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.

Description

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 19, 2022, is named 210010US02_SeqList.txt and is 700 kilobytes in size.

BACKGROUND

The liver plays a critical role in the metabolism of lipids. Abnormalities in normal hepatic lipid metabolism are associated with the development of various liver diseases or disorders such as non-alcoholic fatty liver disease (NAFLD) and its subsequent progression to non-alcoholic steatohepatitis (NASH) and potentially other advanced liver abnormalities.

NAFLD is one of the most common liver diseases, with increasing prevalence worldwide (Loomba R., & Sanyal A. J. NAT. REV. GASTROENTEROL HEPATOL. (2013); 10(11): 686-90). NAFLD is a liver disease characterized by a spectrum of clinical and pathological severity ranging from simple steatosis to nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and liver failure (Bessone F, et al., CELL MOL. LIFE SCI. (2019); 76(1): 99-128). NAFLD is characterized by the presence of fat in the liver in the absence of significant alcohol use and other causes of fat accumulation in the liver such as medications, starvation, and viral disease (Chalasani, N., et al., HEPATOLOGY (Baltimore, Md.), (2012); 55(6): 2005-23). Additionally, as the disease progresses, NASH patients also have an increased risk of developing extra-hepatic complications, particularly cardiovascular diseases (CVD), which are among the most common causes of death in this patient population (Patil R, et al., WORLD J. GASTROINTEST. PATHOPHYSIOL. (2017); 8(2): 51-8). The abnormalities in hepatic lipid metabolism that lead to NAFLD also drive the progression of atherogenic dyslipidemia, where elevated plasma triglycerides (TG) cholesterol and lipoprotein particles infiltrate the arterial wall and subsequently develop atherosclerotic plaques (Loomba R & Sanyal A J NAT. REV. GASTROENTEROL. HEPATOL. (2013); 10(11): 686-90). Thus, there is a significant medical need for the development of disease modifying therapeutics for NAFLD.

SUMMARY OF DISCLOSURE

The disclosure is based in part on the discovery of oligonucleotides (e.g., RNAi oligonucleotides) that reduce NR1H3 (nuclear receptor subfamily 1, group H, member 3) expression in the liver. Specifically, target sequences within NR1H3 mRNA were identified and oligonucleotides that bind to these target sequences and inhibit NR1H3 mRNA expression were generated. As demonstrated herein, the oligonucleotides inhibited murine, monkey and/or human NR1H3 expression in the liver. Without being bound by theory, the oligonucleotides described herein are useful for treating a disease, disorder or condition associated with NR1H3 expression (e.g., non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus).

In an aspect, the invention provides an RNAi oligonucleotide 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 antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length. In an aspect, the invention provides an RNAi oligonucleotide 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 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.

In some embodiments, the RNAi oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is selected from SEQ ID NOs: 786, 787, 1537 and 813, and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, the RNAi oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is selected from SEQ ID NOs: 1509, 1510 1409, and 1511 and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments of the RNAi oligonucleotide: (i) the sense strand is 15 to 50 or 18 to 36 nucleotides in length, optionally 36 nucleotides in length; optionally (ii) the antisense strand is 15 to 30 nucleotides in length, optionally 22 nucleotides in length; and optionally (iii) the duplex region is at least 19 nucleotides or at least 20 nucleotides in length.

In some embodiments of the RNAi oligonucleotide, the region of complementarity is at least 19 contiguous nucleotides in length, optionally at least 20 contiguous nucleotides in length, optionally 20 contiguous nucleotides, and optionally wherein the region of complementarity is fully complementary to the mRNA target sequence at nucleotide positions 2-8 of the antisense strand or positions 2-11 of the antisense strand, nucleotide numbering 5′ to 3′.

In some embodiments of the RNAi oligonucleotide: the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein (i) S1 is complementary to S2, optionally wherein S1 and S2 are each 1-10 nucleotides in length and have the same length, optionally wherein S1 and S2 are each 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length, further optionally wherein S1 and S2 are 6 nucleotides in length; and (ii) L forms a loop between S1 and S2 of 3-5 nucleotides in length, optionally wherein L is a triloop or a tetraloop, optionally wherein the tetraloop comprises the sequence 5′-GAAA-3′, optionally wherein the stem-loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1121). In some embodiments of the RNAi oligonucleotide comprises a nicked tetraloop structure or comprises a nick between the 3′ terminus of the sense strand and the 5′ terminus of the antisense strand.

In some embodiments of the RNAi oligonucleotide: the antisense strand comprises an overhang sequence of one or more nucleotides in length at the 3′ terminus, optionally wherein the overhang comprises purine nucleotides, optionally wherein the overhang sequence is 2 nucleotides in length, optionally wherein the overhang is selected from AA, GG, AG, and GA, optionally wherein the overhang is GG.

In some embodiments of the RNAi oligonucleotide: (i) the oligonucleotide comprises at least one modified nucleotide, optionally wherein the modified nucleotide comprises a 2′-modification, optionally wherein: (a) the 2′-modification is a modification selected from 2′-aminoethyl, 2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid, optionally wherein the modification is selected from 2′-fluoro and 2′-O-methyl, optionally wherein all nucleotides of the oligonucleotide are modified, wherein the modification is 2′-fluoro and 2′-O-methyl; (b) about 10-15%, 10%, 11%, 12%, 13%, 14%, or 15% of the nucleotides of the sense strand comprise a 2′-fluoro modification; (c) about 25-35%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the antisense strand comprise a 2′-fluoro modification; (d) about 25-35%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the oligonucleotide comprise a 2′-fluoro modification; (e) the sense strand comprises 36 nucleotides with positions 1-36 from 5′ to 3′, wherein positions 8-11 comprise a 2′-fluoro modification; (f) 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/or (g) the remaining nucleotides comprise a 2′-O-methyl modification, and/or (ii) the oligonucleotide comprises at least one modified internucleotide linkage, optionally wherein the at least one modified internucleotide linkage is a phosphorothioate linkage, optionally wherein: (a) the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) 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 (iii) the antisense strand comprises a phosphorylated nucleotide at the 5′ terminus, wherein the phosphorylated nucleotide is selected from uridine and adenosine, optionally wherein the phosphorylated nucleotide is uridine, and/or (iv) the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, optionally wherein the phosphate analog is oxymethylphosphonate, vinylphosphonate or malonylphosphonate, optionally wherein the phosphate analog is a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy, and/or (v) at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands, optionally wherein: (a) each targeting ligand comprises a carbohydrate, amino sugar, cholesterol, polypeptide or lipid; (b) the stem loop comprises one or more targeting ligands conjugated to one or more nucleotides of the stem loop; (c) the one or more targeting ligands is conjugated to one or more nucleotides of the loop, optionally 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, wherein the targeting ligands are the same or different; (d) each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety, optionally wherein the GalNAc moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety; and/or (e) up to 4 nucleotides of L of the stem-loop are each conjugated to a monovalent GalNAc moiety.

In some embodiments of the RNAi oligonucleotide, the targeting ligand comprises at least one GalNAc moiety and targets human liver cells (e.g., human hepatocytes).

In some embodiments of the RNAi oligonucleotide: (i) the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 769-856, SEQ ID NOs: 1519-1552, SEQ ID NOs: 1409, 1509-1511, or SEQ ID NOs: 945-1032, optionally a nucleotide sequence selected from SEQ ID NOs: SEQ ID NOs: 786, 787, 813, and 1537; and optionally (ii) the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 857-944 or SEQ ID NOs: 1033-1120, optionally a nucleotide sequence selected from SEQ ID NOs: 874, 875, 901, and 929.

In some embodiments of the RNAi oligonucleotide: 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.

In some embodiments of the RNAi oligonucleotide: 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.In some embodiments of the RNAi oligonucleotide:(i) the sense strand comprises the sequence and all of the modifications of 5′-mCs-mU-mC-mA-mA-mG-mG-fA-fU-fU-fU-mC-mA-mG-mU-mU-mA-mU-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 963), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fUs-fAs-fU-fA-mA-fC-mU-mG-fA-mA-mA-mU-fC-mC-mU-mU-mG-mA-mGs-mGs-mG-3′ (SEQ ID NO: 1051), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=Chem. formula 5

(ii) the sense strand comprises the sequence and all of the modifications of 5′-mUs-mC-mA-mA-mG-mG-mA-fU-fU-fU-fC-mA-mG-mU-mU-mA-mU-mA-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 964), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fUs-fUs-fA-fU-mA-fA-mC-mU-fG-mA-mA-mA-fU-mC-mC-mU-mU-mG-mAs-mGs-mG-3′ (SEQ ID NO: 1052), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=Chem. formula 5

(iii) the sense strand comprises the sequence and all of the modifications of 5′-mAs-mG-mC-mA-mG-mC-mG-fU-fC-fC-fA-mC-mU-mC-mA-mG-mA-mG-mC-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1006), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fGs-fCs-fU-fC-mU-fG-mA-mG-fU-mG-mG-mA-fC-mG-mC-mU-mG-mC-mUs-mGs-mG-3′ (SEQ ID NO: 1094), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=Chem. formula 5

(iv) the sense strand comprises the sequence and all of the modifications of 5′-mAs-mU-mG-mU-mG-mC-mA-fC-fG-fA-fA-mU-mG-mA-mC-mU-mG-mU-mU-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1018), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fAs-fAs-fC-fA-mG-fU-mC-mA-fU-mU-mC-mG-fU-mG-mC-mA-mC-mA-mUs-mGs-mG-3′ (SEQ ID NO: 1106), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=Chem. formula 5

optionally wherein the oligonucleotide is a Dicer substrate.

In an aspect, the invention provides a pharmaceutical composition comprising the RNAi oligonucleotide according to the invention and a pharmaceutically acceptable carrier, delivery agent or excipient.

In an aspect, the invention provides a kit comprising the RNAi oligonucleotide according to the invention, an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administration to a subject having a disease, disorder or condition associated with NR1H3 expression, optionally for the treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus

In an aspect, the invention provides the use of the RNAi oligonucleotide according to the invention, or the pharmaceutical composition according to the invention, in the manufacture of a medicament for the treatment of a disease, disorder or condition associated with NR1H3 expression, optionally for the treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus, optionally for use in in combination with a second composition or therapeutic agent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A provides a drawing of an oligonucleotide comprising a nicked tetraloop structure.

FIG. 1B provides a graph depicting the percent (%) remaining human NR1H3 mRNA in liver of mice exogenously expressing human NR1H3 (hydrodynamic injection model) after treatment with GalNAc-conjugated NR1H3 oligonucleotides. Three days post-dose mice were hydrodynamically injected (HDI) with the human NR1H3 mRNA construct. 18 hours later, livers were collected and human and mouse NR1H3 mRNA levels were measured. Exons indicate the location on the mRNA where the construct targets. Constructs tested in FIG. 1B were selected from the screen described in Example 2. White arrows indicate potential constructs for non-human primate (NHP) studies.

FIG. 2 provides graphs depicting the percentage (%) of remaining human or mouse NR1H3 mRNA in liver of mice exogenously expressing human NR1H3 (hydrodynamic injection model) after treatment with GalNAc-conjugated NR1H3 oligonucleotides designed based on sequences identified using the algorithm described in Example 2. Mice were dosed subcutaneously with 2 mg/kg of the indicated NR1H3-GalNAc construct. Three days post-dose mice were hydrodynamically injected (HDI) with the human NR1H3 mRNA construct. 18 hours later, livers were collected and human and mouse NR1H3 mRNA levels were measured. Exons indicate the location on the mRNA where the construct targets. Benchmark constructs (NR1H3-769 and NR1H3-1469) were selected from prior sequence screening conducted at Dicerna.

FIG. 3 provides a graph depicting the percent (%) remaining human NR1H3 mRNA in liver of mice exogenously expressing human NR1H3 (HDI model) after treatment with GalNAc-conjugated NR1H3 oligonucleotides. Constructs tested in FIG. 3 are a repeat assay validating the constructs tested in FIG. 2. White arrows indicate potential constructs for non-human primate studies.

FIG. 4 provides a graph depicting the percent (%) remaining human NR1H3 mRNA in liver of mice exogenously expressing human NR1H3 (HDI model) after treatment with GalNAc-conjugated NR1H3 oligonucleotides. Constructs tested in FIG. 1B and FIG. 2 were validated and repeated in two assays (experiment 1 and experiment 2) using the same methods. White arrows indicate potential constructs for non-human primate studies.

FIG. 5 provides a schematic depicting the dosing scheme and specimen collection for treatment of non-human primates with GalNAc-conjugated NR1H3 oligonucleotides. 1 mg/kg or 4 mg/kg are dosed once every 4 weeks for four months (Q4W×4). Timing for liver biopsies and blood collection is shown.

