAi agent comprises a uracil nucleobase at the 5' terminus and the sense strand of the RN Ai agent comprises an adenine nucleobase at the 3' terminus. The addition of an extra uracil nucleobase at the 5' terminus of the antisense strand and / or an extra adenine nucleobase at the 3' terminus of the sense strand can optimize performance of the RNAi agent by promoting the correct strand uptake by the RNA-induced silencing complex (RISC), enhancing duplex stability, protecting against degradation, and minimizing off-target effects. These modifications may help ensure that the designed siRNA is efficient and effective in gene silencing. The antisense strand sequences provided herein may comprise an extra uracil nucleobase at the 5' terminus, and / or the sense strand sequences provided herein may comprise an extra adenine nucleobase at the 3' terminus. In some embodiments, the antisense strand comprises, in order, nucleotides 2-23 of any one of SEQ ID NOS: 1-96, 385-457, 677- 688, 193-288, 531-603, and 701-712. In some embodiments, the sense strand comprises, nucleotides 1-22 of any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731.

[0134] In some embodiments, the antisense strand and the sense strand of the RNAi agent are self-complementary (i.e., each strand comprises a nucleotide sequence that is complementary to nucleotide sequence of the other strand) or at least partially complementary. In this instance, the antisense strand and sense strand will form a duplex (i.e., double stranded structure) that does not comprise overhangs. In some embodiments, the RNAi agent comprises a duplex structure. In some embodiments, the RNAi agent comprises a duplex length of at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 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 nucleotides long. In some embodiments, the RNAi agent comprises a duplex of between 5 to 25 nucleotides long, 10 to 30 nucleotides long, 15 to 35 nucleotides long, 20 to 40 nucleotides long, 10 to 2095MOFO-359437731Attorney Docket No: 208782001943 nucleotides long, 15 to 25 nucleotides long, 20 to 30 nucleotides long, 25 to 35 nucleotides long, 30 to 40 nucleotides long, 5 to 20 nucleotides long, 10 to 25 nucleotides long, 15 to 30 nucleotides long, 20 to 35 nucleotides long, or 25 to 40 nucleotides long. In an exemplary embodiment, the RNAi agent comprises a duplex of between 15 to 30 nucleotides long. In some embodiments, the RNAi agent comprises a duplex of 14 nucleotides in length, a duplex of 15 nucleotides in length, 16 nucleotides in length, 17 nucleotides in length, 18 nucleotides in length, 19 nucleotides in length, or 20 nucleotides in length. In a specific embodiment, the RNAi agent comprises a duplex of 16 nucleotides in length.

[0135] In some embodiments, the RNAi agent comprises a duplex region of any length that permits specific degradation of a desired target mRNA (i.e., IRS1) through RISC, and may range from about 9 to 36 nucleotides in length, e.g., about 10-30, 10-35, 14-30, 14-35, 15-30, 15-35, 24-30, or 19-23 nucleotides in length. In some embodiments, the RNAi agent comprises a duplex region of about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 nucleotides in length, such as about 14-30, 14- 35, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length. Ranges and lengths intermediate to the above recited example ranges and lengths are also contemplated to be part of the invention.

[0136] The sequences disclosed here may refer to a nucleobase sequence, a nucleotide sequence, or a modified nucleotide sequence, for example as described in Tables 1-3 and otherwise described herein.Table 1. IRS1 RNAi agent antisense strand sequences.96MOFO-359437731Attorney Docket No: 20878200194397MOFO-359437731Attorney Docket No: 20878200194398MOFO-359437731Attorney Docket No: 20878200194399MOFO-359437731Attorney Docket No: 208782001943Table 2. IRS1 RNAi agent sense strand sequences.100MOFO-359437731Attorney Docket No: 208782001943101MOFO-359437731Attorney Docket No: 208782001943102MOFO-359437731Attorney Docket No: 208782001943103MOFO-359437731Attorney Docket No: 208782001943

[0137] In some embodiments, the antisense strand of the RNAi agent comprises a nucleotide sequence of any of the sequences in Table 1. In some embodiments, the antisense strand comprises a nucleotide sequence set forth in any of SEQ ID NOs: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712. In some embodiments, the antisense comprises a sequence that has at least at or about 80%, at or about 81%, at or about 82%, at or about 83%, at or about 84%, at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequences set forth in any of SEQ ID NOs: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712. In some embodiments, the antisense strand or a subsequence thereof of the RNAi agent differs by 0, 1, 2, 3, or 4 nucleotides from an equal length portion of any of the antisense strand sequences set forth in any of SEQ ID NOs: 1-96, 385-457, 677- 688, 193-288, 531-603, and 701-712, wherein the subsequence is at least 14, 15, 16, 17, 18, 19, 20, or 21 bases in length.

[0138] In some embodiments, the antisense strand of the RNAi agent comprises at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous bases from any one of SEQ ID NOs: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712. In some embodiments, the antisense strand comprises, in order, nucleobases 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2 23, 3-18, 4-19, 4-20, 4-21, 4-22, 4-23, 5-21, 5-22, 5-23, 6-20, 6-21, 6-22, 6-23, 7-22, 7-23, or 8-23 of any one of SEQ ID NOS: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712.

[0139] In some embodiments, the sense strand of the RNAi agent comprises a nucleotide sequence of any of the sequences in Table 2. In some embodiments, the antisense strand comprises a nucleotide sequence set forth in any of SEQ ID NOs: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731. In some embodiments, the sense strand comprises a sequence that has at least at or about 80%, at or about 81%, at or about 82%, at or about 83%, at or about 84%, at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequences set forth in any of SEQ ID NOs: 97-192, 458-530, 689- 700, 289-384, 604-676, and 713-724. In some embodiments, the sense strand or a104MOFO-359437731Attorney Docket No: 208782001943 subsequence thereof of the RNAi agent differs by 0, 1, 2, 3, or 4 nucleotides from an equal length portion of any of the sense strand sequences set forth in any of SEQ ID NOs: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731, wherein the subsequence is at least 14, 15, 16, 17, 18, 19, 20, or 21 bases in length.

[0140] In some embodiments, the sense strand of the RNAi agent comprises at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous bases from any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731. In some embodiments, the sense strand comprises, in order, nucleobases 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2 23, 3-18, 4-19, 4-20, 4-21, 4-22, 4-23, 5-21, 5-22, 5-23, 6-20, 6-21, 6-22, 6-23, 7-22, 7-23, or 8-23 of any one of SEQ ID NOS: 97-192, 458-530, 689-700, 289-384, 604-676, 713-724, and 726-731.

[0141] Among the RNAi agents provided herein, the RNAi agent comprises an antisense strand comprising a nucleotide sequence having at least at or about 80%, at or about 81%, at or about 82%, at or about 83%, at or about 84%, at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequences set forth in any of SEQ ID NOs: 1-96, 385-457, 677-688, 193-288, 531-603, and 701-712 and a sense strand comprising a nucleotide sequence having at least at or about 80%, at or about 81%, at or about 82%, at or about 83%, at or about 84%, at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequences set forth in any of SEQ ID NOs: 97-192, 458- 530, 689-700, 289-384, 604-676, 713-724, and 726-731.

