Compositions and methods for inhibiting nuclear receptor subfamily 1 group h member 3 (nr1h3) expression

Abstract

Oligonucleotides are provided herein that inhibit NR1H3 expression. Also provided are compositions including the same and uses thereof, particularly uses relating to treating diseases, disorders and/or conditions associated with NR1H3 expression.

1 . A double stranded RNAi oligonucleotide (dsRNAi) for reducing NR1H3 expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of:
 (a) SEQ ID NOs: 945 and 1033, respectively;   (b) SEQ ID NOs: 946 and 1034, respectively;   (c) SEQ ID NOs: 947 and 1035, respectively;   (d) SEQ ID NOs: 948 and 1036, respectively;   (e) SEQ ID NOs: 949 and 1037, respectively;   (f) SEQ ID NOs: 950 and 1038, respectively;   (g) SEQ ID NOs: 951 and 1039, respectively;   (h) SEQ ID NOs: 952 and 1040, respectively;   (i) SEQ ID NOs: 953 and 1041, respectively;   (j) SEQ ID NOs: 954 and 1042, respectively;   (k) SEQ ID NOs: 955 and 1043, respectively;   (l) SEQ ID NOs: 956 and 1044 respectively;   (m) SEQ ID NOs: 957 and 1045, respectively;   (n) SEQ ID NOs: 958 and 1046, respectively;   (o) SEQ ID NOs: 959 and 1047, respectively;   (p) SEQ ID NOs: 960 and 1048, respectively;   (q) SEQ ID NOs: 961 and 1049, respectively;   (r) SEQ ID NOs: 962 and 1050, respectively;   (s) SEQ ID NOs: 963 and 1051, respectively;   (t) SEQ ID NOs: 964 and 1052, respectively;   (u) SEQ ID NOs: 965 and 1053, respectively;   (v) SEQ ID NOs: 966 and 1054, respectively;   (w) SEQ ID NOs: 967 and 1055, respectively;   (x) SEQ ID NOs: 968 and 1056, respectively;   (y) SEQ ID NOs: 969 and 1057, respectively;   (z) SEQ ID NOs: 970 and 1058, respectively;   (aa) SEQ ID NOs: 971 and 1059, respectively;   (bb) SEQ ID NOs: 972 and 1060, respectively;   (cc) SEQ ID NOs: 973 and 1061, respectively;   (dd) SEQ ID NOs: 974 and 1062, respectively;   (ee) SEQ ID NOs: 975 and 1063, respectively;   (ff) SEQ ID NOs: 976 and 1064, respectively;   (gg) SEQ ID NOs: 977 and 1065, respectively;   (hh) SEQ ID NOs: 978 and 1066, respectively;   (ii) SEQ ID NOs: 979 and 1067, respectively;   (jj) SEQ ID NOs: 980 and 1068, respectively;   (kk) SEQ ID NOs: 981 and 1069, respectively;   (ll) SEQ ID NOs: 982 and 1070, respectively;   (mm) SEQ ID NOs: 983 and 1071, respectively;   (nn) SEQ ID NOs: 984 and 1072, respectively;   (oo) SEQ ID NOs: 985 and 1073, respectively;   (pp) SEQ ID NOs: 986 and 1074, respectively;   (qq) SEQ ID NOs: 987 and 1075, respectively;   (rr) SEQ ID NOs: 988 and 1076, respectively;   (ss) SEQ ID NOs: 989 and 1077, respectively;   (tt) SEQ ID NOs: 990 and 1078, respectively;   (uu) SEQ ID NOs: 991 and 1079, respectively;   (vv) SEQ ID NOs: 992 and 1080, respectively;   (ww) SEQ ID NOs: 993 and 1081, respectively;   (xx) SEQ ID NOs: 994 and 1082, respectively;   (yy) SEQ ID NOs: 995 and 1083, respectively;   (zz) SEQ ID NOs: 996 and 1084, respectively;   (aaa) SEQ ID NOs: 997 and 1085, respectively;   (bbb) SEQ ID NOs: 998 and 1086, respectively;   (ccc) SEQ ID NOs: 999 and 1087, respectively;   (ddd) SEQ ID NOs: 1000 and 1088, respectively;   (eee) SEQ ID NOs: 1001 and 1089, respectively;   (fff) SEQ ID NOs: 1002 and 1090, respectively;   (ggg) SEQ ID NOs: 1003 and 1091, respectively;   (hhh) SEQ ID NOs: 1004 and 1092 respectively;   (iii) SEQ ID NOs: 1005 and 1093 respectively;   (jjj) SEQ ID NOs: 1006 and 1094, respectively;   (kkk) SEQ ID NOs: 1007 and 1095, respectively;   (lll) SEQ ID NOs: 1008 and 1096, respectively;   (mmm) SEQ ID NOs: 1009 and 1097, respectively;   (nnn) SEQ ID NOs: 1010 and 1098, respectively;   (ooo) SEQ ID NOs: 1011 and 1099, respectively;   (ppp) SEQ ID NOs: 1012 and 1100, respectively;   (qqq) SEQ ID NOs: 1013 and 1101, respectively;   (rrr) SEQ ID NOs: 1014 and 1102 respectively;   (sss) SEQ ID NOs: 1015 and 1103, respectively;   (ttt) SEQ ID NOs: 1016 and 1104, respectively;   (uuu) SEQ ID NOs: 1017 and 1105, respectively;   (vvv) SEQ ID NOs: 1018 and 1106, respectively;   (www) SEQ ID NOs: 1019 and 1107, respectively;   (xxx) SEQ ID NOs: 1020 and 1108, respectively;   (yyy) SEQ ID NOs: 1021 and 1109, respectively;   (zzz) SEQ ID NOs: 1022 and 1110, respectively;   (aaaa) SEQ ID NOs: 1023 and 1111, respectively;   (bbbb) SEQ ID NOs: 1024 and 1112, respectively;   (cccc) SEQ ID NOs: 1025 and 1113, respectively;   (dddd) SEQ ID NOs: 1026 and 1114, respectively;   (eeee) SEQ ID NOs: 1027 and 1115, respectively;   (ffff) SEQ ID NOs: 1028 and 1116, respectively;   (gggg) SEQ ID NOs: 1029 and 1117, respectively;   (hhhh) SEQ ID NOs: 1030 and 1118, respectively;   (iiii) SEQ ID NOs: 1031 and 1119, respectively; and,   (jjjj) SEQ ID NOs: 1032 and 1120, respectively.   
     