DETAILED DESCRIPTION

The liver X receptors α (LXRα; encoded by the NR1H3 gene) and β (LXRβ; encoded by NR1H2 gene) are nuclear receptors that function in the regulation of lipid and cholesterol homeostasis, as well as inflammation (Venkateswaran, A., et al., PROC. NATL. ACAD. SCI. U.S.A, (2000); 97: 12097-102). LXRα is highly expressed in lipid metabolism-related organs such as the liver, small intestine, kidney, spleen, adrenal gland, and adipose tissue, whereas LXRβ expression is distributed ubiquitously. The hypothesis of specific inhibition of LXRα in the hepatocytes to treat NASH-related dyslipidemia is supported by several clinical and pre-clinical observations. Activation of LXRα increases plasma and hepatic TG and plasma LDLc, as was demonstrated in human subjects treated with LXR agonist in a dose-dependent manner (Kirchgessner, T. G., et al., CELL METAB, (2016); 24(2): 223-33). Consistent with this observation, hepatic deletion of LXRα in mice lowers liver fat and reduces plasma triglycerides. (J. CLIN. INVEST. (2012); 122(5): 1688-99.

In addition, hepatic expression of LXRα is significantly upregulated in liver biopsies from NAFLD and NASH patients (Ahn, S. B., et al. DIG. DIS. SCI. (2014); 59: 2975-82). However, avoiding inhibition of LXRα in macrophages is desirable as LXRα activation increases reverse cholesterol transport (RCT) which prevents atherosclerosis (CURR. OPIN. INVESTIG. DRUGS. (2003); 4(9): 1053-8). Taken together, and without being bound by theory, antagonism/inhibition of LXRα specifically in hepatocytes (e.g., via NR1H3-targeted RNAi oligonucleotides) decreases de novo lipogenesis with concomitant preservation of LXRα function in macrophages and stellate cells for their positive roles in preventing inflammation and fibrosis respectively, thus representing a promising approach for treatment of NAFLD and/or NASH. (Higuchi, N., et al., HEPATOL. RES. (2008); 38: 1122-29) (Repa, J. J.; and, Mangelsdorf, D. J. ANNU. REV. CELL DEV. BIOL. (2000); 16: 459-81). This approach may be best managed by a specific and targeted reduction of the NR1H3 expression in the liver while other organs, tissues or cells expressing NR1H3 are left essentially alone. In this sense the current invention may provide an improved modality of treatment given its specific targeting of mRNA production in the liver.

According to some aspects, the disclosure provides oligonucleotides (e.g., RNAi oligonucleotides) that reduce NR1H3 expression in the liver. In some embodiments, the oligonucleotides provided herein are designed to treat diseases associated with NR1H3 expression in the liver, e.g., non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH). In some respects, the disclosure provides methods of treating a disease associated with NR1H3 expression by reducing NR1H3 expression in cells (e.g., cells of the liver) or in organs (e.g., liver).

Oligonucleotide Inhibitors of NR1H3 Expression

NR1H3 Target Sequences

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) is targeted to a target sequence comprising a NR1H3 mRNA. In some embodiments, an oligonucleotide described herein is targeted to a target sequence within a NR1H3 mRNA sequence. In some embodiments, the oligonucleotide described herein corresponds to a target sequence within a NR1H3 mRNA sequence. In some embodiments, the oligonucleotide, or a portion, fragment, or strand thereof (e.g., an antisense strand or a guide strand of a double-stranded (ds) RNAi oligonucleotide) binds or anneals to a target sequence comprising NR1H3 mRNA, thereby inhibiting NR1H3 expression.

In some embodiments, the oligonucleotide is targeted to a NR1H3 target sequence for the purpose of inhibiting NR1H3 expression in vivo. In some embodiments, the amount or extent of inhibition of NR1H3 expression by an oligonucleotide targeted to a NR1H3 target sequence correlates with the potency of the oligonucleotide. In some embodiments, the amount or extent of inhibition of NR1H3 expression by an oligonucleotide targeted to a NR1H3 target sequence correlates with the amount or extent of therapeutic benefit in a subject or patient having a disease, disorder or condition associated with NR1H3 expression treated with the oligonucleotide.

Through examination of the nucleotide sequence of mRNAs encoding NR1H3, including mRNAs of multiple different species (e.g., human, cynomolgus monkey, mouse, and rat; see, e.g., Example 2) and as a result of in vitro and in vivo testing (see, e.g., Examples 2-5), it has been discovered that certain nucleotide sequences of NR1H3 mRNA are more amenable than others to oligonucleotide-based inhibition and are thus useful as target sequences for the oligonucleotides herein. In some embodiments, a sense strand of an oligonucleotide (e.g., an RNAi oligonucleotide) described herein comprises a NR1H3 target sequence. In some embodiments, a portion or region of the sense strand of an oligonucleotide described herein (e.g., an RNAi oligonucleotide) comprises a NR1H3 target sequence. In some embodiments, a NR1H3 target sequence comprises, or consists of, a sequence of any one of SEQ ID NOs: 1-384. In some embodiments, a NR1H3 target sequence can consist of one of the sequences set forth in SEQ ID NO: 92, 285, and/or 354.

NR1H3 Targeting Sequences

In some embodiments, the oligonucleotides herein (e.g., RNAi oligonucleotides) have regions of complementarity to NR1H3 mRNA (e.g., within a target sequence of NR1H3 mRNA) for purposes of targeting the NR1H3 mRNA in cells and inhibiting and/or reducing NR1H3 expression. In some embodiments, the oligonucleotides herein comprise a NR1H3 targeting sequence (e.g., an antisense strand or a guide strand of a dsRNAi oligonucleotide) having a region of complementarity that binds or anneals to a NR1H3 target sequence by complementary (Watson-Crick) base pairing. The targeting sequence or region of complementarity is generally of a suitable length and base content to enable binding or annealing of the oligonucleotide (or a strand thereof) to a NR1H3 mRNA for purposes of inhibiting and/or reducing NR1H3 expression. In some embodiments, the targeting sequence or region of complementarity is at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, or at least about 30 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is about 12 to about 30 (e.g., 12 to 30, 12 to 22, 15 to 25, 17 to 21, 18 to 27, 19 to 27, or 15 to 30) nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 18 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 19 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 20 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 21 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 22 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 23 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 24 nucleotides in length. In some embodiments, an oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1-384. In some embodiments, an oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1125-1511 and the targeting sequence or region of complementarity is 18 nucleotides in length. In some embodiments, an oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1-384, and the targeting sequence or region of complementarity is 19 nucleotides in length. In some embodiments, an oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1125-1511, and the targeting sequence or region of complementarity is 19 nucleotides in length.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or a region of complementarity (e.g., an antisense strand or a guide strand of a double-stranded oligonucleotide) that is fully complementary to a NR1H3 target sequence. In some embodiments, the targeting sequence or region of complementarity is partially complementary to a NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to a NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to a NR1H3 target sequence.

In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to a sequence of any one of SEQ ID NOs: 1-384. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to a sequence of any one of SEQ ID NOs: 1125-1511. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to the sequence set forth in SEQ ID NO: 1409, 1509, 1510 or 1511. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to a sequence of any one of SEQ ID NOs: 1-384. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to a sequence of any one of SEQ ID NOs: 1125-1511. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to the sequence set forth in SEQ ID NO: 1409, 1509, 1510 or 1511.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a NR1H3 mRNA, wherein the contiguous sequence of nucleotides is about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 20, 12 to 18, 12 to 16, 14 to 22, 16 to 20, 18 to 20, or 18 to 19 nucleotides in length). In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a NR1H3 mRNA, wherein the contiguous sequence of nucleotides is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a NR1H3 mRNA, wherein the contiguous sequence of nucleotides is 19 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a NR1H3 mRNA, wherein the contiguous sequence of nucleotides is 20 nucleotides in length.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384. In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, optionally wherein the contiguous sequence of nucleotides is 19 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs:1409, 1509, 1510 or 1511, wherein the contiguous sequence of nucleotides is 19 nucleotides in length.

In some embodiments, a targeting sequence or region of complementarity of an oligonucleotide herein (e.g., an RNAi oligonucleotide) is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384. In some embodiments, a targeting sequence or region of complementarity of an oligonucleotide herein (e.g., an RNAi oligonucleotide) is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511. In some embodiments, a targeting sequence or region of complementarity of an oligonucleotide herein (e.g., an RNAi oligonucleotide) is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384 and spans the entire length of an antisense strand. In some embodiments, a targeting sequence or region of complementarity of the oligonucleotide is complementary to a contiguous sequence of nucleotides of SEQ ID NOs: 1-384 and spans a portion of the entire length of an antisense strand. In some embodiments, a targeting sequence or region of complementarity of the oligonucleotide is complementary to a contiguous sequence of nucleotides of SEQ ID NOs: 1125-1511 and spans a portion of the entire length of an antisense strand. In some embodiments, a targeting sequence or region of complementarity of the oligonucleotide is complementary to a contiguous sequence of nucleotides of SEQ ID NOs: 1125-1511 and spans a portion of the entire length of an antisense strand. In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a region of complementarity (e.g., on an antisense strand of a dsRNA) that is at least partially (e.g., fully) complementary to a contiguous stretch of nucleotides spanning nucleotides 1-19 or 1-20 of a sequence as set forth in any one of SEQ ID NOs: 1-384. In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a region of complementarity (e.g., on an antisense strand of a dsRNA) that is at least partially (e.g., fully) complementary to a contiguous stretch of nucleotides spanning nucleotides 1-19 or 1-20 of a sequence as set forth in any one of SEQ ID NOs: 1125-1511.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or region of complementarity having one or more base pair (bp) mismatches with the corresponding NR1H3 target sequence. In some embodiments, the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding NR1H3 target sequence provided that the ability of the targeting sequence or region of complementarity to bind or anneal to the NR1H3 mRNA under appropriate hybridization conditions and/or the ability of the oligonucleotide to inhibit NR1H3 expression is maintained. Alternatively, the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding NR1H3 target sequence provided that the ability of the targeting sequence or region of complementarity to bind or anneal to the NR1H3 mRNA under appropriate hybridization conditions and/or the ability of the oligonucleotide to inhibit NR1H3 expression is maintained. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 1 mismatch with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 2 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 3 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 4 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 5 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having more than one mismatch (e.g., 2, 3, 4, 5 or more mismatches) with the corresponding target sequence, wherein at least 2 (e.g., all) of the mismatches are positioned consecutively (e.g., 2, 3, 4, 5 or more mismatches in a row), or wherein the mismatches are interspersed throughout the targeting sequence or region of complementarity. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having more than one mismatch (e.g., 2, 3, 4, 5 or more mismatches) with the corresponding target sequence, wherein at least 2 (e.g., all) of the mismatches are positioned consecutively (e.g., 2, 3, 4, 5 or more mismatches in a row), or wherein at least one or more non-mismatched base pair is located between the mismatches, or a combination thereof. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, wherein the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, wherein the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, wherein the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, wherein the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs:1409, 1509, 1510 or 1511, wherein the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1409, 1509, 1510 or 1511, wherein the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding NR1H3 target sequence.

Types of Oligonucleotides

A variety of oligonucleotide types and/or structures are useful for targeting NR1H3 in the methods herein including, but not limited to, RNAi oligonucleotides, antisense oligonucleotides (ASOs), miRNAs, etc. Any of the oligonucleotide types described herein or elsewhere are contemplated for use as a framework to incorporate a NR1H3 targeting sequence herein for the purposes of inhibiting NR1H3 expression.

In some embodiments, the oligonucleotides herein inhibit NR1H3 expression by engaging with RNA interference (RNAi) pathways upstream or downstream of Dicer involvement. For example, RNAi oligonucleotides have been developed with each strand having sizes of about 19-25 nucleotides with at least one 3′-overhang of 1 to 5 nucleotides (see, e.g., U.S. Pat. No. 8,372,968). Longer oligonucleotides also have been developed that are processed by Dicer to generate active RNAi products (see, e.g., U.S. Pat. No. 8,883,996). Further work produced extended dsRNAs where at least one end of at least one strand is extended beyond a duplex targeting region, including structures where one of the strands includes a thermodynamically stabilizing tetraloop structure (see, e.g., U.S. Pat. Nos. 8,513,207 and 8,927,705, as well as Intl. Patent Application Publication No. WO 2010/033225). Such structures may include single-stranded (ss) extensions (on one or both sides of the molecule) as well as double-stranded (ds) extensions.

In some embodiments, the oligonucleotides herein engage with the RNAi pathway downstream of the involvement of Dicer (e.g., Dicer cleavage). In some embodiments, the oligonucleotides described herein are Dicer substrates. In some embodiments, upon endogenous Dicer processing, double-stranded nucleic acids of 19-23 nucleotides in length capable of reducing NR1H3 expression are produced. In some embodiments, the oligonucleotide has an overhang (e.g., of 1, 2, or 3 nucleotides in length) in the 3′ end of the sense strand. In some embodiments, the oligonucleotide (e.g., siRNA) comprises a 21-nucleotide guide strand that is antisense to a target RNA and a complementary passenger strand, in which both strands anneal to form a 19-bp duplex and 2 nucleotide overhangs at either or both 3′ ends. Longer oligonucleotide designs also are available including oligonucleotides having a guide strand of 23 nucleotides and a passenger strand of 21 nucleotides, where there is a blunt end on the right side of the molecule (3′ end of passenger strand/5′ end of guide strand) and a two nucleotide 3′-guide strand overhang on the left side of the molecule (5′ end of the passenger strand/3′ end of the guide strand). In such molecules, there is a 21 bp duplex region. See, e.g., U.S. Pat. Nos. 9,012,138; 9,012,621 and 9,193,753.