[0142] In some embodiments, the antisense strand of the RNAi agent comprises a nucleotide sequence of any of SEQ ID NO: 1-96, 385-457, and 677-688, and the sense strand of the RNAi agent comprises a nucleotide sequence of any of SEQ ID NO: 97-192, 458-530, and 689-700. In some embodiments, the antisense and the sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 1 and 97, respectively; SEQ ID NOs: 2 and 98, respectively; SEQ ID NOs: 3 and 99, respectively; SEQ ID NOs: 4 and 100, respectively; SEQ ID NOs: 5 and 101, respectively; SEQ ID NOs: 6 and 102, respectively; SEQ ID NOs: 7 and 103, respectively; SEQ ID NOs: 8 and 104, respectively; SEQ ID NOs: 9 and 105, respectively; SEQ ID NOs: 10 and 106, respectively; SEQ ID NOs: 11 and 107,105MOFO-359437731Attorney Docket No: 208782001943 respectively; SEQ ID NOs: 12 and 108, respectively; SEQ ID NOs: 13 and 109, respectively; SEQ ID NOs: 14 and 110, respectively; SEQ ID NOs: 15 and 111, respectively; SEQ ID NOs: 16 and 112, respectively; SEQ ID NOs: 17 and 113, respectively; SEQ ID NOs: 18 and 114, respectively; SEQ ID NOs: 19 and 115, respectively; or SEQ ID NOs: 20 and 116, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0143] In some embodiments, the antisense and the sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 21 and 117, respectively; SEQ ID NOs: 22 and 118, respectively; SEQ ID NOs: 23 and 119, respectively; SEQ ID NOs: 24 and 120, respectively; SEQ ID NOs: 25 and 121, respectively; SEQ ID NOs: 26 and 122, respectively; SEQ ID NOs: 27 and 123, respectively; SEQ ID NOs: 28 and 124, respectively; SEQ ID NOs: 29 and 125, respectively; SEQ ID NOs: 30 and 126, respectively; SEQ ID NOs: 31 and 127, respectively; SEQ ID NOs: 32 and 128, respectively; SEQ ID NOs: 33 and 129, respectively; SEQ ID NOs: 34 and 130, respectively; SEQ ID NOs: 35 and 131, respectively; SEQ ID NOs: 36 and 132, respectively; SEQ ID NOs: 37 and 133, respectively; SEQ ID NOs: 38 and 134, respectively; SEQ ID NOs: 39 and 135, respectively; or SEQ ID NOs: 40 and 136, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0144] In some embodiments, the antisense and the sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 41 and 137, respectively; SEQ ID NOs: 42 and 138, respectively; SEQ ID NOs: 43 and 139, respectively; SEQ ID NOs: 44 and 140, respectively; SEQ ID NOs: 45 and 141, respectively; SEQ ID NOs: 46 and 142, respectively; SEQ ID NOs: 47 and 143, respectively; SEQ ID NOs: 48 and 144, respectively; SEQ ID NOs: 49 and 145, respectively; SEQ ID NOs: 50 and 146, respectively; SEQ ID NOs: 51 and 147, respectively; SEQ ID NOs: 52 and 148, respectively; SEQ ID NOs: 53 and 149, respectively; SEQ ID NOs: 54 and 150, respectively; SEQ ID NOs: 55 and 151, respectively; SEQ ID NOs: 56 and 152, respectively; SEQ ID NOs: 57 and 153, respectively; SEQ ID NOs: 58 and 154, respectively; SEQ ID NOs: 59 and 155, respectively; or SEQ ID NOs: 60 and 156, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,106MOFO-359437731Attorney Docket No: 20878200194388%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0145] In some embodiments, the antisense and the sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 61 and 157, respectively; SEQ ID NOs: 62 and 158, respectively; SEQ ID NOs: 63 and 159, respectively; SEQ ID NOs: 64 and 160, respectively; SEQ ID NOs: 65 and 161, respectively; SEQ ID NOs: 66 and 162, respectively; SEQ ID NOs: 67 and 163, respectively; SEQ ID NOs: 68 and 164, respectively; SEQ ID NOs: 69 and 165, respectively; SEQ ID NOs: 70 and 166, respectively; SEQ ID NOs: 71 and 167, respectively; SEQ ID NOs: 72 and 168, respectively; SEQ ID NOs: 73 and 169, respectively; SEQ ID NOs: 74 and 170, respectively; SEQ ID NOs: 75 and 171, respectively; SEQ ID NOs: 76 and 172, respectively; SEQ ID NOs: 77 and 173, respectively; SEQ ID NOs: 78 and 174, respectively; SEQ ID NOs: 79 and 175, respectively; or SEQ ID NOs: 80 and 176, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0146] In some embodiments, the antisense and the sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 81 and 177, respectively; SEQ ID NOs: 82 and 178, respectively; SEQ ID NOs: 83 and 179, respectively; SEQ ID NOs: 84 and 180, respectively; SEQ ID NOs: 85 and 181, respectively; SEQ ID NOs: 86 and 182, respectively; SEQ ID NOs: 87 and 183, respectively; SEQ ID NOs: 88 and 184, respectively; SEQ ID NOs: 89 and 185, respectively; SEQ ID NOs: 90 and 186, respectively; SEQ ID NOs: 91 and 187, respectively; SEQ ID NOs: 92 and 188, respectively; SEQ ID NOs: 93 and 189, respectively; SEQ ID NOs: 94 and 190, respectively; SEQ ID NOs: 95 and 191, respectively; or SEQ ID NOs: 96 and 192, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0147] In some embodiments, the antisense and the sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 385 and 458, respectively; SEQ ID NOs: 386 and 459, respectively; SEQ ID NOs: 387 and 460, respectively; SEQ ID NOs: 388 and 461, respectively; SEQ ID NOs: 389 and 462, respectively; SEQ ID NOs: 390 and 463, respectively; SEQ ID NOs: 391 and 464, respectively; SEQ ID NOs: 392 and 465,107MOFO-359437731Attorney Docket No: 208782001943 respectively; SEQ ID NOs: 393 and 466, respectively; SEQ ID NOs: 394 and 467, respectively; SEQ ID NOs: 395 and 468, respectively; SEQ ID NOs: 396 and 469, respectively; SEQ ID NOs: 397 and 470, respectively; SEQ ID NOs: 398 and 471, respectively; SEQ ID NOs: 399 and 472, respectively; or SEQ ID NOs: 400 and 473, respectively, or any antisense or sense strand that has at least 90% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0148] In some embodiments, the antisense and the sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 401 and 474, respectively; SEQ ID NOs: 402 and 475, respectively; SEQ ID NOs: 403 and 476, respectively; SEQ ID NOs: 404 and 477, respectively; SEQ ID NOs: 405 and 478, respectively; SEQ ID NOs: 406 and 479, respectively; SEQ ID NOs: 407 and 480, respectively; SEQ ID NOs: 408 and 481, respectively; SEQ ID NOs: 409 and 482, respectively; SEQ ID NOs: 410 and 483, respectively; SEQ ID NOs: 411 and 484, respectively; SEQ ID NOs: 412 and 485, respectively; SEQ ID NOs: 413 and 486, respectively; SEQ ID NOs: 414 and 487, respectively; SEQ ID NOs: 415 and 488, respectively; or SEQ ID NOs: 416 and 489, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0149] In some embodiments, the antisense and the sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 417 and 490, respectively; SEQ ID NOs: 418 and 491, respectively; SEQ ID NOs: 419 and 492, respectively; SEQ ID NOs: 420 and 493, respectively; SEQ ID NOs: 421 and 494, respectively; SEQ ID NOs: 422 and 495, respectively; SEQ ID NOs: 423 and 496, respectively; SEQ ID NOs: 424 and 497, respectively; SEQ ID NOs: 425 and 498, respectively; SEQ ID NOs: 426 and 499, respectively; SEQ ID NOs: 427 and 500, respectively; SEQ ID NOs: 428 and 501, respectively; SEQ ID NOs: 429 and 502, respectively; SEQ ID NOs: 430 and 503, respectively; SEQ ID NOs: 431 and 504, respectively; or SEQ ID NOs: 432 and 505, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0150] In some embodiments, the antisense and the sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 433 and 506, respectively; SEQ ID NOs:108MOFO-359437731Attorney Docket No: 208782001943434 and 507, respectively; SEQ ID NOs: 435 and 508, respectively; SEQ ID NOs: 436 and 509, respectively; SEQ ID NOs: 437 and 510, respectively; SEQ ID NOs: 438 and 511, respectively; SEQ ID NOs: 439 and 512, respectively; SEQ ID NOs: 440 and 513, respectively; SEQ ID NOs: 441 and 514, respectively; SEQ ID NOs: 442 and 515, respectively; SEQ ID NOs: 443 and 516, respectively; SEQ ID NOs: 444 and 517, respectively; SEQ ID NOs: 445 and 518, respectively; SEQ ID NOs: 446 and 519, respectively; SEQ ID NOs: 447 and 520, respectively; or SEQ ID NOs: 448 and 521, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0151] In some embodiments, the antisense and the sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 449 and 522, respectively; SEQ ID NOs: 450 and 523, respectively; SEQ ID NOs: 451 and 524, respectively; SEQ ID NOs: 452 and 525, respectively; SEQ ID NOs: 453 and 526, respectively; SEQ ID NOs: 454 and 527, respectively; SEQ ID NOs: 455 and 528, respectively; SEQ ID NOs: 456 and 529, respectively; or SEQ ID NOs: 457 and 530, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0152] In some embodiments, the antisense and the sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 677 and 689, respectively; SEQ ID NOs: 678 and 690, respectively; SEQ ID NOs: 679 and 691, respectively; SEQ ID NOs: 680 and 692, respectively; SEQ ID NOs: 681 and 693, respectively; SEQ ID NOs: 682 and 694, respectively; SEQ ID NOs: 683 and 695, respectively; SEQ ID NOs: 684 and 696, respectively; SEQ ID NOs: 685 and 697, SEQ ID NOs: 686 and 698, respectively; SEQ ID NOs: 687 and 699, respectively; or SEQ ID NOs: 688 and 700, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0153] In some embodiments, the RNAi agent is prepared or provided as a salt, mixed salt, or a free-acid. In some embodiments, the RNAi agent is prepared as a sodium salt. Such forms are within the scope of the embodiments disclosed herein.109MOFO-359437731Attorney Docket No: 208782001943