     
         2 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 1 , wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 964 and 1052, respectively. 
     
     
         3 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 1 , wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 963 and 1051, respectively. 
     
     
         4 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 1 , wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 1006 and 1094, respectively. 
     
     
         5 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 1 , wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 1018 and 1106, respectively. 
     
     
         6 . A double stranded RNAi oligonucleotide (dsRNAi) for reducing NR1H3 expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein
 (i) the sense strand comprises a nucleotide sequence comprising at least 15, 17, or 19 contiguous nucleotides, with 0, 1, 2, or 3 mismatches, of a portion of a nucleotide sequence of any one of SEQ ID NOs: 1-384, or SEQ ID NOs 769-856, or SEQ ID NOs 1519-1552; and   (ii) the antisense strand comprises a nucleotide sequence comprising at least 15, 17, or 19 contiguous nucleotides, with 0, 1, 2, or 3 mismatches, of a portion of a nucleotide sequence of any one of SEQ ID NOs: 385-768, SEQ ID NOs 857-944, or SEQ ID NOs 1512-1515.   
     
     
         7 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 6 , wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:
 (a) SEQ ID NOs: 769 and 857, respectively;   (b) SEQ ID NOs: 770 and 858, respectively;   (c) SEQ ID NOs: 771 and 859, respectively;   (d) SEQ ID NOs: 772 and 860, respectively;   (e) SEQ ID NOs: 773 and 861, respectively;   (f) SEQ ID NOs: 774 and 862, respectively;   (g) SEQ ID NOs: 775 and 863, respectively;   (h) SEQ ID NOs: 776 and 864, respectively;   (i) SEQ ID NOs: 777 and 865, respectively;   (j) SEQ ID NOs: 778 and 866, respectively;   (k) SEQ ID NOs: 779 and 867, respectively;   (l) SEQ ID NOs: 780 and 868, respectively;   (m) SEQ ID NOs: 781 and 869, respectively;   (n) SEQ ID NOs: 782 and 870, respectively;   (o) SEQ ID NOs: 783 and 871, respectively;   (p) SEQ ID NOs: 784 and 872, respectively;   (q) SEQ ID NOs: 785 and 873, respectively;   (r) SEQ ID NOs: 786 and 874, respectively;   (s) SEQ ID NOs: 787 and 875, respectively;   (t) SEQ ID NOs: 788 and 876, respectively;   (u) SEQ ID NOs: 789 and 877, respectively;   (v) SEQ ID NOs: 790 and 878, respectively;   (w) SEQ ID NOs: 791 and 879, respectively;   (x) SEQ ID NOs: 792 and 880, respectively;   (y) SEQ ID NOs: 793 and 881, respectively;   (z) SEQ ID NOs: 794 and 882, respectively;   (aa) SEQ ID NOs: 795 and 883, respectively;   (bb) SEQ ID NOs: 796 and 884, respectively;   (cc) SEQ ID NOs: 797 and 885, respectively;   (dd) SEQ ID NOs: 798 and 886, respectively;   (ee) SEQ ID NOs: 799 and 887, respectively;   (ff) SEQ ID NOs: 800 and 888, respectively;   (gg) SEQ ID NOs: 801 and 889, respectively;   (hh) SEQ ID NOs: 802 and 890, respectively;   (ii) SEQ ID NOs: 803 and 891, respectively;   (jj) SEQ ID NOs: 804 and 892, respectively;   (kk) SEQ ID NOs: 805 and 893, respectively;   (ll) SEQ ID NOs: 806 and 894, respectively;   (mm) SEQ ID NOs: 807 and 895, respectively;   (nn) SEQ ID NOs: 808 and 896, respectively;   (oo) SEQ ID NOs: 809 and 897, respectively;   (pp) SEQ ID NOs: 810 and 898, respectively;   (qq) SEQ ID NOs: 811 and 899, respectively;   (rr) SEQ ID NOs: 812 and 900, respectively;   (ss) SEQ ID NOs: 813 and 901, respectively;   (tt) SEQ ID NOs: 814 and 902, respectively;   (uu) SEQ ID NOs: 815 and 903, respectively;   (vv) SEQ ID NOs: 816 and 904, respectively;   (ww) SEQ ID NOs: 817 and 905, respectively;   (xx) SEQ ID NOs: 818 and 906, respectively;   (yy) SEQ ID NOs: 819 and 907, respectively;   (zz) SEQ ID NOs: 820 and 908, respectively;   (aaa) SEQ ID NOs: 821 and 909, respectively;   (bbb) SEQ ID NOs: 822 and 910, respectively;   (ccc) SEQ ID NOs: 823 and 911, respectively;   (ddd) SEQ ID NOs: 824 and 912, respectively;   (eee) SEQ ID NOs: 825 and 913, respectively;   (fff) SEQ ID NOs: 826 and 914, respectively;   (ggg) SEQ ID NOs: 827 and 915, respectively;   (hhh) SEQ ID NOs: 828 and 916, respectively;   (iii) SEQ ID NOs: 829 and 917, respectively;   (jjj) SEQ ID NOs: 830 and 918, respectively;   (kkk) SEQ ID NOs: 831 and 919, respectively;   (lll) SEQ ID NOs: 832 and 920, respectively;   (mmm) SEQ ID NOs: 833 and 921, respectively;   (nnn) SEQ ID NOs: 834 and 922, respectively;   (ooo) SEQ ID NOs: 835 and 923, respectively;   (ppp) SEQ ID NOs: 836 and 924, respectively;   (qqq) SEQ ID NOs: 837 and 925, respectively;   (rrr) SEQ ID NOs: 838 and 926, respectively;   (sss) SEQ ID NOs: 839 and 927, respectively;   (ttt) SEQ ID NOs: 840 and 928, respectively;   (uuu) SEQ ID NOs: 1537 and 929, respectively;   (vvv) SEQ ID NOs: 842 and 930, respectively;   (www) SEQ ID NOs: 843 and 931, respectively;   (xxx) SEQ ID NOs: 844 and 932, respectively;   (yyy) SEQ ID NOs: 845 and 933, respectively;   (zzz) SEQ ID NOs: 846 and 934, respectively;   (aaaa) SEQ ID NOs: 847 and 935, respectively;   (bbbb) SEQ ID NOs: 848 and 936, respectively;   (cccc) SEQ ID NOs: 849 and 937, respectively;   (dddd) SEQ ID NOs: 850 and 938, respectively;   (eeee) SEQ ID NOs: 851 and 939, respectively;   (ffff) SEQ ID NOs: 852 and 940, respectively;   (gggg) SEQ ID NOs: 853 and 941, respectively;   (hhhh) SEQ ID NOs: 854 and 942, respectively;   (iiii) SEQ ID NOs: 855 and 943, respectively; and,   (jjjj) SEQ ID NOs: 856 and 944, respectively.   
     