In some embodiments, the oligonucleotides herein comprise sense and antisense strands that are both in the range of about 17 to 36 (e.g., 17 to 36, 20 to 25, or 21-23) nucleotides in length. In some embodiments, the oligonucleotides described herein comprise an antisense strand of 19-30 nucleotides in length and a sense strand of 19-50 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand. In some embodiments, an oligonucleotide herein comprises a sense and antisense strand that are both in the range of about 19-22 nucleotides in length. In some embodiments, the sense and antisense strands are of equal length. In some embodiments, an oligonucleotide comprises sense and antisense strands, such that there is a 3′-overhang on either the sense strand or the antisense strand, or both the sense and antisense strand. In some embodiments, for oligonucleotides that have sense and antisense strands that are both in the range of about 21-23 nucleotides in length, a 3′-overhang on the sense, antisense, or both sense and antisense strands is 1 or 2 nucleotides in length. In some embodiments, the oligonucleotide has a guide strand of 22 nucleotides and a passenger strand of 20 nucleotides, where there is a blunt end on the right side of the molecule (3′ end of passenger strand/5′ end of guide strand) and a 2 nucleotide 3′-guide strand overhang on the left side of the molecule (5′ end of the passenger strand/3′ end of the guide strand). In such molecules, there is a 20 bp duplex region.

Other oligonucleotide designs for use with the compositions and methods herein include: 16-mer siRNAs (see, e.g., NUCLEIC ACIDS IN CHEMISTRY AND BIOLOGY. Blackburn (ed.), Royal Society of Chemistry, 2006), shRNAs (e.g., having 19 bp or shorter stems; see, e.g., Moore et al. METHODS MOL. BIOL. (2010); 629: 141-158), blunt siRNAs (e.g., of 19 bps in length; see, e.g., Kraynack & Baker RNA (2006); 12: 163-176), asymmetrical siRNAs (aiRNA; see, e.g., Sun et al. NAT. BIOTECHNOL. (2008); 26: 1379-1382), asymmetric shorter-duplex siRNA (see, e.g., Chang et al. MOL. THER. (2009); 17: 725-32), fork siRNAs (see, e.g., Hohjoh FEBS LETT. (2004); 557: 193-198), ss siRNAs (Elsner NAT. BIOTECHNOL. (2012); 30: 1063), dumbbell-shaped circular siRNAs (see, e.g., Abe et al. J. AM. CHEM. SOC. (2007); 129: 15108-09), and small internally segmented interfering RNA (siRNA; see, e.g., Bramsen et al. NUCLEIC ACIDS RES. (2007); 35: 5886-97). Further non-limiting examples of an oligonucleotide structures that may be used in some embodiments to reduce or inhibit the expression of NR1H3 are microRNA (miRNA), short hairpin RNA (shRNA) and short siRNA (see, e.g., Hamilton et al. EMBO J. (2002); 21: 4671-79; see also, US Patent Application Publication No. 2009/0099115).

Still, in some embodiments, an oligonucleotide for reducing or inhibiting NR1H3 expression herein is single-stranded (ss). Such structures may include but are not limited to single-stranded RNAi molecules. Recent efforts have demonstrated the activity of ss RNAi molecules (see, e.g., Matsui et al. MOL. THER. (2016); 24: 946-55). However, in some embodiments, oligonucleotides herein are antisense oligonucleotides (ASOs). An antisense oligonucleotide is a single-stranded oligonucleotide that has a nucleobase sequence which, when written in the 5′ to 3′ direction, comprises the reverse complement of a targeted segment of a particular nucleic acid and is suitably modified (e.g., as a gapmer) so as to induce RNaseH-mediated cleavage of its target RNA in cells or (e.g., as a mixmer) so as to inhibit translation of the target mRNA in cells. ASOs for use herein may be modified in any suitable manner known in the art including, for example, as shown in U.S. Pat. No. 9,567,587 (including, e.g., length, sugar moieties of the nucleobase (pyrimidine, purine), and alterations of the heterocyclic portion of the nucleobase). Further, ASOs have been used for decades to reduce expression of specific target genes (see, e.g., Bennett et al. ANNU. REV. PHARMACOL. (2017); 57: 81-105).

In some embodiments, the antisense oligonucleotide shares a region of complementarity with NR1H3 mRNA. In some embodiments, the antisense oligonucleotide targets the human NR1H3 mRNA (Homo sapiens NR1H3, mRNA, transcript variant 5, NCBI Reference Sequence: NM_001251935.1). In some embodiments, the antisense oligonucleotide is 15-50 nucleotides in length. In some embodiments, the antisense oligonucleotide is 15-25 nucleotides in length. In some embodiments, the antisense oligonucleotide is 22 nucleotides in length. In some embodiments, the antisense oligonucleotide is complementary to any one of SEQ ID NOs: 1-384. In some embodiments, the antisense oligonucleotide is complementary to any one of SEQ ID NOs: 1125-1511. In some embodiments, the antisense oligonucleotide is at least 15 contiguous nucleotides in length. In some embodiments, the antisense oligonucleotide is at least 19 contiguous nucleotides in length. In some embodiments, the antisense oligonucleotide is at least 20 contiguous nucleotides in length. In some embodiments, the antisense oligonucleotide differs by 1, 2, or 3 nucleotides from the target sequence.

Double-Stranded Oligonucleotides

In some aspects, the disclosure provides double-stranded (ds) RNAi oligonucleotides for targeting NR1H3 mRNA and inhibiting NR1H3 expression (e.g., via the RNAi pathway) comprising a sense strand (also referred to herein as a passenger strand) and an antisense strand (also referred to herein as a guide strand). In some embodiments, the sense strand and antisense strand are separate strands and are not covalently linked. In some embodiments, the sense strand and antisense strand are covalently linked. In some embodiments, the sense strand and antisense strand form a duplex region, wherein the sense strand and antisense strand, or a portion thereof, binds with one another in a complementary fashion (e.g., by Watson-Crick base pairing).

In some embodiments, the sense strand has a first region (R1) and a second region (R2), wherein R2 comprises a first subregion (S1), a tetraloop (L) or triloop (triL), and a second subregion (S2), wherein L or triL is located between S1 and S2, and wherein S1 and S2 form a second duplex (D2). D2 may have various length. In some embodiments, D2 is about 1-6 bp in length. In some embodiments, D2 is 2-6, 3-6, 4-6, 5-6, 1-5, 2-5, 3-5, or 4-5 bp in length. In some embodiments, D2 is 1, 2, 3, 4, 5, or 6 bp in length. In some embodiments, D2 is 6 bp in length. In some embodiments, R1 of the sense strand and the antisense strand form a first duplex (D1). In some embodiments, D1 is at least about 15 (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21) nucleotides in length. In some embodiments, D1 is in the range of about 12 to 30 nucleotides in length (e.g., 12 to 30, 12 to 27, 15 to 22, 18 to 22, 18 to 25, 18 to 27, 18 to 30, or 21 to 30 nucleotides in length). In some embodiments, D1 is at least 12 nucleotides in length (e.g., at least 12, at least 15, at least 20, at least 25, or at least 30 nucleotides in length). In some embodiments, D1 is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, D1 is 20 nucleotides in length. In some embodiments, D1 comprising sense strand and antisense strand does not span the entire length of the sense strand and/or antisense strand. In some embodiments, D1 comprising the sense strand and antisense strand spans the entire length of either the sense strand or antisense strand or both. In certain embodiments, D1 comprising the sense strand and antisense strand spans the entire length of both the sense strand and the antisense strand.

In some embodiments, an oligonucleotide provided herein comprises a sense strand having a sequence of any one of SEQ ID NOs: 1-384 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 385-768. In some embodiments, an oligonucleotide provided herein comprises a sense strand having a sequence of any one of SEQ ID NOs: 1125-1511 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 1512-1515.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand having a sequence of any one of SEQ ID NOs: 769-856 or 1519-1552 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 857-944 as is arranged in Tables 3 and 4.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand comprising nucleotide sequences selected from:

(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.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand comprising nucleotide sequences selected from:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively; and,(d) SEQ ID NOs: 813 and 901, respectively.

In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 786 and the antisense strand comprises the sequence of SEQ ID NO: 874.

In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 787 and the antisense strand comprises the sequence of SEQ ID NO: 875.

In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 1537 and the antisense strand comprises the sequence of SEQ ID NO: 929.

In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 813 and the antisense strand comprises the sequence of SEQ ID NO: 901.

It should be appreciated that, in some embodiments, sequences presented in the Sequence Listing may be referred to in describing the structure of an oligonucleotide (e.g., a dsRNAi oligonucleotide) or other nucleic acid. In such embodiments, the actual oligonucleotide or other nucleic acid may have one or more alternative nucleotides (e.g., an RNA counterpart of a DNA nucleotide or a DNA counterpart of an RNA nucleotide) and/or one or more modified nucleotides and/or one or more modified internucleotide linkages and/or one or more other modification when compared with the specified sequence while retaining essentially same or similar complementary properties as the specified sequence.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a 25-nucleotide sense strand and a 27-nucleotide antisense strand that when acted upon by a Dicer enzyme results in an antisense strand that is incorporated into the mature RISC. In some embodiments, the 25-nucleotide sense strand comprises a sequence selected from SEQ ID NOs: 1-384. In some embodiments, the 27-nucleotide antisense strand comprises a sequence selected from SEQ ID NOs: 385-768. In some embodiments, the sense strand of the oligonucleotide is longer than 27 nucleotides (e.g., 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides). In some embodiments, the sense strand of the oligonucleotide is longer than 25 nucleotides (e.g., 26, 27, 28, 29, or 30 nucleotides). In some embodiments, the sense strand of the oligonucleotide comprises a nucleotide sequence selected from SEQ ID NOs: 769-856, wherein the nucleotide sequence is longer than 27 nucleotides (e.g., 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides).). In some embodiments, the sense strand of the oligonucleotide comprises a nucleotide sequence selected from SEQ ID NOs: 1519-1552, wherein the nucleotide sequence is longer than 27 nucleotides (e.g., 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides). In some embodiments, the sense strand of the oligonucleotide comprises a nucleotide sequence selected from SEQ ID NOs: 769-856, wherein the nucleotide sequence is longer than 25 nucleotides (e.g., 26, 27, 28, 29 or 30 nucleotides).

In some embodiments, oligonucleotides herein (e.g., RNAi oligonucleotides) have one 5′ end that is thermodynamically less stable when compared to the other 5′ end. In some embodiments, an asymmetric oligonucleotide is provided that includes a blunt end at the 3′ end of a sense strand and a 3′-overhang at the 3′ end of an antisense strand. In some embodiments, the 3′-overhang on the antisense strand is about 1-8 nucleotides in length (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 nucleotides in length). In some embodiments, the oligonucleotide has an overhang comprising two (2) nucleotides on the 3′ end of the antisense (guide) strand. However, other overhangs are possible. In some embodiments, an overhang is a 3′-overhang comprising a length of between 1 and 6 nucleotides, optionally 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, 5 to 6 nucleotides, or 1, 2, 3, 4, 5, or 6 nucleotides. However, in some embodiments, the overhang is a 5′-overhang comprising a length of between 1 and 6 nucleotides, optionally 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, 5 to 6 nucleotides, or 1, 2, 3, 4, 5, or 6 nucleotides. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, and a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, and a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 769-856, wherein the oligonucleotide comprises a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1519-1552, wherein the oligonucleotide comprises a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises an antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the oligonucleotide comprises a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 769-856 and antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the oligonucleotide comprises a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1519-1552 and antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the oligonucleotide comprises a 5′-overhang comprising a length of between 1 and 6 nucleotides.

In some embodiments, two (2) terminal nucleotides on the 3′ end of an antisense strand are modified. In some embodiments, the two (2) terminal nucleotides on the 3′ end of the antisense strand are complementary with the target mRNA (e.g., NR1H3 mRNA). In some embodiments, the two (2) terminal nucleotides on the 3′ end of the antisense strand are not complementary with the target mRNA. In some embodiments, the two (2) terminal nucleotides on the 3′ end of the antisense strand of an oligonucleotide herein are unpaired. In some embodiments, the two (2) terminal nucleotides on the 3′ end of the antisense strand of an oligonucleotide herein comprise an unpaired GG. In some embodiments, the two (2) terminal nucleotides on the 3′ end of an antisense strand of an oligonucleotide herein are not complementary to the target mRNA. In some embodiments, two (2) terminal nucleotides on each 3′ end of an oligonucleotide are GG. In some embodiments, one or both of the two (2) terminal GG nucleotides on each 3′ end of an oligonucleotide herein is not complementary with the target mRNA. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, wherein the two (2) terminal nucleotides on the 3′ end of the antisense strand of the oligonucleotide herein comprises an unpaired GG. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, wherein the two (2) terminal nucleotides on the 3′ end of the antisense strand of the oligonucleotide herein comprises an unpaired GG. In some embodiments, the oligonucleotide comprises an antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the two (2) terminal nucleotides on the 3′ end of the antisense strand of the oligonucleotide comprises an unpaired GG. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 769-856 and antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the two (2) terminal nucleotides on the 3′ end of the antisense strand of the oligonucleotide comprises an unpaired GG. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1519-1552 and antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the two (2) terminal nucleotides on the 3′ end of the antisense strand of the oligonucleotide comprises an unpaired GG.