[0154] In some embodiments, the IRS1 RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Table 3. In some embodiments, the IRS1 RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense strand / sense strand duplexes of Table 3, and further comprises an asialoglycoprotein receptor ligand targeting group. In some embodiments, the IRS1 RNAi agent comprises any of the duplexes of Table 3.Table 3. Examples of IRS 1 RNAi agent duplexes.110MOFO-359437731Attorney Docket No: 208782001943111MOFO-359437731Attorney Docket No: 208782001943112MOFO-359437731Attorney Docket No: 208782001943113MOFO-359437731Attorney Docket No: 208782001943A. Modified Nucleotides

[0155] In some embodiments, the RNAi agent comprise an antisense strand and a sense strand, wherein all or substantially all of the nucleotides in the sense strand are modified. In some embodiments, the RNAi agent comprise an antisense strand and a sense strand, wherein all or substantially all of the nucleotides in the antisense strand are modified. In some embodiments, the RNAi agent comprises an antisense strand that comprises a nucleobase sequence differing by 0, 1, 2, 3, or 4 nucleobases from an equal length portion of any of SEQ ID NOs: 1-96, 385-457, and 677-688. In some embodiments, the RNAi agent comprises an antisense strand that comprises a nucleobase sequence differing by 1 nucleobases from any of SEQ ID NOs: 1-96, 385-457, and 677-688. In some embodiments, the RNAi agent comprises a sense strand that comprises a nucleobase sequence differing by 0, 1, 2, 3, or 4 nucleobases from any of SEQ ID NOs: 97-192, 458-530, and 689-700. In some embodiments, the RNAi agent comprises a sense strand that comprises a nucleobase sequence differing by 1 nucleobase from any of SEQ ID NOs: 97-192, 458-530, and 689-700.

[0156] In some embodiments, the RNAi agent comprises one or more modified nucleotides. As used herein, a “modified nucleotide” is a nucleotide other than a ribonucleotide (2'- hydroxyl nucleotide). In some embodiments, at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%) of the nucleotides are modified nucleotides. As used herein, modified nucleotides include, but are not limited to, deoxyribonucleotides, nucleotide mimics, abasic nucleotides (represented herein as Ab), 2'-modified nucleotides, 3' to 3' linkages (inverted) nucleotides (represented herein as invdN, invN, invn, invAb), nonnatural base-comprising nucleotides, bridged nucleotides, peptide nucleic acids (PNAs), 2', 3 'seco nucleotide mimics (unlocked nucleobase analogues, represented herein as NuNAorNUNA), locked nucleotides (represented herein as NLNA or NLNA), 3'-O-methoxy (2' intemucleoside linked) nucleotides (represented herein as 3'-OMen), 2'-F-Arabino nucleotides (represented herein as NfANA or ANA), 5'-Me, 2'- fluoro nucleotide (represented herein as 5Me-Nf), morpholino nucleotides, vinyl phosphonate deoxyribonucleotides (represented herein as vpdN), vinyl phosphonate containing114MOFO-359437731Attorney Docket No: 208782001943 nucleotides, and cyclopropyl phosphonate containing nucleotides (cPrpN). 2'-modified nucleotides (i.e. a nucleotide with a group other than a hydroxyl group at the 2' position of the five-membered sugar ring) include, but are not limited to, 2'-O-methyl nucleotides (represented herein as a lower case letter 'n1in a nucleotide sequence), 2'-deoxy-2'-fluoro nucleotides (represented herein as Nf, also represented herein as 2'-fluoro nucleotide), 2'- deoxy nucleotides (represented herein as dN), 2'-methoxyethyl (2'-O-2-methoxylethyl) nucleotides (represented herein as NM or 2'-M0E), 2'-amino nucleotides, and 2'-alkyl nucleotides. It is not necessary for all positions in a given compound to be uniformly modified. Conversely, more than one modification may be incorporated in a single RNAi agent or even in a single nucleotide thereof. The RNAi agent sense strands and antisense strands may be synthesized and / or modified by methods known in the art. Modification at one nucleotide is independent of modification at another nucleotide.

[0157] Modified nucleobases include synthetic and natural nucleobases, such as 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, (e.g., 2- aminopropyladenine, 5-propynyluracil, or 5-propynylcytosine), 5-methylcytosine (5-me-C), 5hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-alkyl (e.g., 6-m ethyl, 6-ethyl, 6-isopropyl, or 6-n-butyl) derivatives of adenine and guanine, 2-alkyl (e.g., 2-methyl, 2-ethyl, 2-isopropyl, or 2-n-butyl) and other alkyl derivatives of adenine and guanine, 2- thiouracil, 2-thiothymine, 2-thiocytosine, 5-halouracil, cytosine, 5propynyl uracil, 5propynyl cytosine, 6-azo uracil, 6-azo cytosine, 6-azo thymine, 5-uracil (pseudouracil), 4thiouracil, 8- halo, 8amino, 8-sulfhydryl, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo (e.g., 5-bromo), 5-trifluoromethyl, and other 5-substituted uracils and cytosines, 7methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7- deazaguanine, 7deazaadenine, 3 -deazaguanine, and 3 -deazaadenine.

[0158] In some embodiments, the 3' end and / or the 5' end of the sense strand may include additional abasic nucleosides. In some embodiments, an “A” may be added to the 3' terminal end of the sense strand. In some embodiments, the one or more abasic nucleosides added to the 3' end or 5' end of the sense strand may be inverted (invAb). In some embodiments, one or more inverted abasic nucleosides may be inserted between the targeting ligand and the nucleobase sequence of the sense strand of the RNAi agent. In some embodiments, the inclusion of one or more inverted abasic nucleosides at or near the terminal end or terminal ends of the sense strand of an RNAi agent may allow for enhanced activity or other desired properties of an RNAi agent.115MOFO-359437731Attorney Docket No: 208782001943

[0159] In some embodiments, the 3' end and / or the 5' end of the antisense strand may include additional abasic nucleosides. In some embodiments, a “U” may be added to the 5' terminal end of the antisense strand. In some embodiments, the one or more abasic nucleosides added to the 3' end or 5' end of the antisense strand may be inverted (invAb). In some embodiments, one or more inverted abasic nucleosides may be inserted between the targeting ligand and the nucleobase sequence of the sense strand of the RNAi agent. In some embodiments, the inclusion of one or more inverted abasic nucleosides at or near the terminal end or terminal ends of the antisense strand of an RNAi agent may allow for enhanced activity or other desired properties of an RNAi agent.

[0160] In some embodiments, the modification comprises fluorinated bases. In some embodiments, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more bases of the sense strand and / or antisense strand of the RNAi agent are fluorinated. In some embodiments, base 1, 2, ,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and / or 20 of the sense strand of the RNAi agent are fluorinated. In some embodiments, bases 7, 9, 10, and 11 of the sense strand of the RNAi agent are fluorinated. In some embodiments, base 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and / or 20 of the antisense strand of the RNAi agent are fluorinated. In some embodiments, bases 2, 6, 14, and 16 of the antisense strand are fluorinated.

[0161] In some embodiments, the modification comprises 2'-O-methyl (2'-OMe) and / or 2'- deoxy -2 '-fluoro (2'-F) ribosugar modifications. In some embodiments, the modification comprises those described in Foster, et al., Molecular Therapy. Vol. 26 No 3 March 2018 which is herein incorporated by reference. In some embodiments, all or substantially all of the nucleotides of the RNAi agent are modified nucleotides. As used herein, an RNAi agent wherein substantially all of the nucleotides present are modified nucleotides is an RNAi agent having four or fewer (i.e., 0, 1, 2, 3, or 4) nucleotides in both the sense strand and the antisense strand being ribonucleotides. As used herein, a sense strand wherein substantially all of the nucleotides present are modified nucleotides is a sense strand having two or fewer (i.e., 0, 1, or 2) nucleotides in the sense strand being ribonucleotides. As used herein, an antisense sense strand wherein substantially all of the nucleotides present are modified nucleotides is an antisense strand having two or fewer (i.e., 0, 1, or 2) nucleotides in the sense strand being ribonucleotides. In some embodiments, one or more nucleotides of an RNAi agent is a ribonucleotide.116MOFO-359437731Attorney Docket No: 208782001943

[0162] In some embodiments, the modified antisense strand of the RNAi agent comprises a nucleotide sequence of any of the sequences in Table 1. In some embodiments, the modified sense strand of the RNAi agent comprises a nucleotide sequence of any of the sequences in Table 2.

[0163] Among the RNAi agents provided herein, the RNAi agent comprises a modified antisense strand comprising a nucleotide sequence having at least at or about 80%, at or about 81%, at or about 82%, at or about 83%, at or about 84%, at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequences set forth in any of SEQ ID NOs: 193-288, 531-603, and 701-712 and a modified sense strand comprising a nucleotide sequence having at least at or about 80%, at or about 81%, at or about 82%, at or about 83%, at or about 84%, at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequences set forth in any of SEQ ID NOs: 289-384, 604-676, 713- 724, and 726-731. Furthermore, among the RNAi agents provided herein, the RNAi agent comprises a modified antisense strand that differs by 1, 2, 3, or 4 nucleotides from an equal length portion of the sequences set forth in any of SEQ ID NOs: 193-288, 531-603, and 701- 712, or a subsequence thereof, and a modified sense strand that differs by 1, 2, 3, or 4 nucleotides from an equal length portion of the sequences set forth in any of SEQ ID NOs: 289-384, 604-676, 713-724, and 726-731, or a subsequence thereof.