     
         8 . An RNAi oligonucleotide for reducing growth (NR1H3) expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1125-1511 and wherein the region of complementarity is at least 15 contiguous nucleotides in length. 
     
     
         9 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 6 , wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, and wherein
 (i) S1 is complementary to S2, and S1 and S2 have the same length and are each 1-10 nucleotides in length; and 
 (ii) L forms a loop between S1 and S2 of 3-5 nucleotides in length. 
 
     
     
         10 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 9 , wherein S1 and S2 are 6 nucleotides in length; and L is a triloop or a tetraloop. 
     
     
         11 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 10 , wherein L is a tetraloop comprising the sequence 5′-GAAA-3′. 
     
     
         12 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 9 , wherein the stem-loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1121). 
     
     
         13 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 9 , wherein at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands. 
     
     
         14 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 13 , wherein each targeting ligand comprises a carbohydrate, amino sugar, cholesterol, polypeptide or lipid. 
     
     
         15 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 13 , wherein the targeting ligand is a hepatocyte targeting ligand and each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety. 
     
     
         16 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 15 , wherein the N-acetylgalactosamine (GalNAc) moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety. 
     
     
         17 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 13 , wherein the stem loop comprises one or more targeting ligands conjugated to one or more nucleotides of the stem loop or the loop comprises one or more targeting ligands conjugated to one or more nucleotides of the loop. 
     
     
         18 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 17 , wherein the one or more targeting ligands is conjugated to one or more nucleotides of the loop, wherein the loop comprises 4 nucleotides numbered 1-4 from 5′ to 3′, wherein nucleotides at positions 2, 3, and 4 each comprise one or more targeting ligands, and wherein the targeting ligands are the same or different. 
     
     
         19 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 17 , wherein the targeting ligand is a hepatocyte targeting ligand and each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety. 
     
     
         20 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 19 , wherein the N-acetylgalactosamine (GalNAc) moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety. 
     
     
         21 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 17 , wherein the targeting ligand is a hepatocyte targeting ligand and up to 4 nucleotides of L of the stem-loop are each conjugated to a monovalent GalNAc moiety. 
     
     
         22 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 9 , comprising at least one modified nucleotide and said modified nucleotide comprises a 2′-modification selected from the group consisting of 2′-aminoethyl, 2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid. 
     
     
         23 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 22 , wherein all nucleotides of the oligonucleotide are modified, and the modification is 2′-fluoro and 2′-O-methyl. 
     
     
         24 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 22 , wherein about 10-15% of the nucleotides of the sense strand comprise a 2′-fluoro modification; and/or about 25-35% of the nucleotides of the antisense strand comprise a 2′-fluoro modification; and/or about 25-35% of the nucleotides of the oligonucleotide comprise a 2′-fluoro modification. 
     
     
         25 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 22 , wherein the sense strand comprises 36 nucleotides with positions 1-36 from 5′ to 3′, wherein positions 8-11 comprise a 2′-fluoro modification; the antisense strand comprises 22 nucleotides with positions 1-22 from 5′ to 3′, and wherein positions 2, 3, 4, 5, 7, 10, and 14 comprise a 2′-fluoro modification; and the remaining nucleotides comprise a 2′-O-methyl modification. 
     
     
         26 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 25 , wherein
 (i) the oligonucleotide comprises at least one phosphorothioate linkage, wherein
 (a) the antisense strand comprises a phosphorothioate linkage between positions 1 and 2, and between positions 2 and 3; or between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5′ to 3′; and/or 
 (b) the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5′ to 3′, and/or 
   (ii) the antisense strand comprises a phosphorylated nucleotide at the 5′ terminus, selected from uridine and adenosine, and/or   (iii) the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, wherein the phosphate analog is a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy, and/or   (iv) the antisense strand comprises an overhang sequence at the 3′ terminus, and wherein the overhang sequence is 2 nucleotides in length selected from the group consisting of AA, GG, AG, and GA.   
     