In some embodiments, there is one or more (e.g., 1, 2, 3, 4, or 5) mismatch(s) between a sense and antisense strand comprising an oligonucleotide herein (e.g., an RNAi oligonucleotide). If there is more than one mismatch between a sense and antisense strand, they may be positioned consecutively (e.g., 2, 3 or more in a row), or interspersed throughout the region of complementarity. In some embodiments, the 3′ end of the sense strand comprises one or more mismatches. In some embodiments, two (2) mismatches are incorporated at the 3′ end of the sense strand. In some embodiments, base mismatches, or destabilization of segments at the 3′ end of the sense strand of an oligonucleotide herein improves or increases the potency of the oligonucleotide. In some embodiments, the sense and antisense strands of an oligonucleotide herein comprise nucleotides 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,wherein there is one or more (e.g., 1, 2, 3, 4 or 5) mismatch(s) between the sense and antisense strands.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand comprising nucleotide sequences selected from:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively; and,(d) SEQ ID NOs: 813 and 901, respectively,

wherein there is one or more (e.g., 1, 2, 3, 4, or 5) mismatch(s) between the sense and antisense strands.

Antisense Strands

In some embodiments, an antisense strand of an oligonucleotide herein (e.g., an RNAi oligonucleotide) is referred to as a “guide strand”. For example, an antisense strand that engages with RNA-induced silencing complex (RISC) and binds to an Argonaute protein such as Ago2, or engages with or binds to one or more similar factors, and directs silencing of a target gene, as the antisense strand is referred to as a guide strand. In some embodiments, a sense strand comprising a region of complementary to a guide strand is referred to herein as a “passenger strand.” In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises an antisense strand of up to about 50 nucleotides in length (e.g., up to 50, up to 40, up to 35, up to 30, up to 27, up to 25, up to 21, up to 19, up to 17, or up to 12 nucleotides in length).

In some embodiments, an oligonucleotide comprises an antisense strand of at least about 12 nucleotides in length (e.g., at least 12, at least 15, at least 19, at least 21, at least 22, at least 25, at least 27, at least 30, at least 35, or at least 38 nucleotides in length). In some embodiments, an oligonucleotide comprises an antisense strand in a range of about 12 to about 40 (e.g., 12 to 40, 12 to 36, 12 to 32, 12 to 28, 15 to 40, 15 to 36, 15 to 32, 15 to 28, 17 to 22, 17 to 25, 19 to 27, 19 to 30, 20 to 40, 22 to 40, 25 to 40, or 32 to 40) nucleotides in length. In some embodiments, an oligonucleotide comprises antisense strand of 15 to 30 nucleotides in length. In some embodiments, an antisense strand of any one of the oligonucleotides disclosed herein is of 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, an oligonucleotide comprises an antisense strand of 22 nucleotides in length.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) for targeting NR1H3 comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 385-768. In some embodiments, an oligonucleotide herein comprises an antisense strand comprising at least about 12 (e.g., 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, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 385-768. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 857-944. In some embodiments, an oligonucleotide herein comprises an antisense strand comprising at least about 12 (e.g., 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, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 857-944. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 874, 875, 929, and 901. In some embodiments, an oligonucleotide herein comprises an antisense strand comprising at least about 12 (e.g., 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 or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 874, 875, 929, and 901.

In some embodiments, an oligonucleotide herein comprises an antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1512-1515.

Sense Strands

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 1-384. In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 1125-1511. In some embodiments, an oligonucleotide herein has a sense strand comprised of at least about 12 (e.g., 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, or at least 23) contiguous nucleotides of a sequence as set forth in in any one of SEQ ID NOs: 1-384. In some embodiments, an oligonucleotide herein has a sense strand comprised of at least about 12 (e.g., 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 or at least 23) contiguous nucleotides of a sequence as set forth in in any one of SEQ ID NOs: 1125-1511. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 769-856. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 1519-1552. In some embodiments, an oligonucleotide herein has a sense strand comprised of least about 12 (e.g., 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, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 769-856. In some embodiments, an oligonucleotide herein has a sense strand comprised of least about 12 (e.g., 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, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 1519-1552. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 786, 787, 1537, and 813. In some embodiments, an oligonucleotide herein has a sense strand that comprise at least about 12 (e.g., 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, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 786, 787, 1537, and 813. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 1409, 1509, 1510 and 1511. In some embodiments, an oligonucleotide herein has a sense strand that comprise at least about 12 (e.g., 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 or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 1409, 1509, 1510 and 1511.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand (or passenger strand) of up to about 50 nucleotides in length (e.g., up to 50, up to 40, up to 36, up to 30, up to 27, up to 25, up to 21, up to 19, up to 17, or up to 12 nucleotides in length). In some embodiments, an oligonucleotide herein comprises a sense strand of at least about 12 nucleotides in length (e.g., at least 12, at least 15, at least 19, at least 21, at least 25, at least 27, at least 30, at least 36, or at least 38 nucleotides in length). In some embodiments, an oligonucleotide herein comprises a sense strand in a range of about 12 to about 50 (e.g., 12 to 50, 12 to 40, 12 to 36, 12 to 32, 12 to 28, 15 to 40, 15 to 36, 15 to 32, 15 to 28, 17 to 21, 17 to 25, 19 to 27, 19 to 30, 20 to 40, 22 to 40, 25 to 40, or 32 to 40) nucleotides in length. In some embodiments, an oligonucleotide herein comprises a sense strand of 15 to 50 nucleotides in length. In some embodiments, an oligonucleotide herein comprises a sense strand of 18 to 36 nucleotides in length. In some embodiments, an oligonucleotide herein comprises a sense strand of 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, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides in length. In some embodiments, an oligonucleotide herein comprises a sense strand of 36 nucleotides in length.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand comprising a stem-loop structure at the 3′ end of the sense strand. In some embodiments, the stem-loop is formed by intrastrand base pairing. In some embodiments, a sense strand comprises a stem-loop structure at its 5′ end. In some embodiments, the stem of the stem-loop comprises a duplex of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 2 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 3 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 4 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 5 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 6 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 7 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 8 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 9 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 10 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 11 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 12 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 13 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 14 nucleotides in length.

In some embodiments, a stem-loop provides the oligonucleotide protection against degradation (e.g., enzymatic degradation), facilitates or improves targeting and/or delivery to a target cell, tissue, or organ (e.g., the liver), or both. For example, in some embodiments, the loop of a stem-loop is comprised of nucleotides comprising one or more modifications that facilitate, improve, or increase targeting to a target mRNA (e.g., a NR1H3 mRNA), inhibition of target gene expression (e.g., NR1H3 expression), and/or delivery, uptake, and/or penetrance into a target cell, tissue, or organ (e.g., the liver), or a combination thereof. In some embodiments, the stem-loop itself or modification(s) to the stem-loop do not affect or do not substantially affect the inherent gene expression inhibition activity of the oligonucleotide, but facilitates, improves, or increases stability (e.g., provides protection against degradation) and/or delivery, uptake, and/or penetrance of the oligonucleotide to a target cell, tissue, or organ (e.g., the liver). In certain embodiments, an oligonucleotide herein comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop of linked nucleotides between S1 and S2 of up to about 10 nucleotides in length (e.g., 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides in length). In some embodiments, the loop (L) is 3 nucleotides in length. In some embodiments, the loop (L) is 4 nucleotides in length. In some embodiments, the loop (L) is 5 nucleotides in length. In some embodiments, the loop (L) is 6 nucleotides in length. In some embodiments, the loop (L) is 7 nucleotides in length. In some embodiments, the loop (L) is 8 nucleotides in length. In some embodiments, the loop (L) is 9 nucleotides in length. In some embodiments, the loop (L) is 10 nucleotides in length.

In some embodiments, the tetraloop comprises the sequence 5′-GAAA-3′. In some embodiments, the stem loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1121).

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop between S1 and S2 of up to about 10 nucleotides in length (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length). In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop between S1 and S2 of up to about 10 nucleotides in length (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length). In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop between S1 and S2 of 4 nucleotides in length.

In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop between S1 and S2 of 4 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop between S1 and S2 of 4 nucleotides in length.

In some embodiments, a loop (L) of a stem-loop having the structure S1-L-S2 as described herein is a triloop. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384 and a triloop. In some embodiments, the triloop comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, ligands (e.g., delivery ligands), and combinations thereof. In some embodiments, a loop (L) of a stem-loop having the structure S1-L-S2 as described herein is a triloop. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511 and a triloop. In some embodiments, the triloop comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, ligands (e.g., delivery ligands), and combinations thereof.

In some embodiments, a loop (L) of a stem-loop having the structure S1-L-S2 as described above is a tetraloop. In some embodiments, an oligonucleotide herein comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384 and a tetraloop. In some embodiments, the tetraloop comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, ligands (e.g., delivery ligands), and combinations thereof. In some embodiments, a loop (L) of a stem-loop having the structure S1-L-S2 as described above is a tetraloop. In some embodiments, an oligonucleotide herein comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511 and a tetraloop. In some embodiments, the tetraloop comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, ligands (e.g., delivery ligands), and combinations thereof.

Duplex Length

In some embodiments, a duplex formed between a sense and antisense strand is at least 12 (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21) nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is in the range of 12-30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12 to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to 30, or 21 to 30 nucleotides in length). In some embodiments, a duplex formed between a sense and antisense strand is 12, 13, 14, 15, 16, 17, 18, 19, 29, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 12 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 13 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 14 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 15 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 16 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 17 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 18 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 19 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 20 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 21 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 22 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 23 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 24 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 25 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 26 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 27 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 28 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 29 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 30 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand does not span the entire length of the sense strand and/or antisense strand. In some embodiments, a duplex between a sense and antisense strand spans the entire length of either the sense or antisense strands. In some embodiments, a duplex between a sense and antisense strand spans the entire length of both the sense strand and the antisense strand. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides 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,wherein a duplex formed between a sense and antisense strand is in the range of 12-30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12 to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to 30, or 21 to 30 nucleotides in length)

In some embodiments, a duplex between a sense and antisense strand spans the entire length of both the sense strand and the antisense strand. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively; and,(d) SEQ ID NOs: 813 and 901, respectively,wherein a duplex formed between a sense and antisense strand is in the range of 12-30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12 to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to 30, or 21 to 30 nucleotides in length)

Oligonucleotide Termini

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the termini of either or both strands comprise a blunt end. In some embodiments, an oligonucleotide herein comprises sense and antisense strands that are separate strands which form an asymmetric duplex region having an overhang at the 3′ terminus of the antisense strand. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the termini of either or both strands comprise an overhang comprising one or more nucleotides. In some embodiments, the one or more nucleotides comprising the overhang are unpaired nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the 3′ termini of the sense strand and the 5′ termini of the antisense strand comprise a blunt end. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the 5′ termini of the sense strand and the 3′ termini of the antisense strand comprise a blunt end.

In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the 3′ terminus of either or both strands comprise a 3′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the sense strand comprises a 3′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 3′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein both the sense strand and the antisense strand comprises a 3′-overhang comprising one or more nucleotides.

In some embodiments, the 3′-overhang is about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length). In some embodiments, the 3′-overhang is about one (1) to nineteen (19), one (1) to eighteen (18), one (1) to seventeen (17), one (1) to sixteen (16), one (1) to fifteen (15), one (1) to fourteen (14), one (1) to thirteen (13), one (1) to twelve (12), one (1) to eleven (11), one (1) to ten (10), one (1) to nine (9), one (1) to eight (8), one (1) to seven (7), one (1) to six (6), one (1) to five (5), one (1) to four (4), one (1) to three (3), or about one (1) to two (2) nucleotides in length. In some embodiments, the 3′-overhang is (1) nucleotide in length. In some embodiments, the 3′-overhang is two (2) nucleotides in length. In some embodiments, the 3′-overhang is three (3) nucleotides in length. In some embodiments, the 3′-overhang is four (4) nucleotides in length. In some embodiments, the 3′-overhang is five (5) nucleotides in length. In some embodiments, the 3′-overhang is six (6) nucleotides in length. In some embodiments, the 3′-overhang is seven (7) nucleotides in length. In some embodiments, the 3′-overhang is eight (8) nucleotides in length. In some embodiments, the 3′-overhang is nine (9) nucleotides in length. In some embodiments, the 3′-overhang is ten (10) nucleotides in length. In some embodiments, the 3′-overhang is eleven (11) nucleotides in length. In some embodiments, the 3′-overhang is twelve (12) nucleotides in length. In some embodiments, the 3′-overhang is thirteen (13) nucleotides in length. In some embodiments, the 3′-overhang is fourteen (14) nucleotides in length. In some embodiments, the 3′-overhang is fifteen (15) nucleotides in length. In some embodiments, the 3′-overhang is sixteen (16) nucleotides in length. In some embodiments, the 3′-overhang is seventeen (17) nucleotides in length. In some embodiments, the 3′-overhang is eighteen (18) nucleotides in length. In some embodiments, the 3′-overhang is nineteen (19) nucleotides in length. In some embodiments, the 3′-overhang is twenty (20) nucleotides in length.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 3′-overhang, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides 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,and wherein the antisense strand comprises a 3′-overhang about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length), optionally wherein the 3′-overhang is two (2) nucleotides in length.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 3′-overhang, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively; and,(d) SEQ ID NOs: 813 and 901, respectively,and wherein the antisense strand comprises a 3′-overhang about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length), optionally wherein the 3′-overhang is two (2) nucleotides in length.