[0164] In some embodiments, the modified antisense strand of the RN Ai agent comprises a nucleotide sequence of any of SEQ ID NO: 193-288, 531-603, and 701-712 and the modified sense strand of the RNAi agent comprises a nucleotide sequence of any of SEQ ID NO: 289- 384, 604-676, 713-724, and 726-731. In some embodiments, the modified antisense and the modified sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 193 and 289, respectively; SEQ ID NOs: 194 and 290, respectively; SEQ ID NOs: 195 and 291, respectively; SEQ ID NOs: 196 and 292, respectively; SEQ ID NOs: 197 and 293, respectively; SEQ ID NOs: 198 and 294, respectively; SEQ ID NOs: 199 and 295, respectively; SEQ ID NOs: 200 and 296, respectively; SEQ ID NOs: 201 and 297, respectively; SEQ ID NOs: 202 and 298, respectively; SEQ ID NOs: 203 and 299, respectively; SEQ ID NOs: 204 and 300, respectively; SEQ ID NOs: 205 and 301,117MOFO-359437731Attorney Docket No: 208782001943 respectively; SEQ ID NOs: 206 and 302, respectively; SEQ ID NOs: 207 and 303, respectively; SEQ ID NOs: 208 and 304, respectively; SEQ ID NOs: 209 and 305, respectively; SEQ ID NOs: 210 and 306, respectively; SEQ ID NOs: 211 and 307, respectively; or SEQ ID NOs: 212 and 308, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or any antisense or sense stand that differs by 1, 2, 3, or 4 nucleotides from an equal length portion of the sequences of SEQ ID NOs: 193 and 289, respectively; SEQ ID NOs: 194 and 290, respectively; SEQ ID NOs: 195 and 291, respectively; SEQ ID NOs: 196 and 292, respectively; SEQ ID NOs: 197 and 293, respectively; SEQ ID NOs: 198 and 294, respectively; SEQ ID NOs: 199 and 295, respectively; SEQ ID NOs: 200 and 296, respectively; SEQ ID NOs: 201 and 297, respectively; SEQ ID NOs: 202 and 298, respectively; SEQ ID NOs: 203 and 299, respectively; SEQ ID NOs: 204 and 300, respectively; SEQ ID NOs: 205 and 301, respectively; SEQ ID NOs: 206 and 302, respectively; SEQ ID NOs: 207 and 303, respectively; SEQ ID NOs: 208 and 304, respectively; SEQ ID NOs: 209 and 305, respectively; SEQ ID NOs: 210 and 306, respectively; SEQ ID NOs: 211 and 307, respectively; or SEQ ID NOs: 212 and 308, respectively.

[0165] In some embodiments, the modified antisense and the modified sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 213 and 309, respectively; SEQ ID NOs: 214 and 310, respectively; SEQ ID NOs: 215 and 311, respectively; SEQ ID NOs: 216 and 312, respectively; SEQ ID NOs: 217 and 313, respectively; SEQ ID NOs: 218 and 314, respectively; SEQ ID NOs: 219 and 315, respectively; SEQ ID NOs: 220 and 316, respectively; SEQ ID NOs: 221 and 317, respectively; SEQ ID NOs: 222 and 318, respectively; SEQ ID NOs: 223 and 319, respectively; SEQ ID NOs: 224 and 320, respectively; SEQ ID NOs: 225 and 321, respectively; SEQ ID NOs: 226 and 322, respectively; SEQ ID NOs: 227 and 323, respectively; SEQ ID NOs: 228 and 324, respectively; SEQ ID NOs: 229 and 325, respectively; SEQ ID NOs: 230 and 326, respectively; SEQ ID NOs: 231 and 327, respectively; or SEQ ID NOs: 232 and 328, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or any antisense or sense stand that differs by 1, 2, 3, or 4 nucleotides from an equal length118MOFO-359437731Attorney Docket No: 208782001943 portion of the sequences of SEQ ID NOs: 213 and 309, respectively; SEQ ID NOs: 214 and 310, respectively; SEQ ID NOs: 215 and 311, respectively; SEQ ID NOs: 216 and 312, respectively; SEQ ID NOs: 217 and 313, respectively; SEQ ID NOs: 218 and 314, respectively; SEQ ID NOs: 219 and 315, respectively; SEQ ID NOs: 220 and 316, respectively; SEQ ID NOs: 221 and 317, respectively; SEQ ID NOs: 222 and 318, respectively; SEQ ID NOs: 223 and 319, respectively; SEQ ID NOs: 224 and 320, respectively; SEQ ID NOs: 225 and 321, respectively; SEQ ID NOs: 226 and 322, respectively; SEQ ID NOs: 227 and 323, respectively; SEQ ID NOs: 228 and 324, respectively; SEQ ID NOs: 229 and 325, respectively; SEQ ID NOs: 230 and 326, respectively; SEQ ID NOs: 231 and 327, respectively; or SEQ ID NOs: 232 and 328, respectively.

[0166] In some embodiments, the modified antisense and the modified sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 233 and 329, respectively; SEQ ID NOs: 234 and 330, respectively; SEQ ID NOs: 235 and 331, respectively; SEQ ID NOs: 236 and 332, respectively; SEQ ID NOs: 237 and 333, respectively; SEQ ID NOs: 238 and 334, respectively; SEQ ID NOs: 239 and 335, respectively; SEQ ID NOs: 240 and 336, respectively; SEQ ID NOs: 241 and 337, respectively; SEQ ID NOs: 242 and 338, respectively; SEQ ID NOs: 243 and 339, respectively; SEQ ID NOs: 244 and 340, respectively; SEQ ID NOs: 245 and 341, respectively; SEQ ID NOs: 246 and 342, respectively; SEQ ID NOs: 247 and 343, respectively; SEQ ID NOs: 248 and 344, respectively; SEQ ID NOs: 249 and 345, respectively; SEQ ID NOs: 250 and 346, respectively; SEQ ID NOs: 251 and 347, respectively; or SEQ ID NOs: 252 and 348, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or any antisense or sense stand that differs by 1, 2, 3, or 4 nucleotides from an equal length portion of the sequences of SEQ ID NOs: 233 and 329, respectively; SEQ ID NOs: 234 and 330, respectively; SEQ ID NOs: 235 and 331, respectively; SEQ ID NOs: 236 and 332, respectively; SEQ ID NOs: 237 and 333, respectively; SEQ ID NOs: 238 and 334, respectively; SEQ ID NOs: 239 and 335, respectively; SEQ ID NOs: 240 and 336, respectively; SEQ ID NOs: 241 and 337, respectively; SEQ ID NOs: 242 and 338, respectively; SEQ ID NOs: 243 and 339, respectively; SEQ ID NOs: 244 and 340, respectively; SEQ ID NOs: 245 and 341, respectively; SEQ ID NOs: 246 and 342,119MOFO-359437731Attorney Docket No: 208782001943 respectively; SEQ ID NOs: 247 and 343, respectively; SEQ ID NOs: 248 and 344, respectively; SEQ ID NOs: 249 and 345, respectively; SEQ ID NOs: 250 and 346, respectively; SEQ ID NOs: 251 and 347, respectively; or SEQ ID NOs: 252 and 348.

[0167] In some embodiments, the modified antisense and the modified sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 253 and 349, respectively; SEQ ID NOs: 254 and 350, respectively; SEQ ID NOs: 255 and 351 , respectively; SEQ ID NOs: 256 and 352, respectively; SEQ ID NOs: 257 and 353, respectively; SEQ ID NOs: 258 and 354, respectively; SEQ ID NOs: 259 and 355, respectively; SEQ ID NOs: 260 and 356, respectively; SEQ ID NOs: 261 and 357, respectively; SEQ ID NOs: 262 and 358, respectively; SEQ ID NOs: 263 and 359, respectively; SEQ ID NOs: 264 and 360, respectively; SEQ ID NOs: 265 and 361, respectively; SEQ ID NOs: 266 and 362, respectively; SEQ ID NOs: 267 and 363, respectively; SEQ ID NOs: 268 and 364, respectively; SEQ ID NOs: 269 and 365, respectively; SEQ ID NOs: 270 and 366, respectively; SEQ ID NOs: 271 and 367, respectively; or SEQ ID NOs: 272 and 368, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or any antisense or sense stand that differs by 1, 2, 3, or 4 nucleotides from an equal length portion of the sequences of SEQ ID NOs: 253 and 349, respectively; SEQ ID NOs: 254 and 350, respectively; SEQ ID NOs: 255 and 351, respectively; SEQ ID NOs: 256 and 352, respectively; SEQ ID NOs: 257 and 353, respectively; SEQ ID NOs: 258 and 354, respectively; SEQ ID NOs: 259 and 355, respectively; SEQ ID NOs: 260 and 356, respectively; SEQ ID NOs: 261 and 357, respectively; SEQ ID NOs: 262 and 358, respectively; SEQ ID NOs: 263 and 359, respectively; SEQ ID NOs: 264 and 360, respectively; SEQ ID NOs: 265 and 361, respectively; SEQ ID NOs: 266 and 362, respectively; SEQ ID NOs: 267 and 363, respectively; SEQ ID NOs: 268 and 364, respectively; SEQ ID NOs: 269 and 365, respectively; SEQ ID NOs: 270 and 366, respectively; SEQ ID NOs: 271 and 367, respectively; or SEQ ID NOs: 272 and 368, respectively.