     
         27 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 7 , wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, and wherein
 (i) S1 is complementary to S2, and S1 and S2 have the same length and are each 1-10 nucleotides in length; and 
 (ii) L forms a loop between S1 and S2 of 3-5 nucleotides in length. 
 
     
     
         28 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 27 , wherein S1 and S2 are 6 nucleotides in length; and L is a triloop or a tetraloop. 
     
     
         29 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 28 , wherein L is a tetraloop comprising the sequence 5′-GAAA-3′. 
     
     
         30 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 27 , wherein the stem-loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1121). 
     
     
         31 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 27 , wherein at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands. 
     
     
         32 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 31 , wherein each targeting ligand comprises a carbohydrate, amino sugar, cholesterol, polypeptide or lipid. 
     
     
         33 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 31 , wherein the targeting ligand is a hepatocyte targeting ligand and each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety. 
     
     
         34 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 33 , wherein the N-acetylgalactosamine (GalNAc) moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety. 
     
     
         35 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 31 , wherein the stem loop comprises one or more targeting ligands conjugated to one or more nucleotides of the stem loop or the loop comprises one or more targeting ligands conjugated to one or more nucleotides of the loop. 
     
     
         36 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 35 , wherein the one or more targeting ligands is conjugated to one or more nucleotides of the loop, wherein the loop comprises 4 nucleotides numbered 1-4 from 5′ to 3′, wherein nucleotides at positions 2, 3, and 4 each comprise one or more targeting ligands, and wherein the targeting ligands are the same or different. 
     
     
         37 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 35 , wherein the targeting ligand is a hepatocyte targeting ligand and each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety. 
     
     
         38 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 37 , wherein the N-acetylgalactosamine (GalNAc) moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety. 
     
     
         39 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 35 , wherein the targeting ligand is a hepatocyte targeting ligand and up to 4 nucleotides of L of the stem-loop are each conjugated to a monovalent GalNAc moiety. 
     
     
         40 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 27 , comprising at least one modified nucleotide and said modified nucleotide comprises a 2′-modification selected from the group consisting of 2′-aminoethyl, 2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid. 
     
     
         41 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 40 , wherein all nucleotides of the oligonucleotide are modified, and the modification is 2′-fluoro and 2′-O-methyl. 
     
     
         42 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 40 , wherein about 10-15%, of the nucleotides of the sense strand comprise a 2′-fluoro modification; and/or about 25-35% of the nucleotides of the antisense strand comprise a 2′-fluoro modification; and/or about 25-35% of the nucleotides of the oligonucleotide comprise a 2′-fluoro modification. 
     
     
         43 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 40 , wherein the sense strand comprises 36 nucleotides with positions 1-36 from 5′ to 3′, wherein positions 8-11 comprise a 2′-fluoro modification; the antisense strand comprises 22 nucleotides with positions 1-22 from 5′ to 3′, and wherein positions 2, 3, 4, 5, 7, 10, and 14 comprise a 2′-fluoro modification; and the remaining nucleotides comprise a 2′-O-methyl modification. 
     
     
         44 . The double stranded RNAi oligonucleotide (dsRNAi) of  claim 43 , wherein
 (i) the oligonucleotide comprises at least one phosphorothioate linkage, wherein
 (a) the antisense strand comprises a phosphorothioate linkage between positions 1 and 2, and between positions 2 and 3; or between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5′ to 3′; and/or 
 (b) the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5′ to 3′, and/or 
   (ii) the antisense strand comprises a phosphorylated nucleotide at the 5′ terminus, selected from uridine and adenosine, and/or   (iii) the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, wherein the phosphate analog is a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy, and/or   (iv) the antisense strand comprises an overhang sequence at the 3′ terminus, and wherein the overhang sequence is 2 nucleotides in length selected from the group consisting of AA, GG, AG, and GA.   
     
     
         45 . A pharmaceutical composition comprising a double stranded RNAi oligonucleotide of  claim 1 , and a pharmaceutically acceptable carrier, delivery agent or excipient. 
     
     
         46 . A method of treating non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus, comprising administering to a patient in need thereof a double stranded RNAi oligonucleotide of  claim 1 . 
     
     
         47 . A method of treating non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus, comprising administering to a patient in need thereof the pharmaceutical composition of  claim 45 .