In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the 5′ terminus of either or both strands comprise a 5′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the sense strand comprises a 5′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 5′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein both the sense strand and the antisense strand comprises a 5′-overhang comprising one or more nucleotides.

In some embodiments, the 5′-overhang is about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length). In some embodiments, the 5′-overhang is about one (1) to nineteen (19), one (1) to eighteen (18), one (1) to seventeen (17), one (1) to sixteen (16), one (1) to fifteen (15), one (1) to fourteen (14), one (1) to thirteen (13), one (1) to twelve (12), one (1) to eleven (11), one (1) to ten (10), one (1) to nine (9), one (1) to eight (8), one (1) to seven (7), one (1) to six (6), one (1) to five (5), one (1) to four (4), one (1) to three (3), or about one (1) to two (2) nucleotides in length. In some embodiments, the 5′-overhang is (1) nucleotide in length. In some embodiments, the 5′-overhang is two (2) nucleotides in length. In some embodiments, the 5′-overhang is three (3) nucleotides in length. In some embodiments, the 5′-overhang is four (4) nucleotides in length. In some embodiments, the 5′-overhang is five (5) nucleotides in length. In some embodiments, the 5′-overhang is six (6) nucleotides in length. In some embodiments, the 5′-overhang is seven (7) nucleotides in length. In some embodiments, the 5′-overhang is eight (8) nucleotides in length. In some embodiments, the 5′-overhang is nine (9) nucleotides in length. In some embodiments, the 5′-overhang is ten (10) nucleotides in length. In some embodiments, the 5′-overhang is eleven (11) nucleotides in length. In some embodiments, the 5′-overhang is twelve (12) nucleotides in length. In some embodiments, the 5′-overhang is thirteen (13) nucleotides in length. In some embodiments, the 5′-overhang is fourteen (14) nucleotides in length. In some embodiments, the 5′-overhang is fifteen (15) nucleotides in length. In some embodiments, the 5′-overhang is sixteen (16) nucleotides in length. In some embodiments, the 5′-overhang is seventeen (17) nucleotides in length. In some embodiments, the 5′-overhang is eighteen (18) nucleotides in length. In some embodiments, the 5′-overhang is nineteen (19) nucleotides in length. In some embodiments, the 5′-overhang is twenty (20) nucleotides in length.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 5′-overhang, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides 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,and wherein the antisense strand comprises a 3′-overhang about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length), optionally wherein the 3′-overhang is two (2) nucleotides in length.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 5′-overhang, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively; and,(d) SEQ ID NOs: 813 and 901, respectively,and wherein the antisense strand comprises a 5′-overhang about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length), optionally wherein the 5′-overhang is two (2) nucleotides in length.

In some embodiments, one or more (e.g., 2, 3, 4, 5, or more) nucleotides comprising the 3′ terminus or 5′ terminus of a sense and/or antisense strand are modified. For example, in some embodiments, one or two terminal nucleotides of the 3′ terminus of the antisense strand are modified. In some embodiments, the last nucleotide at the 3′ terminus of an antisense strand is modified, e.g., comprises 2′ modification, e.g., a 2′-O-methoxyethyl. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 1-7, 12-27 and 31-36 modified with 2′OMe. In some embodiments, the last one or two terminal nucleotides at the 3′ terminus of an antisense strand are complementary with the target. In some embodiments, the last one or two nucleotides at the 3′ terminus of the antisense strand are not complementary with the target.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the 3′ terminus of the sense strand comprises a stem-loop described herein (see FIG. 1A) and the 3′ terminus of the antisense strand comprises a 3′-overhang described herein. In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand that form a nicked tetraloop structure described herein (see FIG. 1A), wherein the 3′ terminus of the sense strand comprises a stem-loop, wherein the loop is a tetraloop described herein, and wherein the 3′ terminus of the antisense strand comprises a 3′-overhang described herein (see FIG. 1A). In some embodiments, the 3′-overhang is two (2) nucleotides in length. In some embodiments, the two (2) nucleotides comprising the 3′-overhang both comprise guanine (G) nucleobases. Typically, one or both of the nucleotides comprising the 3′-overhang of the antisense strand are not complementary with the target mRNA.

Oligonucleotide Modifications

In some embodiments, an oligonucleotide described herein (e.g., an RNAi oligonucleotide) comprises a modification. Oligonucleotides (e.g., RNAi oligonucleotides) may be modified in various ways to improve or control specificity, stability, delivery, bioavailability, resistance from nuclease degradation, immunogenicity, base-pairing properties, RNA distribution and cellular uptake and other features relevant to therapeutic or research use.

In some embodiments, the modification is a modified sugar. In some embodiments, the modification is a 5′-terminal phosphate group. In some embodiments, the modification is a modified internucleotide linkage. In some embodiments, the modification is a modified base. In some embodiments, an oligonucleotide described herein can comprise any one of the modifications described herein or any combination thereof. For example, in some embodiments, an oligonucleotide described herein comprises at least one modified sugar, a 5′-terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides 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,wherein the oligonucleotide comprises at least one modified sugar, a 5′-terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base.

In some embodiments, an oligonucleotide described herein comprises at least one modified sugar, a 5′-terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively; and,(d) SEQ ID NOs: 813 and 901, respectively,wherein the oligonucleotide comprises at least one modified sugar, a 5′-terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base.

The number of modifications on an oligonucleotide (e.g., an RNAi oligonucleotide) and the position of those nucleotide modifications may influence the properties of an oligonucleotide. For example, oligonucleotides may be delivered in vivo by conjugating them to or encompassing them in a lipid nanoparticle (LNP) or similar carrier. However, when an oligonucleotide is not protected by an LNP or similar carrier, it may be advantageous for at least some of the nucleotides to be modified. Accordingly, in some embodiments, all or substantially all the nucleotides of an oligonucleotide are modified. In some embodiments, more than half of the nucleotides are modified. In some embodiments, less than half of the nucleotides are modified. In some embodiments, the sugar moiety of all nucleotides comprising the oligonucleotide is modified at the 2′ position. The modifications may be reversible or irreversible. In some embodiments, an oligonucleotide as disclosed herein has a number and type of modified nucleotides sufficient to cause the desired characteristics (e.g., protection from enzymatic degradation, capacity to target a desired cell after in vivo administration, and/or thermodynamic stability).

Sugar Modifications

In some embodiments, an oligonucleotide described herein (e.g., an RNAi oligonucleotide) comprises a modified sugar. In some embodiments, a modified sugar (also referred herein to a sugar analog) includes a modified deoxyribose or ribose moiety in which, for example, one or more modifications occur at the 2′, 3′, 4′ and/or 5′ carbon position of the sugar. In some embodiments, a modified sugar may also include non-natural alternative carbon structures such as those present in locked nucleic acids (“LNA”; see, e.g., Koshkin et al. TETRAHEDON (1998); 54: 3607-30), unlocked nucleic acids (“UNA”; see, e.g., Snead et al. MOL. THER-NUCL. ACIDS (2013); 2: e103) and bridged nucleic acids (“BNA”; see, e.g., Imanishi & Obika CHEM. COMMUN. (CAMB) (2002); 21: 1653-59).

In some embodiments, a nucleotide modification in a sugar comprises a 2′-modification. In some embodiments, a 2′-modification may be 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-fluoro (2′-F), 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA) or 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA). In some embodiments, the modification is 2′-F, 2′-OMe or 2′-MOE. In some embodiments, a modification in a sugar comprises a modification of the sugar ring, which may comprise modification of one or more carbons of the sugar ring. For example, a modification of a sugar of a nucleotide may comprise a 2′-oxygen of a sugar is linked to a 1′-carbon or 4′-carbon of the sugar, or a 2′-oxygen is linked to the 1′-carbon or 4′-carbon via an ethylene or methylene bridge. In some embodiments, a modified nucleotide has an acyclic sugar that lacks a 2′-carbon to 3′-carbon bond. In some embodiments, a modified nucleotide has a thiol group, e.g., in the 4′ position of the sugar.

In some embodiments, an oligonucleotide (e.g., an RNAi oligonucleotide) described herein comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, or more). In some embodiments, the sense strand of the oligonucleotide comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, or more). In some embodiments, the antisense strand of the oligonucleotide comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, or more).

In some embodiments, all the nucleotides of the sense strand of the oligonucleotide are modified. In some embodiments, all the nucleotides of the antisense strand of the oligonucleotide are modified. In some embodiments, all the nucleotides of the oligonucleotide (i.e., both the sense strand and the antisense strand) are modified. In some embodiments, the modified nucleotide comprises a 2′-modification (e.g., a 2′-F or 2′-OMe, 2′-MOE, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid).

In some embodiments, the disclosure provides oligonucleotides having different modification patterns. In some embodiments, an oligonucleotide herein comprises a sense strand having a modification pattern as set forth in the Examples and Sequence Listing and an antisense strand having a modification pattern as set forth in the Examples and Sequence Listing.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises an antisense strand having nucleotides that are modified with 2′-F. In some embodiments, an oligonucleotide herein comprises an antisense strand comprising nucleotides that are modified with 2′-F and 2′-OMe. In some embodiments, an oligonucleotide disclosed herein comprises a sense strand having nucleotides that are modified with 2′-F. In some embodiments, an oligonucleotide disclosed herein comprises a sense strand comprises nucleotides that are modified with 2′-F and 2′-OMe.

In some embodiments, an oligonucleotide described herein comprises a sense strand with about 10-15%, 10%, 11%, 12%, 13%, 14%, or 15% of the nucleotides of the sense strand comprising a 2′-fluoro modification. In some embodiments, about 11% of the nucleotides of the sense strand comprise a 2-fluoro modification. In some embodiments, an oligonucleotide described herein comprises an antisense strand with about 25-35%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the antisense strand comprising a 2′-fluoro modification. In some embodiments, about 32% of the nucleotides of the antisense strand comprise a 2′-fluoro modification. In some embodiments, the oligonucleotide has about 15-25%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of its nucleotides comprising a 2′-fluoro modification. In some embodiments, about 19% of the nucleotides in the dsRNAi oligonucleotide comprise a 2′-fluoro modification.

In some embodiments, one or more of positions 8, 9, 10, or 11 of the sense strand is modified with a 2′—F group. In some embodiments, one or more of positions 3, 8, 9, 10, 12, 13, and 17 of the sense strand is modified with a 2′—F group. In some embodiments, one or more of positions 2, 3, 4, 5, 7, 10, and 14 of the antisense strand is modified with a 2′—F group. In some embodiments, one or more of positions 2, 3, 4, 5, 7, 8, 10, 14, 16, and 19 is modified with a 2′—F group. In some embodiments, the sugar moiety at each of nucleotides at positions 1-7 and 12-20 in the sense strand is modified with a 2′-OMe. In some embodiments, the sugar moiety at each of nucleotides at positions 1-7, 12-27, and 31-36 in the sense strand is modified with a 2′-OMe. In some embodiments, the sugar moiety at each of nucleotides at positions 6, 9, 11-13, 15, 17, 18, and 20-22 in the sense strand is modified with a 2′-OMe.

In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides 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,wherein one or more of positions 8, 9, 10 or 11 of the sense strand is modified with a 2′—F group.

In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively, and;(d) SEQ ID NOs: 813 and 901, respectively,wherein one or more of positions 8, 9, 10, or 11 of the sense strand is modified with a 2′—F group.

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 5, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 1, 2, 5, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 4, 5, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 1, 2, 3, 5, 7, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 1, 2, 3, 5, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 5, 7, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, 8, 10, 14, 16, and 19 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with 2′-F.

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with 2′-OMe.