[0168] In some embodiments, the modified antisense and the modified sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 273 and 369, respectively; SEQ ID NOs: 274 and 370, respectively; SEQ ID NOs: 275 and 371, respectively; SEQ ID NOs: 276 and 372, respectively; SEQ ID NOs: 277 and 373, respectively; SEQ ID NOs: 278120MOFO-359437731Attorney Docket No: 208782001943 and 374, respectively; Sl .Q ID NOs: 279 and 375, respectively; SEQ ID NOs: 280 and 376, respectively; SEQ ID NOs: 281 and 377, respectively; SEQ ID NOs: 282 and 378, respectively; SEQ ID NOs: 283 and 379, respectively; SEQ ID NOs: 284 and 380, respectively; SEQ ID NOs: 285 and 381, respectively; SEQ ID NOs: 286 and 382, respectively; SEQ ID NOs: 287 and 383, respectively; or SEQ ID NOs: 288 and 384, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or any antisense or sense stand that differs by 1, 2, 3, or 4 nucleotides from an equal length portion of the sequences of SEQ ID NOs: 273 and 369, respectively; SEQ ID NOs: 274 and 370, respectively; SEQ ID NOs: 275 and 371, respectively; SEQ ID NOs: 276 and 372, respectively; SEQ ID NOs: 277 and 373, respectively; SEQ ID NOs: 278 and 374, respectively; SEQ ID NOs: 279 and 375, respectively; SEQ ID NOs: 280 and 376, respectively; SEQ ID NOs: 281 and 377, respectively; SEQ ID NOs: 282 and 378, respectively; SEQ ID NOs: 283 and 379, respectively; SEQ ID NOs: 284 and 380, respectively; SEQ ID NOs: 285 and 381, respectively; SEQ ID NOs: 286 and 382, respectively; SEQ ID NOs: 287 and 383, respectively; or SEQ ID NOs: 288 and 384, respectively.

[0169] In some embodiments, the RNAi agent is prepared or provided as a salt, mixed salt, or a free-acid. In some embodiments, the RNAi agent is prepared as a sodium salt. Such forms are within the scope of the embodiments disclosed herein.

[0170] In some embodiments, the modified antisense and the modified sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 531 and 604, respectively; SEQ ID NOs: 532 and 605, respectively; SEQ ID NOs: 533 and 606, respectively; SEQ ID NOs: 534 and 607, respectively; SEQ ID NOs: 535 and 608, respectively; SEQ ID NOs: 536 and 609, respectively; SEQ ID NOs: 537 and 610, respectively; SEQ ID NOs: 538 and 611, respectively; SEQ ID NOs: 539 and 612, respectively; SEQ ID NOs: 540 and 613, respectively; SEQ ID NOs: 541 and 614, respectively; SEQ ID NOs: 542 and 615, respectively; SEQ ID NOs: 543 and 616, respectively; SEQ ID NOs: 544 and 617, respectively; SEQ ID NOs: 545 and 618, respectively; or SEQ ID NOs: 546 and 619, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto,121MOFO-359437731Attorney Docket No: 208782001943 or any antisense or sense stand that differs by 1, 2, 3, or 4 nucleotides from an equal length portion of the sequences of SEQ ID NOs: 531 and 604, respectively; SEQ ID NOs: 532 and 605, respectively; SEQ ID NOs: 533 and 606, respectively; SEQ ID NOs: 534 and 607, respectively; SEQ ID NOs: 535 and 608, respectively; SEQ ID NOs: 536 and 609, respectively; SEQ ID NOs: 537 and 610, respectively; SEQ ID NOs: 538 and 611, respectively; SEQ ID NOs: 539 and 612, respectively; SEQ ID NOs: 540 and 613, respectively; SEQ ID NOs: 541 and 614, respectively; SEQ ID NOs: 542 and 615, respectively; SEQ ID NOs: 543 and 616, respectively; SEQ ID NOs: 544 and 617, respectively; SEQ ID NOs: 545 and 618, respectively; or SEQ ID NOs: 546 and 619, respectively.

[0171] In some embodiments, the modified antisense and the modified sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 547 and 620, respectively; SEQ ID NOs: 548 and 621, respectively; SEQ ID NOs: 549 and 622, respectively; SEQ ID NOs: 550 and 623, respectively; SEQ ID NOs: 551 and 624, respectively; SEQ ID NOs: 552 and 625, respectively; SEQ ID NOs: 553 and 626, respectively; SEQ ID NOs: 554 and 627, respectively; SEQ ID NOs: 555 and 628, respectively; SEQ ID NOs: 556 and 629, respectively; SEQ ID NOs: 557 and 630, respectively; SEQ ID NOs: 558 and 631, respectively; SEQ ID NOs: 559 and 632, respectively; SEQ ID NOs: 560 and 633, respectively; SEQ ID NOs: 561 and 634, respectively; or SEQ ID NOs: 562 and 635, respectively, or any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or any antisense or sense stand that differs by 1, 2, 3, or 4 nucleotides from an equal length portion of the sequences of SEQ ID NOs: 547 and 620, respectively; SEQ ID NOs: 548 and 621, respectively; SEQ ID NOs: 549 and 622, respectively; SEQ ID NOs: 550 and 623, respectively; SEQ ID NOs: 551 and 624, respectively; SEQ ID NOs: 552 and 625, respectively; SEQ ID NOs: 553 and 626, respectively; SEQ ID NOs: 554 and 627, respectively; SEQ ID NOs: 555 and 628, respectively; SEQ ID NOs: 556 and 629, respectively; SEQ ID NOs: 557 and 630, respectively; SEQ ID NOs: 558 and 631, respectively; SEQ ID NOs: 559 and 632, respectively; SEQ ID NOs: 560 and 633, respectively; SEQ ID NOs: 561 and 634, respectively; or SEQ ID NOs: 562 and 635, respectively.122MOFO-359437731Attorney Docket No: 208782001943

[0172] In some embodiments, the modified antisense and the modified sense strands of the RNAi agent comprise the nucleotide sequences of SEQ ID NOs: 563 and 636, respectively; SEQ ID NOs: 564 and 637, respectively; SEQ ID NOs: 565 and 638, respectively; SEQ ID NOs: 566 and 639, respectively; SEQ ID NOs: 567 and 640, respectively; SEQ ID NOs: 568 and 641, respectively; SEQ ID NOs: 569 and 642, respectively; SEQ ID NOs: 570 and 643, respectively; SEQ ID NOs: 571 and 644, respectively; SEQ ID NOs: 572 and 645, respectively; SEQ ID NOs: 573 and 646, respectively; SEQ ID NOs: 574 and 647, respectively; SEQ ID NOs: 575 and 648, respectively; SEQ ID NOs: 576 and 649, respectively; SEQ ID NOs: 577 and 650, respectively; or SEQ ID NOs: 578 and 651, respectively, any antisense or sense strand that has at least 80% sequence identity to any of the above sequences, such as at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or any antisense or sense stand that differs by 1, 2, 3, or 4 nucleotides from an equal length portion of the sequences of SEQ ID NOs: 563 and 636, respectively; SEQ ID NOs: 564 and 637, respectively; SEQ ID NOs: 565 and 638, respectively; SEQ ID NOs: 566 and 639, respectively; SEQ ID NOs: 567 and 640, respectively; SEQ ID NOs: 5...

Claims

Attorney Docket No: 208782001943CLAIMSWhat is claimed is:

1. An RNAi agent that inhibits expression of insulin receptor substrate-1 (IRS 1) comprising an antisense strand and a sense strand that at least partially complements the antisense strand, wherein:(a) the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 385-457 and 677-688; and / or(b) the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 458-530 and 689-700.

2. The RNAi agent of claim 1, wherein one or more bases of the antisense stand and / or the sense strand are modified.

3. The RNAi agent of claim 2, wherein the antisense strand has a modification pattern according to nsNfsnnnNfnnnnnnnNfnNfnnnnnsnsn.