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 8-11 modified with 2′-F. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 3, 8, 9, 10, 12, 13 and 17 modified with 2′-F. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 1-7 and 12-17 or 12-20 modified with 2′OMe. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety of each of the nucleotides at positions 1-7 and 12-17 or 12-20 of the sense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA). In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 1-2, 4-7, 11, 14-16, and 18-20 modified with 2′OMe. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety of each of the nucleotides at positions 1-2, 4-7, 11, 14-16, and 18-20 of the sense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with 2′-F. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with 2′-OMe.

In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

5′-Terminal Phosphate

In some embodiments, an oligonucleotide described herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 5′-terminal phosphate. In some embodiments, 5′-terminal phosphate groups of an RNAi oligonucleotide enhance the interaction with Ago2. However, oligonucleotides comprising a 5′-phosphate group may be susceptible to degradation via phosphatases or other enzymes, which can limit their performance and/or bioavailability in vivo. In some embodiments, an oligonucleotide herein includes analogs of 5′ phosphates that are resistant to such degradation. In some embodiments, the phosphate analog is oxymethylphosphonate, vinylphosphonate or malonylphosphonate, or a combination thereof. In certain embodiments, the 5′ terminus of an oligonucleotide strand is attached to chemical moiety that mimics the electrostatic and steric properties of a natural 5′-phosphate group (“phosphate mimic”). In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides 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,wherein the oligonucleotide comprises a 5′-terminal phosphate, optionally a 5′-terminal phosphate analog.

In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively; and,(d) SEQ ID NOs: 813 and 901, respectively,wherein the oligonucleotide comprises a 5′-terminal phosphate, optionally a 5′-terminal phosphate analog.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) has a phosphate analog at a 4′-carbon position of the sugar (referred to as a “4′-phosphate analog”). See, e.g., Intl. Patent Application Publication No. WO 2018/045317. In some embodiments, an oligonucleotide herein comprises a 4′-phosphate analog at a 5′-terminal nucleotide. In some embodiments, a phosphate analog is an oxymethylphosphonate, in which the oxygen atom of the oxymethyl group is bound to the sugar moiety (e.g., at its 4′-carbon) or analog thereof. In other embodiments, a 4′-phosphate analog is a thiomethylphosphonate or an aminomethylphosphonate, in which the sulfur atom of the thiomethyl group or the nitrogen atom of the amino methyl group is bound to the 4′-carbon of the sugar moiety or analog thereof. In certain embodiments, a 4′-phosphate analog is an oxymethylphosphonate. In some embodiments, an oxymethylphosphonate is represented by the formula —O—CH₂—PO(OH)₂, —O—CH₂—PO(OR)₂, or —O—CH₂—PO(OH)(R), in which R is independently selected from —H, —CH₃, an alkyl group, —CH₂CH₂CN, —CH₂OCOC(CH₃)₃, —CH₂OCH₂CH₂Si(CH₃)₃ or a protecting group. In certain embodiments, the alkyl group is —CH₂CH₃. More typically, R is independently selected from H, —CH₃ or —CH₂CH₃. In some embodiment, R is —CH₃. In some embodiments, the 4′-phosphate analog is 5′-methoxyphosphonate-4′-oxy.

In some embodiments, an oligonucleotide provided herein comprises an antisense strand comprising a 4′-phosphate analog at the 5′-terminal nucleotide, wherein 5′-terminal nucleotide comprises the following structure (Chem. formula 1).

5′-methoxyphosphonate-4′-oxy-2′-O-methyluridine phosphorothioate [MePhosphonate-40-mUs]

Modified Internucleotide Linkage

In some embodiments, an oligonucleotide provided herein (e.g., a RNAi oligonucleotide) comprises a modified internucleotide linkage. In some embodiments, phosphate modifications or substitutions result in an oligonucleotide that comprises at least about 1 (e.g., at least 1, at least 2, at least 3, or at least 5) modified internucleotide linkage. In some embodiments, any one of the oligonucleotides disclosed herein comprises about 1 to about 10 (e.g., 1 to 10, 2 to 8, 4 to 6, 3 to 10, 5 to 10, 1 to 5, 1 to 3, or 1 to 2) modified internucleotide linkages. In some embodiments, any one of the oligonucleotides disclosed herein comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 modified internucleotide linkages.

A modified internucleotide linkage may be a phosphorodithioate linkage, a phosphorothioate linkage, a phosphotriester linkage, a thionoalkylphosphonate linkage, a thionalkylphosphotriester linkage, a phosphoramidite linkage, a phosphonate linkage or a boranophosphate linkage. In some embodiments, at least one modified internucleotide linkage of any one of the oligonucleotides as disclosed herein is a phosphorothioate linkage.

In some embodiments, an oligonucleotide provided herein (e.g., a RNAi oligonucleotide) has a phosphorothioate linkage between one or more of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 3 and 4 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the oligonucleotide described herein has a phosphorothioate linkage between each of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides 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,wherein the oligonucleotide comprises a modified internucleotide linkage.

In some embodiments, the oligonucleotide described herein has a phosphorothioate linkage between each of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively, and;(d) SEQ ID NOs: 813 and 901, respectively,wherein the oligonucleotide comprises a modified internucleotide linkage.

Base Modifications

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotides) comprises one or more modified nucleobases. In some embodiments, modified nucleobases (also referred to herein as base analogs) are linked at the 1′ position of a nucleotide sugar moiety. In certain embodiments, a modified nucleobase is a nitrogenous base. In some embodiments, a modified nucleobase does not contain nitrogen atom. See, e.g., US Patent Application Publication No. 2008/0274462. In some embodiments, a modified nucleotide comprises a universal base. In some embodiments, a modified nucleotide does not contain a nucleobase (abasic). In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides 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,wherein the oligonucleotide comprises one or more modified nucleobases.

In some embodiments, a modified nucleotide comprises a universal base. In some embodiments, a modified nucleotide does not contain a nucleobase (abasic). In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively; and,(d) SEQ ID NOs: 813 and 901, respectively,wherein the oligonucleotide comprises one or more modified nucleobases.

In some embodiments, a universal base is a heterocyclic moiety located at the 1′ position of a nucleotide sugar moiety in a modified nucleotide, or the equivalent position in a nucleotide sugar moiety substitution, that, when present in a duplex, can be positioned opposite more than one type of base without substantially altering structure of the duplex. In some embodiments, compared to a reference single-stranded nucleic acid (e.g., oligonucleotide) that is fully complementary to a target nucleic acid (e.g., a NR1H3 mRNA), a single-stranded nucleic acid containing a universal base forms a duplex with the target nucleic acid that has a lower T_m than a duplex formed with the complementary nucleic acid. In some embodiments, when compared to a reference single-stranded nucleic acid in which the universal base has been replaced with a base to generate a single mismatch, the single-stranded nucleic acid containing the universal base forms a duplex with the target nucleic acid that has a higher T_m than a duplex formed with the nucleic acid comprising the mismatched base.

Non-limiting examples of universal-binding nucleotides include, but are not limited to, inosine, 1-β-D-ribofuranosyl-5-nitroindole and/or 1-β-D-ribofuranosyl-3-nitropyrrole (see, US Patent Application Publication No. 2007/0254362; Van Aerschot et al. NUCLEIC ACIDS RES. (1995); 23: 4363-4370; Loakes et al. NUCLEIC ACIDS RES. (1995); 23: 2361-66; and Loakes & Brown NUCLEIC ACIDS RES. (1994); 22: 4039-43).

Targeting Ligands

In some embodiments, it is desirable to target an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) to one or more cells or cell type, tissues, organs, or anatomical regions or compartments. Such a strategy may help to avoid undesirable effects and/or to avoid undue loss of the oligonucleotide to cells, tissues, organs, or anatomical regions or compartments that would not benefit from the oligonucleotide or its effects (e.g., inhibition or reduction of NR1H3 expression). Accordingly, in some embodiments, oligonucleotides disclosed herein (e.g., RNAi oligonucleotides) are modified to facilitate targeting and/or delivery to particular cells or cell types, tissues, organs, or anatomical regions or compartments (e.g., to facilitate delivery of the oligonucleotide to the liver). In some embodiments, an oligonucleotide comprises at least one nucleotide (e.g., 1, 2, 3, 4, 5, 6, or more nucleotides) conjugated to one or more targeting ligand(s). In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides 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,wherein the oligonucleotide comprises a targeting ligand conjugated to at least one nucleotide.

In some embodiments, an oligonucleotide comprises at least one nucleotide (e.g., 1, 2, 3, 4, 5, 6, or more nucleotides) conjugated to one or more targeting ligand(s). In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively, and;(d) SEQ ID NOs: 813 and 901, respectively,wherein the oligonucleotide comprises a targeting ligand conjugated to at least one nucleotide.

In some embodiments, the targeting ligand comprises a carbohydrate, amino sugar, cholesterol, peptide, polypeptide, protein, or part of a protein (e.g., an antibody or antibody fragment), or lipid. In certain embodiments, the targeting ligand is a carbohydrate comprising at least one GalNAc moiety.

In some embodiments, 1 or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides of an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) are each conjugated to a separate targeting ligand (e.g., a GalNAc moiety). In some embodiments, 2 to 4 nucleotides of an oligonucleotide are each conjugated to a separate targeting ligand. In some embodiments, targeting ligands are conjugated to 2 to 4 nucleotides at either ends of the sense or antisense strand (e.g., targeting ligands are conjugated to a 2 to 4 nucleotide overhang or extension on the 5′ or 3′ terminus of the sense or antisense strand) such that the targeting ligands resemble bristles of a toothbrush and the oligonucleotide resembles a toothbrush. For example, an oligonucleotide may comprise a stem-loop at either the 5′ or 3′ terminus of the sense strand and 1, 2, 3, or 4 nucleotides of the loop of the stem may be individually conjugated to a targeting ligand. In some embodiments, an oligonucleotide provided by the disclosure (e.g., a RNAi oligonucleotide) comprises a stem-loop at the 3′ terminus of the sense strand, wherein the loop of the stem-loop comprises a triloop or a tetraloop, and wherein the 3 or 4 nucleotides comprising the triloop or tetraloop, respectively, are individually conjugated to a targeting ligand. In some embodiments, an oligonucleotide provided by the disclosure (e.g., a RNAi oligonucleotide) comprises a stem-loop at the 3′ terminus of the sense strand, wherein the loop of the stem-loop comprises a tetraloop, and wherein 3 nucleotides of the tetraloop are individually conjugated to a targeting ligand.

GalNAc is a high affinity carbohydrate ligand for the asialoglycoprotein receptor (ASGPR), which is primarily expressed on the surface of hepatocyte cells and has a major role in binding, internalizing and subsequent clearing circulating glycoproteins that contain terminal galactose or GalNAc residues (asialoglycoproteins). Conjugation (either indirect or direct) of GalNAc moieties to oligonucleotides of the instant disclosure can be used to target these oligonucleotides to the ASGPR expressed on cells. In some embodiments, an oligonucleotide of the instant disclosure (e.g., an RNAi oligonucleotide) is conjugated to at least one or more GalNAc moieties, wherein the GalNAc moieties target the oligonucleotide to an ASGPR expressed on human liver cells (e.g., human hepatocytes). In some embodiments, the GalNAc moiety target the oligonucleotide to the liver.

In some embodiments, an oligonucleotide of the instant disclosure (e.g., an RNAi oligonucleotide) is conjugated directly or indirectly to a monovalent GalNAc moiety. In some embodiments, the oligonucleotide is conjugated directly or indirectly to more than one monovalent GalNAc (i.e., is conjugated to 2, 3, or 4 monovalent GalNAc moieties and is typically conjugated to 3 or 4 monovalent GalNAc moieties). In some embodiments, an oligonucleotide is conjugated to one or more bivalent GalNAc, trivalent GalNAc or tetravalent GalNAc moieties. In some embodiments, a bivalent, trivalent or tetravalent GalNAc moiety is conjugated to an oligonucleotide via a branched linker. In some embodiments, a monovalent GalNAc moiety is conjugated to a first nucleotide and a bivalent, trivalent, or tetravalent GalNAc moiety is conjugated to a second nucleotide via a branched linker.

In some embodiments, one (1) or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides of an oligonucleotide described herein (e.g., an RNAi oligonucleotide) are each conjugated to a GalNAc moiety. In some embodiments, two (2) to four (4) nucleotides of a tetraloop are each conjugated to a separate GalNAc moiety. In some embodiments, one (1) to three (3) nucleotides of a triloop are each conjugated to a separate GalNAc moiety. In some embodiments, targeting ligands are conjugated to two (2) to four (4) nucleotides at either ends of the sense or antisense strand (e.g., ligands are conjugated to a two (2) to four (4) nucleotide overhang or extension on the 5′ or 3′ terminus of the sense or antisense strand) such that the GalNAc moieties resemble bristles of a toothbrush and the oligonucleotide resembles a toothbrush. In some embodiments, GalNAc moieties are conjugated to a nucleotide of the sense strand. For example, three (3) or four (4) GalNAc moieties can be conjugated to nucleotides in the tetraloop of the sense strand where each GalNAc moiety is conjugated to one (1) nucleotide.