4. The RNAi agent of claim 2 or 3, wherein the sense strand has a modification pattern according to nsnsnnnnNfnNfNfNfnnnnnnnnsnsn.

5. The RNAi agent of claim 2 or 3, wherein the sense strand has a modification pattern according to nsnsnnnnNfnNfNfNfnnnnnnnnnn.

6. The RNAi agent of any one of claims 1-5, wherein:(a) the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 531-603 and 701-712; and / or(b) the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 604-676, 713-724, and 726-731.

7. The RNAi agent of any one of claims 1-6, further comprising a targeting ligand conjugated to the antisense strand or the sense strand, wherein the targeting ligand targets a hepatocyte.330MOFO-359437731Attorney Docket No: 2087820019438. The RNAi agent of any one of claims 1-7, wherein the antisense strand comprises at least 14 contiguous bases that complement a sequence in an mRNA molecule that encodes IRS1 (SEQ ID NO: 725).

9. The RNAi agent of any one of claims 1-8, wherein the antisense strand and the sense strand form a duplex of at least 14 bases in length.

10. The RNAi agent of any one of claims 1-9, wherein the antisense strand and the sense strand form a duplex of between 15 and 30 bases in length.

11. The RNAi agent of any one of claims 1-10, wherein the antisense strand or a subsequence thereof differs by 0, 1, 2, 3, or 4 nucleotides from an equal length portion of any one of SEQ ID NOS: 385-457, 677-688, 531-603, and 701-712, wherein the subsequence is at least 14, 15, 16, 17, 18, 19, 20, or 21 bases in length.

12. The RNAi agent of claim 11, wherein the antisense strand comprises, in order, nucleotides 2-23 of any one of SEQ ID NOS:385-457, 677-688, 531-603, and 701-712.

13. The RNAi agent of any one of claims 1-12, wherein the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 385-457, 677-688, 531-603, and 701-712.

14. The RNAi agent of any one of claims 1-13, wherein the antisense strand comprises, in order, nucleobases 1-14 of any one of SEQ ID NOS: 385-457, 677-688, 531-603, and 701- 712.

15. The RNAi agent of any one of claims 1-14, wherein the antisense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 449, 450, 457, 595, 596, 603, 677, 679, 680, 701, 703, and 704.

16. The RNAi agent of any one of claims 1-15, wherein the sense strand or a subsequence thereof differs by 0, 1, 2, 3, or 4 nucleotides from an equal length portion of any one of SEQ331MOFO-359437731Attorney Docket No: 208782001943ID NOS: 458-530, 689-700, 604-676, 713-724, and 726-731, wherein the subsequence is at least 14, 15, 16, 17, 18, 19, 20, or 21 bases in length.

17. The RNAi agent of claim 16, wherein the sense strand comprises, in order, nucleotides 1- 22 of any one of SEQ ID NOS: 458-530, 689-700, 604-676, 713-724, and 726-731.

18. The RNAi agent of any one of claims 1-17, wherein the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 458-530, 689-700, 604-676, 713-724, and 726-731.

19. The RNAi agent of any one of claims 1-18, wherein the sense strand comprises, in order, nucleobases 1-14 of any one of SEQ ID NOS: 458-530, 689-700, 604-676, 713-724, and 726- 731.

20. The RNAi agent of claim 19, wherein the sense strand comprises at least 14 contiguous bases from any one of SEQ ID NOS: 522, 523, 530, 689, 691, 692, 668, 669, 676, 713, 715, 716, and 726-731.

21. The RNAi agent of any one of claims 1-20, wherein the antisense strand comprises at least 16 contiguous bases that complement a sequence in an mRNA molecule that encodes IRS1 (SEQ ID NO: 725).

22. The RNAi agent of any one of claims 1-21, wherein the antisense strand and the sense strand form a duplex of at least 16 bases in length.

23. The RNAi agent of any one of claims 1-22, wherein the antisense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS: 385-457, 677-688, 531-603, and 701-712.

24. The RNAi agent of claim 23, wherein the antisense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS: 449, 450, 457, 595, 596, 603, 677, 679, 680, 701, 703, and 704.332MOFO-359437731Attorney Docket No: 20878200194325. The RNAi agent of any one of claims 1-24, wherein the antisense strand comprises, in order, nucleobases 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 3-18, 4-19, 4-20, 4-21, 4-22, 4-23, 5-21, 5-22, 5-23, 6-20, 6-21, 6-22, 6-23, 7-22, 7-23, or 8-23 of any one of SEQ ID NOS: 385-457, 677-688, 531-603, and 701-712.

26. The RNAi agent of any one of claims 1-25, wherein the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOS: 385-457, and 677-688.

27. The RNAi agent of claim 26, wherein one or more nucleotides are modified.

28. The RNAi agent of claim 26, wherein the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOS: 449, 450, 457, 677, 679, and 680.

29. The RNAi agent of claim 28, wherein one or more nucleotides are modified.

30. The RNAi agent of claim 27 or 29, wherein the antisense strand has a modification pattern according to nsNfsnnnNfnnnnnnnNfnNfnnnnnsnsn.

31. The RNAi agent of any one of claims 26-30, wherein the antisense strand comprises a modified nucleotide sequence of any one of SEQ ID NOS: 531-603 and 701-712.

32. The RNAi agent of claim 31, wherein the antisense strand comprises a modified nucleotide sequence of any one of SEQ ID NOS: 595, 596, 603, 701, 703, and 704.

33. The RNAi agent of any one of claims 1-32, wherein the sense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS:458-530, 689-700, 604-676, 713-724, and 726-731.

34. The RNAi agent of claim 33, wherein the sense strand comprises at least 16 contiguous bases from any one of SEQ ID NOS: 522, 523, 530, 689, 691, 692, and 726-731.333MOFO-359437731Attorney Docket No: 20878200194335. The RNAi agent of any one of claims 1-34, wherein the sense strand comprises, in order, nucleobases 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 3-18, 4-19, 4-20, 4-21, 4-22, 4-23, 5-21, 5-22, 5-23, 6-20, 6-21, 6-22, 6-23, 7-22, 7-23, or 8-23 of any one of SEQ ID NOS: 458-530, 689-700, 604-676, 713-724, and 726-731.

36. The RNAi agent of any one of claims 1-35, wherein the sense strand comprises a nucleobase sequence of any one of SEQ ID NOS: 458-530, and 689-700.

37. The RNAi agent of claim 36, wherein one or more nucleotides are modified.

38. The RNAi agent of claim 36, wherein the sense strand comprises a nucleobase sequence of any one of SEQ ID NOS: 522, 523, 530, 689, 691, and 692.

39. The RNAi agent of claim 38, wherein one or more nucleotides are modified.

40. The RNAi agent of claim 37 or 39, wherein the sense strand has a modification pattern according to nsnsnnnnNfnNfNfNfnnnnnnnnsnsn.

41. The RNAi agent of claim 37 or 39, wherein the sense strand has a modification pattern according to nsnsnnnnNfnNfNfNfnnnnnnnnnn.

42. The RNAi agent of any one of claims 36-41, wherein the sense strand comprises a modified nucleotide sequence of any one of SEQ ID NOS: 604-676, 713-724, and 726-731.

43. The RNAi agent of claim 42, wherein the sense strand comprises a modified nucleotide sequence of any one of SEQ ID NOS: 668, 669, 676, 713, 715, 716, and 726-731.