In some embodiments, an oligonucleotide described herein (e.g., an RNAi oligonucleotide) comprises a tetraloop, wherein the tetraloop (L) is any combination of adenine (A) and guanine (G) nucleotides. In some embodiments, the tetraloop (L) comprises a monovalent GalNAc moiety attached to any one or more guanine (G) nucleotides of the tetraloop via any linker described herein, as depicted below (X=heteroatom) in Chem. formula 2:

In some embodiments, the tetraloop (L) has a monovalent GalNAc attached to any one or more adenine nucleotides of the tetraloop via any linker described herein, as depicted below (X=heteroatom) in Chem. formula 3:

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a monovalent GalNAc moiety attached to a guanine (G) nucleotide referred to as [ademG-GalNAc] or 2′-aminodiethoxymethanol-Guanine-GalNAc, as depicted below in Chem. formula 4:

In some embodiments, an oligonucleotide herein comprises a monovalent GalNAc moiety attached to an adenine nucleotide, referred to as [ademA-GalNAc] or 2′-aminodiethoxymethanol-Adenine-GalNAc, as depicted below Chem. formula 5:

An example of such conjugation is shown below for a loop comprising from 5′ to 3′ the nucleotide sequence GAAA (L=linker, X=heteroatom). Such a loop may be present, for example, at positions 27-30 of a sense strand provided herein. In the Chem. formula 6 is used to describe an attachment point to the oligonucleotide strand.

Appropriate methods or chemistry (e.g., click chemistry) can be used to link a targeting ligand to a nucleotide. In some embodiments, a targeting ligand is conjugated to a nucleotide comprising an oligonucleotide herein (e.g., an RNAi oligonucleotide) using a click linker. In some embodiments, an acetal-based linker is used to conjugate a targeting ligand to a nucleotide of any one of the oligonucleotides described herein. Acetal-based linkers are disclosed, for example, in Intl. Patent Application Publication No. WO2016/100401. In some embodiments, the linker is a labile linker. However, in other embodiments, the linker is stable. An example is shown below for a loop comprising from 5′ to 3′ the nucleotides GAAA, in which GalNAc moieties are attached to nucleotides of the loop using an acetal linker. Such a loop may be present, for example, at positions 27-30 of the any one of the sense strands. In the Chem. formula 7 is an attachment point to the oligonucleotide strand.

As mentioned, various appropriate methods or chemistry synthetic techniques (e.g., click chemistry) can be used to link a targeting ligand to a nucleotide. In some embodiments, a targeting ligand is conjugated to a nucleotide using a click linker. In some embodiments, an acetal-based linker is used to conjugate a targeting ligand to a nucleotide of any one of the oligonucleotides described herein. Acetal-based linkers are disclosed, for example, in Intl. Patent Application Publication No. WO 2016/100401. In some embodiments, the linker is a labile linker. However, in other embodiments, the linker is a stable linker.

In some embodiments, a duplex extension (e.g., of up to 3, 4, 5, or 6 bp in length) is provided between a targeting ligand (e.g., a GalNAc moiety) and the oligonucleotide. In some embodiments, the oligonucleotides herein (e.g., RNAi oligonucleotides) do not have a GalNAc conjugated thereto.

In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides 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,wherein the oligonucleotide comprises at least one GalNAc moiety conjugated to a nucleotide.

In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively; and,(d) SEQ ID NOs: 813 and 901, respectively,wherein the oligonucleotide comprises at least one GalNAc moiety conjugated to a nucleotide.

Exemplary Oligonucleotides for Reducing NR1H3 Expression

In some embodiments, the NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression provided by the disclosure comprise a sense strand and an antisense strand, wherein all nucleotides comprising the sense strand and antisense strand are modified, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length. In some embodiments, the 5′-terminal nucleotide of the antisense strand comprises 5′-methoxyphosphonate-4′-oxy-2′-O-methyluridine [MePhosphonate-4O-mU], as described herein. In some embodiments, the 5′-terminal nucleotide of the antisense strand comprises a phosphorothioate linkage. In some embodiments, the antisense strand and the sense strand comprise one or more 2′-fluoro (2′-F) and 2′-O-methyl (2′-OMe) modified nucleotides and at least one phosphorothioate linkage. In some embodiments, the antisense strand comprises four (4) phosphorothioate linkages and the sense strand comprises one (1) phosphorothioate linkage. In some embodiments, the antisense strand comprises five (5) phosphorothioate linkages and the sense strand comprises one (1) phosphorothioate linkage.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand having a sequence of any one of SEQ ID NOs: 1-384 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 385-768.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand having a sequence of any one of SEQ ID NOs: 769-856 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 857-944.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand having a sequence of any one of SEQ ID NOs: 1519-1552 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 857-944.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand having a sequence of any one of SEQ ID NOs: 945-1032 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 1033-1120.

In some embodiments, an oligonucleotide provided herein (e.g., and RNAi oligonucleotide) for reducing NR1H3 expression comprises:

a sense strand comprising a 2′-F modified nucleotide at positions 8-11, a 2′-OMe modified nucleotide at positions 1-7, 12-27, and 31-36, a GalNAc-conjugated nucleotide at position 28, 29 and 30; and a phosphorothioate linkage between positions 1 and 2;

an antisense strand comprising a 2′-F modified nucleotide at positions 2, 3, 4, 5, 7, 10 and 14, a 2′-OMe at positions 1, 6, 8, 9, 11-13, and 15-22, a phosphorothioate linkage between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 20 and 21, and positions 21 and 22, and a 5′-terminal nucleotide at position 1 comprising a 4′-phosphate analog, optionally wherein the 5′-terminal nucleotide comprises 5′-methoxyphosphonate-4′-oxy-2′-O-methyluridine [MePhosphonate-4O-mU]; wherein positions 1-20 of the antisense strand form a duplex region with positions 1-20 of the sense strand, wherein positions 21-36 of the sense strand form a stem-loop, wherein positions 27-30 form the loop of the stem-loop, optionally wherein positions 27-30 comprise a tetraloop, wherein positions 21 and 22 of the antisense strand comprise an overhang, and 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,

In some embodiments, the NR1H3-targeting dsRNAi oligonucleotides for reducing NR1H3 expression comprise:

a sense strand comprising a 2′-F modified nucleotide at positions 8-11, a 2′-OMe modified nucleotide at positions 1-7, 12-27, and 31-36, a GalNAc-conjugated nucleotide at position 28, 29 and 30; and a phosphorothioate linkage between positions 1 and 2;

an antisense strand comprising a 2′-F modified nucleotide at positions 2, 3, 4, 5, 7, 10 and 14, a 2′-OMe at positions 1, 6, 8, 9, 11-13, and 15-22, a phosphorothioate linkage between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 20 and 21, and positions 21 and 22, and a 5′-terminal nucleotide at position 1 comprising a 4′-phosphate analog, optionally wherein the 5′-terminal nucleotide comprises 5′-methoxyphosphonate-4′-oxy-2′-O-methyluridine [MePhosphonate-4O-mU]; wherein positions 1-20 of the antisense strand form a duplex region with positions 1-20 of the sense strand, wherein positions 21-36 of the sense strand form a stem-loop, wherein positions 27-30 form the loop of the stem-loop, optionally wherein positions 27-30 comprise a tetraloop, wherein positions 21 and 22 of the antisense strand comprise an overhang, and wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively;(b) SEQ ID NOs: 787 and 875, respectively;(c) SEQ ID NOs: 1537 and 929, respectively; and,(d) SEQ ID NOs: 813 and 901, respectively.

In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 786 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 874. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 787 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 875. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1537 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 929. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 813 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 901.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1512; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1513; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1515; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1512; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1513; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1515; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1512; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1509, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1513; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1510, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1409, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1515; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1511, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1512; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1509, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1513; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1510, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1409, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1515; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1511, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, the disclosure provides an oligonucleotide (e.g., an RNAi oligonucleotide) for reducing NR1H3 expression, wherein the oligonucleotide comprises a sense strand and an antisense strand according to:

Sense Strand: 5′-mX-S-mX-mX-mX-mX-mX-mX-fX-fX-fX-fX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mX-mX-mX-mX-mX-mX-3′;hybridized to:

Antisense Strand: 5′-[MePhosphonate-40-mX]-S-fX-S-fX-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-mX-mX-mX-mX-mX-S-mX-S-mX-3′;

wherein mX=2′-O-methyl modified nucleotide, fX=2′-fluoro modified nucleotide, -S-=phosphorothioate linkage, -=phosphodiester linkage, [MePhosphonate-40-mX]=5′-methoxyphosphonate-4-oxy modified nucleotide, and ademA-GalNAc=GalNAc attached to an adenine nucleotide.

In some embodiments, the disclosure provides an oligonucleotide (e.g., an RNAi oligonucleotide) for reducing NR1H3 expression, wherein the oligonucleotide comprises a sense strand and an antisense strand according to:

Sense Strand: 5′-mX-S-mX-mX-mX-mX-mX-mX-fX-fX-fX-fX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mX-mX-mX-mX-mX-mX-3′;hybridized to:

Antisense Strand: 5′-[MePhosphonate-40-mX]-S-fX-S-fX-S-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-mX-mX-mX-mX-mX-S-mX-S-mX-3′;

wherein mX=2′-O-methyl modified nucleotide, fX=2′-fluoro modified nucleotide, -S-=phosphorothioate linkage, -=phosphodiester linkage, [MePhosphonate-40-mX]=5′-methoxyphosphonate-4-oxy modified nucleotide, and ademA-GalNAc=GalNAc attached to an adenine nucleotide.

In some embodiments, the disclosure provides an oligonucleotide (e.g., an RNAi oligonucleotide) for reducing NR1H3 expression, wherein the oligonucleotide comprises a sense strand and an antisense strand comprising 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.

In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 963 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1051. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 964 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1052. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1006 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1094. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1018 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1106.

Formulations

Various formulations (e.g., pharmaceutical formulations) have been developed for oligonucleotide use. For example, oligonucleotides (e.g., RNAi oligonucleotides) can be delivered to a subject or a cellular environment using a formulation that minimizes degradation, facilitates delivery and/or uptake, or provides another beneficial property to the oligonucleotides in the formulation. In some embodiments, provided herein are compositions comprising oligonucleotides (e.g., RNAi oligonucleotides) reduce the expression of NR1H3. Such compositions can be suitably formulated such that when administered to a subject, either into the immediate environment of a target cell or systemically, a sufficient portion of the oligonucleotides enter the cell to reduce NR1H3 expression. Any variety of suitable oligonucleotide formulations can be used to deliver oligonucleotides for the reduction of NR1H3 as disclosed herein. In some embodiments, an oligonucleotide is formulated in buffer solutions such as phosphate buffered saline solutions, liposomes, micellar structures, and capsids. Any of the oligonucleotides described herein may be provided not only as nucleic acids, but also in the form of a pharmaceutically acceptable salt.

Formulations of oligonucleotides with cationic lipids can be used to facilitate transfection of the oligonucleotides into cells. For example, cationic lipids, such as lipofectin, cationic glycerol derivatives, and polycationic molecules (e.g., polylysine), can be used. Suitable lipids include Oligofectamine, Lipofectamine (Life Technologies), NC388 (Ribozyme Pharmaceuticals, Inc., Boulder, Colo.), or FuGene 6 (Roche) all of which can be used according to the manufacturer's instructions.

Accordingly, in some embodiments, a formulation comprises a lipid nanoparticle. In some embodiments, an excipient comprises a liposome, a lipid, a lipid complex, a microsphere, a microparticle, a nanosphere or a nanoparticle, or may be otherwise formulated for administration to the cells, tissues, organs, or body of a subject in need thereof (see, e.g., Remington: THE SCIENCE AND PRACTICE OF PHARMACY, 22nd edition, Pharmaceutical Press, 2013).

In some embodiments, the formulations herein comprise an excipient. In some embodiments, an excipient confers to a composition improved stability, improved absorption, improved solubility and/or therapeutic enhancement of the active ingredient. In some embodiments, an excipient is a buffering agent (e.g., sodium citrate, sodium phosphate, a tris base, or sodium hydroxide) or a vehicle (e.g., a buffered solution, petrolatum, dimethyl sulfoxide, or mineral oil). In some embodiments, an oligonucleotide is lyophilized for extending its shelf-life and then made into a solution before use (e.g., administration to a subject). Accordingly, an excipient in a composition comprising any one of the oligonucleotides described herein may be a lyoprotectant (e.g., mannitol, lactose, polyethylene glycol or polyvinylpyrrolidone) or a collapse temperature modifier (e.g., dextran, Ficoll™ or gelatin).

In some embodiments, a pharmaceutical composition is formulated to be compatible with its intended route of administration. The route of administration may be any route which effectively transports a compound of this invention to the desired or appropriate place in the body. Examples of routes of administration include parenteral (e.g., intravenous, intramuscular, intraperitoneal, intradermal, subcutaneous), oral (e.g., inhalation), transdermal (e.g., topical), transmucosal and rectal administration.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Sterile injectable solutions can be prepared by incorporating the oligonucleotides in a required amount in a selected solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.