44. The RNAi agent of any one of claims 1-43, wherein:(a) the sense strand comprises a nucleobase sequence of SEQ ID NO: 458 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 385;(b) the sense strand comprises a nucleobase sequence of SEQ ID NO: 459 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 386;334MOFO-359437731Attorney Docket No: 208782001943(c) the sense strand comprises a nucleobase sequence of SEQ ID NO: 460 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 387;(d) the sense strand comprises a nucleobase sequence of SEQ ID NO: 461 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 388;(e) the sense strand comprises a nucleobase sequence of SEQ ID NO: 462 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 389;(f) the sense strand comprises a nucleobase sequence of SEQ ID NO: 463 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 390;(g) the sense strand comprises a nucleobase sequence of SEQ ID NO: 464 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 391;(h) the sense strand comprises a nucleobase sequence of SEQ ID NO: 465 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 392;(i) the sense strand comprises a nucleobase sequence of SEQ ID NO: 466 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 393;(j) the sense strand comprises a nucleobase sequence of SEQ ID NO: 467 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 394;(k) the sense strand comprises a nucleobase sequence of SEQ ID NO: 468 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 395;(l) the sense strand comprises a nucleobase sequence of SEQ ID NO: 469 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 396;(m) the sense strand comprises a nucleobase sequence of SEQ ID NO: 470 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 397;(n) the sense strand comprises a nucleobase sequence of SEQ ID NO: 471 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 398;(o) the sense strand comprises a nucleobase sequence of SEQ ID NO: 472 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 399;(p) the sense strand comprises a nucleobase sequence of SEQ ID NO: 473 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 400;(q) the sense strand comprises a nucleobase sequence of SEQ ID NO: 474 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 401;(r) the sense strand comprises a nucleobase sequence of SEQ ID NO: 475 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 402;335MOFO-359437731Attorney Docket No: 208782001943(s) the sense strand comprises a nucleobase sequence of SEQ ID NO: 476 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 403;(t) the sense strand comprises a nucleobase sequence of SEQ ID NO: 477 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 404;(u) the sense strand comprises a nucleobase sequence of SEQ ID NO: 478 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 405;(v) the sense strand comprises a nucleobase sequence of SEQ ID NO: 479 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 406;(w) the sense strand comprises a nucleobase sequence of SEQ ID NO: 480 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 407;(x) the sense strand comprises a nucleobase sequence of SEQ ID NO: 481 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 408;(y) the sense strand comprises a nucleobase sequence of SEQ ID NO: 482 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 409;(z) the sense strand comprises a nucleobase sequence of SEQ ID NO: 483 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 410;(aa) the sense strand comprises a nucleobase sequence of SEQ ID NO: 484 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 411;(bb) the sense strand comprises a nucleobase sequence of SEQ ID NO: 485 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 412;(cc) the sense strand comprises a nucleobase sequence of SEQ ID NO: 486 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 413;(dd) the sense strand comprises a nucleobase sequence of SEQ ID NO: 487 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 414;(ee) the sense strand comprises a nucleobase sequence of SEQ ID NO: 488 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 415;(ff) the sense strand comprises a nucleobase sequence of SEQ ID NO: 489 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 416;(gg) the sense strand comprises a nucleobase sequence of SEQ ID NO: 490 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 417;(hh) the sense strand comprises a nucleobase sequence of SEQ ID NO: 491 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 418;336MOFO-359437731Attorney Docket No: 208782001943(ii) the sense strand comprises a nucleobase sequence of SEQ ID NO: 492 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 419;(jj) the sense strand comprises a nucleobase sequence of SEQ ID NO: 493 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 420;(kk) the sense strand comprises a nucleobase sequence of SEQ ID NO: 494 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 421;(11) the sense strand comprises a nucleobase sequence of SEQ ID NO: 495 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 422;(mm) the sense strand comprises a nucleobase sequence of SEQ ID NO: 496 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 423;(nn) the sense strand comprises a nucleobase sequence of SEQ ID NO: 497 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 424;(oo) the sense strand comprises a nucleobase sequence of SEQ ID NO: 498 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 425;(pp) the sense strand comprises a nucleobase sequence of SEQ ID NO: 499 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 426;(qq) the sense strand comprises a nucleobase sequence of SEQ ID NO: 500 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 427;(rr) the sense strand comprises a nucleobase sequence of SEQ ID NO: 501 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 428;(ss) the sense strand comprises a nucleobase sequence of SEQ ID NO: 502 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 429;(tt) the sense strand comprises a nucleobase sequence of SEQ ID NO: 503 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 430;(uu) the sense strand comprises a nucleobase sequence of SEQ ID NO: 504 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 431;(vv) the sense strand comprises a nucleobase sequence of SEQ ID NO: 505 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 432;(ww) the sense strand comprises a nucleobase sequence of SEQ ID NO: 506 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 433;(xx) the sense strand comprises a nucleobase sequence of SEQ ID NO: 507 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 434;337MOFO-359437731Attorney Docket No: 208782001943(yy) the sense strand comprises a nucleobase sequence of SEQ ID NO: 508 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 435;(zz) the sense strand comprises a nucleobase sequence of SEQ ID NO: 509 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 436;(aaa) the sense strand comprises a nucleobase sequence of SEQ ID NO: 510 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 437;(bbb) the sense strand comprises a nucleobase sequence of SEQ ID NO: 511 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 438;(ccc) the sense strand comprises a nucleobase sequence of SEQ ID NO: 512 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 439;(ddd) the sense strand comprises a nucleobase sequence of SEQ ID NO: 513 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 440;(eee) the sense strand comprises a nucleobase sequence of SEQ ID NO: 514 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 441;(fff) the sense strand comprises a nucleobase sequence of SEQ ID NO: 515 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 442;(ggg) the sense strand comprises a nucleobase sequence of SEQ ID NO: 516 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 443;(hhh) the sense strand comprises a nucleobase sequence of SEQ ID NO: 517 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 444;(iii) the sense strand comprises a nucleobase sequence of SEQ ID NO: 518 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 445;(jjj) the sense strand comprises a nucleobase sequence of SEQ ID NO: 519 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 446;(kkk) the sense strand comprises a nucleobase sequence of SEQ ID NO: 520 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 447;(111) the sense strand comprises a nucleobase sequence of SEQ ID NO: 521 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 448;(mmm) the sense strand comprises a nucleobase sequence of SEQ ID NO: 522 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 449;(nnn) the sense strand comprises a nucleobase sequence of SEQ ID NO: 523 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 450;338MOFO-359437731Attorney Docket No: 208782001943(poo) the sense strand comprises a nucleobase sequence of SEQ ID NO: 524 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 451;(ppp) the sense strand comprises a nucleobase sequence of SEQ ID NO: 525 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 452;(qqq) the sense strand comprises a nucleobase sequence of SEQ ID NO: 526 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 453;(rrr) the sense strand comprises a nucleobase sequence of SEQ ID NO: 527 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 454;(sss) the sense strand comprises a nucleobase sequence of SEQ ID NO: 528 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 455;(ttt) the sense strand comprises a nucleobase sequence of SEQ ID NO: 529 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 456;(uuu) the sense strand comprises a nucleobase sequence of SEQ ID NO: 530 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 457;(vvv) the sense strand comprises a nucleobase sequence of SEQ ID NO: 689 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 677;(www) the sense strand comprises a nucleobase sequence of SEQ ID NO: 690 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 678;(xxx) the sense strand comprises a nucleobase sequence of SEQ ID NO: 691 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 679;(yyy) the sense strand comprises a nucleobase sequence of SEQ ID NO: 692 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 680;(zzz) the sense strand comprises a nucleobase sequence of SEQ ID NO: 693 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 681;(aaaa) the sense strand comprises a nucleobase sequence of SEQ ID NO: 694 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 682;(bbbb) the sense strand comprises a nucleobase sequence of SEQ ID NO: 695 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 683;(cccc) the sense strand comprises a nucleobase sequence of SEQ ID NO: 696 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 684;(dddd) the sense strand comprises a nucleobase sequence of SEQ ID NO: 697 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 685;339MOFO-359437731Attorney Docket No: 208782001943(eeee) the sense strand comprises a nucleobase sequence of SEQ ID NO: 698 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 686;(ffff) the sense strand comprises a nucleobase sequence of SEQ ID NO: 699 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 687; or(gggg) the sense strand comprises a nucleobase sequence of SEQ ID NO: 700 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 688.

45. The RNAi agent of claim 44, wherein:(a) the sense strand comprises a nucleobase sequence of SEQ ID NO: 530 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 457;(b) the sense strand comprises a nucleobase sequence of SEQ ID NO: 523 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 450;(c) the sense strand comprises a nucleobase sequence of SEQ ID NO: 691 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 679;(d) the sense strand comprises a nucleobase sequence of SEQ ID NO: 689 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 677;(e) the sense strand comprises a nucleobase sequence of SEQ ID NO: 522 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 449; or(f) the sense strand comprises a nucleobase sequence of SEQ ID NO: 692 and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 680.

46. The RNAi agent of claim 44 or 45, wherein:(a) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 604 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 531;(b) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 605 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 532;(c) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 606 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 533;(d) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 607 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 534;(e) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 608 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 535;340MOFO-359437731Attorney Docket No: 208782001943(f) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 609 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 536;(g) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 610 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 537;(h) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 611 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 538;(i) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 612 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 539;(j) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 613 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 540;(k) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 614 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 541;(l) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 615 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 542;(m) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 616 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 543;(n) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 617 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 544;(o) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 618 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 545;(p) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 619 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 546;(q) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 620 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 547;(r) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 621 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 548;(s) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 622 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 549;(t) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 623 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 550;(u) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 624 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 551;341MOFO-359437731Attorney Docket No: 208782001943(v) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 625 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 552;(w) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 626 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 553;(x) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 627 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 554;(y) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 628 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 555;(z) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 629 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 556;(aa) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 630 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 557;(bb) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 631 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 558;(cc) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 632 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 559;(dd) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 633 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 560;(ee) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 634 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 561;(ff) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 635 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 562;(gg) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 636 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 563;(hh) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 637 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 564;(ii) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 638 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 565;(jj) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 639 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 566;(kk) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 640 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 567;342MOFO-359437731Attorney Docket No: 208782001943(11) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 641 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 568;(mm) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 642 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 569;(nn) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 643 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 570;(oo) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 644 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 571;(pp) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 645 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 572;(qq) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 646 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 573;(rr) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 647 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 574;(ss) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 648 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 575;(tt) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 649 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 576;(uu) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 650 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 577;(vv) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 651 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 578;(ww) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 652 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 579;(xx) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 653 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 580;(yy) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 654 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 581;(zz) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 655 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 582;(aaa) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 656 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 583;343MOFO-359437731Attorney Docket No: 208782001943(bbb) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 657 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 584;(ccc) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 658 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 585;(ddd) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 659 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 586;(eee) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 660 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 587;(fff) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 661 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 588;(ggg) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 662 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 589;(hhh) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 663 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 590;(iii) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 664 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 591;(jjj) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 665 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 592;(kkk) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 666 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 593;(111) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 667 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 594;(mmm) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 668 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 595;(nnn) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 669 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 596;(ooo) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 670 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 597;(ppp) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 671 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 598;(qqq) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 672 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 599;344MOFO-359437731Attorney Docket No: 208782001943(rrr) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 673 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 600;(sss) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 674 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 601;(ttt) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 675 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 602;(uuu) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 676 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 603;(vvv) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 713 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 701;(www) the sense strand comprises a modified nucleotide sequence of SEQ ID NO:714 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 702;(xxx) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 715 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 703;(yyy) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 716 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 704;(zzz) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 717 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 705;(aaaa) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 718 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 706;(bbbb) the sense strand comprises a modified nucleotide sequence of SEQ ID NO:719 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 707;(cccc) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 720 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 708;(dddd) the sense strand comprises a modified nucleotide sequence of SEQ ID NO:721 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 709;(eeee) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 722 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 710;(ffff) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 723 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 711;(gggg) the sense strand comprises a modified nucleotide sequence of SEQ ID NO:724 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 712;345MOFO-359437731Attorney Docket No: 208782001943(hhhh) the sense strand comprises a modified nucleotide sequence of SEQ ID NO:726 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 603;(iiii) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 727 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 596;(jjjj) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 728 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 703;(kkkk) the sense strand comprises a modified nucleotide sequence of SEQ ID NO:729 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 701;(1111) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 730 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 595; or(mmmm) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 731 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 704.

47. The RNAi agent of claim 46, wherein:(a) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 676 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 603;(b) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 669 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 596;(c) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 715 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 703;(d) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 713 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 701;(e) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 668 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 595;(f) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 716 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 704;(g) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 726 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 603;(h) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 727 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 596;(i) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 728 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 703;346MOFO-359437731Attorney Docket No: 208782001943(j) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 729 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 701;(k) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 730 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 595; or(l) the sense strand comprises a modified nucleotide sequence of SEQ ID NO: 731 and the antisense strand comprises a modified nucleotide sequence of SEQ ID NO: 704.

48. The RNAi agent of claim 47, wherein the RNAi agent comprises a targeting ligand comprising a structure according to Formula I:wherein R is a linker conjugated to the wherein the targeting ligand is conjugated to the 3' end of the sense strand, wherein R comprises a structure according to Formula III:Formula III and wherein connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to the 3' end of the sense strand.

49. The RNAi agent of any one of claims 1-45, wherein the sense strand comprises a 3' overhang of 1-5 nucleotides in length.

50. The RNAi agent of any one of claims 1-45 and 49, wherein the sense strand comprises a347MOFO-359437731Attorney Docket No: 2087820019435' overhang of 1-5 nucleotides in length.

51. The RNAi agent of any one of claims 1-45, wherein the antisense strand comprises a 3' overhang of 1-5 nucleotides in length.

52. The RNAi agent of any one of claims 1-45 and 51, wherein the antisense strand comprises a 5' overhang of 1-5 nucleotides in length.

53. The RNAi agent of any one of claims 1-52, wherein the sense strand or the antisense strand comprises at least one modified nucleotide or at least one modified intemucleoside linkage.

54. The RNAi agent of claim 53, wherein the sense strand and or the antisense strand comprises a modified internucleoside linkage at a first, second, penultimate, or final intemucleoside linkage position.

55. The RNAi agent of claim 53 or 54, wherein the at least one modified nucleotide or at least one modified intemucleoside linkage comprises a 2'-O-methyl modified nucleotide, a nucleotide comprising a 5'-phosphorothioate group, a 2'-deoxy-2 '-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, deoxythymidine, an inverted deoxythymidine, a 2'-amino-modified nucleotide, a 2'-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, or a non-natural base comprising nucleotide56. The RNAi agent of any one of claims 7-47 and 49-55, wherein the targeting ligand is conjugated to the sense strand.

57. The RNAi agent of claim 56, wherein the targeting ligand is conjugated to the 3' end of the sense strand.

58. The RNAi agent of claim 56, wherein the targeting ligand is conjugated to the 5' end of the sense strand.348MOFO-359437731Attorney Docket No: 20878200194359. The RNAi agent of any one of claims 7-47 and 49-55, wherein the targeting ligand is conjugated to the antisense strand.

60. The RNAi agent of claim 59, wherein the targeting ligand is conjugated to the 3' end of the antisense strand.

61. The RNAi agent of claim 59, wherein the targeting ligand is conjugated to the 5' end of the antisense strand.

62. The RNAi agent of any one of claims 7-47 and 49-61, wherein the targeting ligand comprises a galactose trimer.

63. The RNAi agent of any one of claims 7-47 and 49-62, wherein the targeting ligand comprises N-acetylgalactosamine (GalNac).

64. The RNAi agent of any one of claims 7-47 and 49-63, wherein the targeting ligand comprises a structure according to Formula I:wherein R is:(i) the sense strand or the antisense strand; or(ii) a linker conjugated to the sense strand or the antisense strand.

65. The RNAi agent of claim 64, wherein R is a linker conjugated to the sense strand or the antisense strand having a structure according to Formula III:349MOFO-359437731Attorney Docket No: 208782001943Formula III wherein:(i) connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to the sense strand or the antisense strand; or(ii) connection point C of Formula III is conjugated to Formula I, and connection point D of Formula III is conjugated to a phosphate group which is conjugated to the sense strand or the antisense strand.

66. The RNAi agent of claim 65, wherein Formula III or the phosphate group is conjugated to the 3' end or the 5' end of the sense strand or the antisense strand.

67. The RNAi agent of claim 65, wherein Formula III or the phosphate group is conjugated to an internal nucleotide or nucleoside base of the sense strand or the antisense strand.

68. The RNAi agent of any one of claims 7-47 and 49-63, wherein the RNAi agent comprises a targeting ligand and linker according to Formula V:

69. The RNAi agent of any one of claims 1-68, wherein the RNAi agent is an siRNA molecule.350MOFO-359437731Attorney Docket No: 20878200194370. The RNAi agent of any one of claims 1-68, wherein the RNAi agent is an shRNA molecule.

71. A pharmaceutical composition comprising the RNAi agent of any one of claims 1-70 and a pharmaceutically acceptable carrier.

72. A lipid nanoparticle comprising the RNAi agent of any one of claims l-70or the pharmaceutical composition of claim 71.

73. A method of making a pharmaceutical composition, comprising combining the RNAi agent of any one of claims 1-70 with a delivery vehicle selected from the group consisting of a phosphate-buffered saline (PBS), lipid, a nanoparticle, a polymer, a liposome, a micelle, a dynamic polyconjugate (DPC), and antibody-oligo conjugate.

74. A method of treating nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) in a subject, comprising administering to the subject an effective amount of the RNAi agent of any one of claims 1-70.

75. Use of the RNAi agent of any one of claims 1-70 for the manufacture of a medicament for the treatment of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) in a subject.

76. A method of inhibiting expression of insulin receptor substrate-1 (IRS1) in a subject, comprising administering to the subject an effective amount of the RNAi agent of any one of claims 1-70.

77. Use of the RNAi agent of any one of claims 1-70 in the manufacture of a medicament for inhibiting expression of insulin receptor substrate 1 (IRS1) in a hepatocyte of a subject.351MOFO-359437731Attorney Docket No: 20878200194378. A method of controlling or reducing liver fat accumulation in a subject, comprising administering to the subject an effective amount of the RNAi agent of any one of claims 1-70.

79. Use of the RNAi agent of any one of claims 1-70 in the manufacture of a medicament for controlling or reducing liver fat accumulation in a subject.

80. The method or use of claim 78 or 79, wherein the method treats metabolic dysfunction- associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH) in the subject.

81. The method or use of claim 78 or 79, wherein the method treats nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) in the subject.

82. The method or use of any one of claims 73-81, wherein the RNAi agent is an siRNA molecule.

83. The method or use of any one of claims 73-81, wherein the RNAi agent is an shRNA molecule.

84. A method of producing the RNAi agent of any one of claims 1-70, comprising annealing together the sense strand and the antisense strand.

85. The method of claim 84, comprising synthesizing the antisense strand and / or the sense strand.352MOFO-359437731

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