In some embodiments, a composition may contain at least about 0.1% of the therapeutic agent (e.g., a RNAi oligonucleotide for reducing NR1H3 expression) or more, although the percentage of the active ingredient(s) may be between about 1% to about 80% or more of the weight or volume of the total composition. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable.

Methods of Use

Reducing NR1H3 Expression

In some embodiments, the disclosure provides methods for contacting or delivering to a cell or population of cells an effective amount of oligonucleotides provided herein (e.g., RNAi oligonucleotides) to reduce NR1H3 expression. In some embodiments, a reduction of NR1H3 expression is determined by measuring a reduction in the amount or level of NR1H3 mRNA, NR1H3 protein, or NR1H3 activity in a cell. The methods include those described herein and known to one of ordinary skill in the art.

Methods provided herein are useful in any appropriate cell type. In some embodiments, a cell is any cell that expresses NR1H3 mRNA (e.g., hepatocytes). In some embodiments, the cell is a primary cell obtained from a subject. In some embodiments, the primary cell has undergone a limited number of passages such that the cell substantially maintains its natural phenotypic properties. In some embodiments, a cell to which the oligonucleotide is delivered is ex vivo or in vitro (i.e., can be delivered to a cell in culture or to an organism in which the cell resides).

In some embodiments, the oligonucleotides herein (e.g., RNAi oligonucleotides) are delivered to a cell or population of cells using a nucleic acid delivery method known in the art including, but not limited to, injection of a solution containing the oligonucleotides, bombardment by particles covered by the oligonucleotides, exposing the cell or population of cells to a solution containing the oligonucleotides, or electroporation of cell membranes in the presence of the oligonucleotides. Other methods known in the art for delivering oligonucleotides to cells may be used, such as lipid-mediated carrier transport, chemical-mediated transport, and cationic liposome transfection such as calcium phosphate, and others.

In some embodiments, reduction of NR1H3 expression is determined by an assay or technique that evaluates one or more molecules, properties, or characteristics of a cell or population of cells associated with NR1H3 expression, or by an assay or technique that evaluates molecules that are directly indicative of NR1H3 expression in a cell or population of cells (e.g., NR1H3 mRNA or NR1H3 protein). In some embodiments, the extent to which an oligonucleotide provided herein reduces NR1H3 expression is evaluated by comparing NR1H3 expression in a cell or population of cells contacted with the oligonucleotide to an appropriate control (e.g., an appropriate cell or population of cells not contacted with the oligonucleotide or contacted with a control oligonucleotide). In some embodiments, a control amount or level of NR1H3 expression in a control cell or population of cells is predetermined, such that the control amount or level need not be measured in every instance the assay or technique is performed. The predetermined level or value can take a variety of forms. In some embodiments, a predetermined level or value can be single cut-off value, such as a median or mean.

In some embodiments, contacting or delivering an oligonucleotide described herein (e.g., an RNAi oligonucleotide) to a cell or a population of cells results in a reduction in NR1H3 expression in a cell or population of cells not contacted with the oligonucleotide or contacted with a control oligonucleotide. In some embodiments, the reduction in NR1H3 expression is about 1% or lower, about 5% or lower, about 10% or lower, about 15% or lower, about 20% or lower, about 25% or lower, about 30% or lower, about 35% or lower, about 40% or lower, about 45% or lower, about 50% or lower, about 55% or lower, about 60% or lower, about 70% or lower, about 80% or lower, or about 90% or lower relative to a control amount or level of NR1H3 expression. In some embodiments, the control amount or level of NR1H3 expression is an amount or level of NR1H3 mRNA and/or NR1H3 protein in a cell or population of cells that has not been contacted with an oligonucleotide herein. In some embodiments, the effect of delivery of an oligonucleotide herein to a cell or population of cells according to a method herein is assessed after any finite period or amount of time (e.g., minutes, hours, days, weeks, months). For example, in some embodiments, NR1H3 expression is determined in a cell or population of cells at least about 4 hours, about 8 hours, about 12 hours, about 18 hours, about 24 hours; or at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, about 56 days, about 63 days, about 70 days, about 77 days, or about 84 days or more after contacting or delivering the oligonucleotide to the cell or population of cells. In some embodiments, NR1H3 expression is determined in a cell or population of cells at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months or more after contacting or delivering the oligonucleotide to the cell or population of cells.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) is delivered in the form of a transgene that is engineered to express in a cell the oligonucleotide or strands comprising the oligonucleotide (e.g., its sense and antisense strands). In some embodiments, an oligonucleotide herein is delivered using a transgene engineered to express any oligonucleotide disclosed herein. Transgenes may be delivered using viral vectors (e.g., adenovirus, retrovirus, vaccinia virus, poxvirus, adeno-associated virus, or herpes simplex virus) or non-viral vectors (e.g., plasmids or synthetic mRNAs). In some embodiments, transgenes can be injected directly to a subject.

Treatment Methods

The disclosure provides oligonucleotides (e.g., RNAi oligonucleotides) for use as a medicament, in particular for use in a method for the treatment of diseases, disorders, and conditions associated with expression of NR1H3. The disclosure also provides oligonucleotides for use, or adaptable for use, to treat a subject (e.g., a human having a disease, disorder or condition associated with NR1H3 expression) that would benefit from reducing NR1H3 expression. In some respects, the disclosure provides oligonucleotides for use, or adapted for use, to treat a subject having a disease, disorder or condition associated with expression of NR1H3. The disclosure also provides oligonucleotides for use, or adaptable for use, in the manufacture of a medicament or pharmaceutical composition for treating a disease, disorder or condition associated with NR1H3 expression. In some embodiments, the oligonucleotides for use, or adaptable for use, target NR1H3 mRNA and reduce NR1H3 expression (e.g., via the RNAi pathway). In some embodiments, the oligonucleotides for use, or adaptable for use, target NR1H3 mRNA and reduce the amount or level of NR1H3 mRNA, NR1H3 protein and/or NR1H3 activity.

In addition, in some embodiments of the methods herein, a subject having a disease, disorder, or condition associated with NR1H3 expression or is predisposed to the same is selected for treatment with an oligonucleotide provided herein (e.g., an RNAi oligonucleotide). In some embodiments, the method comprises selecting an individual having a marker (e.g., a biomarker) for a disease, disorder, or condition associated with NR1H3 expression or predisposed to the same, such as, but not limited to, NR1H3 mRNA, NR1H3 protein, or a combination thereof. Likewise, and as detailed below, some embodiments of the methods provided by the disclosure include steps such as measuring or obtaining a baseline value for a marker of NR1H3 expression (e.g., NR1H3 mRNA), and then comparing such obtained value to one or more other baseline values or values obtained after the subject is administered the oligonucleotide to assess the effectiveness of treatment.

The disclosure also provides methods of treating a subject having, suspected of having, or at risk of developing a disease, disorder or condition associated with a NR1H3 expression with an oligonucleotide provided herein. In some respects, the current disclosure provides methods of treating or attenuating the onset or progression of a disease, disorder or condition associated with NR1H3 expression using the oligonucleotides herein. In other aspects, the disclosure provides methods to achieve one or more therapeutic benefits in a subject having a disease, disorder, or condition associated with NR1H3 expression using the oligonucleotides provided herein. In some embodiments of the methods herein, the subject is treated by administering a therapeutically effective amount of any one or more of the oligonucleotides provided herein. In some embodiments, treatment comprises reducing NR1H3 expression. In some embodiments, the subject is treated therapeutically. In some embodiments, the subject is treated prophylactically.

In some embodiments of the methods herein, one or more oligonucleotides herein (e.g., RNAi oligonucleotides), or a pharmaceutical composition comprising one or more oligonucleotides, is administered to a subject having a disease, disorder or condition associated with NR1H3 expression such that NR1H3 expression is reduced in the subject, thereby treating the subject. In some embodiments, an amount or level of NR1H3 mRNA is reduced in the subject. In some embodiments, an amount or level of NR1H3 protein is reduced in the subject. In some embodiments, an amount or level of NR1H3 activity is reduced in the subject.

In some embodiments of the methods herein, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide), or a pharmaceutical composition comprising the oligonucleotide, is administered to a subject having a disease, disorder or condition associated with NR1H3 such that NR1H3 expression is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to NR1H3 expression prior to administration of one or more oligonucleotides or pharmaceutical composition. In some embodiments, NR1H3 expression is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to NR1H3 expression in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or oligonucleotides or pharmaceutical composition or receiving a control oligonucleotide or oligonucleotides, pharmaceutical composition or treatment.

In some embodiments of the methods herein, an oligonucleotide or oligonucleotides herein (e.g., RNAi oligonucleotides), or a pharmaceutical composition comprising the oligonucleotide or oligonucleotides, is administered to a subject having a disease, disorder or condition associated with NR1H3 expression such that an amount or level of NR1H3 mRNA is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to the amount or level of NR1H3 mRNA prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments, an amount or level of NR1H3 mRNA is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to an amount or level of NR1H3 mRNA in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or oligonucleotides or pharmaceutical composition or receiving a control oligonucleotide or oligonucleotides, pharmaceutical composition or treatment.

In some embodiments of the methods herein, an oligonucleotide or oligonucleotides herein, or a pharmaceutical composition comprising the oligonucleotide or oligonucleotides, is administered to a subject having a disease, disorder or condition associated with NR1H3 expression such that an amount or level of NR1H3 protein is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or greater than 99% when compared to the amount or level of NR1H3 protein prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments, an amount or level of NR1H3 protein is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to an amount or level of NR1H3 protein in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or oligonucleotides or pharmaceutical composition or receiving a control oligonucleotide, oligonucleotides or pharmaceutical composition or treatment.

In some embodiments of the methods herein, an oligonucleotide or oligonucleotides (e.g., RNAi oligonucleotides) herein, or a pharmaceutical composition comprising the oligonucleotide or oligonucleotides, is administered to a subject having a disease, disorder or condition associated with NR1H3 such that an amount or level of NR1H3 gene activity/expression is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to the amount or level of NR1H3 activity prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments, an amount or level of NR1H3 activity is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to an amount or level of NR1H3 activity in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or pharmaceutical composition or receiving a control oligonucleotide, pharmaceutical composition or treatment.

Suitable methods for determining NR1H3 expression, the amount or level of NR1H3 mRNA, NR1H3 protein, NR1H3 activity, or a biomarker related to or affected by modulation of NR1H3 expression (e.g., a plasma biomarker), in the subject, or in a sample from the subject, are known in the art. Further, the Examples set forth herein illustrate methods for determining NR1H3 expression.

In some embodiments, NR1H3 expression, the amount or level of NR1H3 mRNA, NR1H3 protein, NR1H3 activity, or a biomarker related to or affected by modulation of NR1H3 expression, or any combination thereof, is reduced in a cell (e.g., a hepatocyte), a population or a group of cells (e.g., an organoid), an organ (e.g., liver), blood or a fraction thereof (e.g., plasma), a tissue (e.g., liver tissue), a sample (e.g., a liver biopsy sample), or any other appropriate biological material obtained or isolated from the subject. In some embodiments, NR1H3 expression, the amount or level of NR1H3 mRNA, NR1H3 protein, NR1H3 activity, or a biomarker related to or affected by modulation of NR1H3 expression, or any combination thereof, is reduced in more than one type of cell (e.g., a hepatocyte and one or more other type(s) of cell), more than one groups of cells, more than one organ (e.g., liver and one or more other organ(s)), more than one fraction of blood (e.g., plasma and one or more other blood fraction(s)), more than one type of tissue (e.g., liver tissue and one or more other type(s) of tissue), or more than one type of sample (e.g., a liver biopsy sample and one or more other type(s) of biopsy sample).

Because of their high specificity, the oligonucleotides provided herein (e.g., dsRNAi oligonucleotides) specifically target mRNA of target genes (e.g., NR1H3 mRNA) of cells and tissue(s), or organs(s) (e.g., liver). In preventing disease, the target gene may be one which is required for initiation or maintenance of the disease or which has been identified as being associated with a higher risk of contracting the disease. In treating disease, the oligonucleotide can be brought into contact with the cells, tissue(s), or organ(s) (e.g., liver) exhibiting or responsible for mediating the disease. For example, an oligonucleotide (e.g., an RNAi oligonucleotide) substantially identical to all or part of a wild-type (i.e., native) or mutated gene associated with a disorder or condition associated with NR1H3 expression may be brought into contact with or introduced into a cell or tissue type of interest such as a hepatocyte or other liver cell.

In some embodiments, the target gene may be a target gene from any mammal, such as a human target. Any target gene may be silenced according to the method described herein.

Methods described herein typically involve administering to a subject an effective amount of an oligonucleotide herein (e.g., a RNAi oligonucleotide), that is, an amount that produces or generates a desirable therapeutic result. A therapeutically acceptable amount may be an amount that therapeutically treats a disease or disorder. The appropriate dosage for any one subject will depend on certain factors, including the subject's size, body surface area, age, the composition to be administered, the active ingredient(s) in the composition, time and route of administration, general health, and other drugs being administered concurrently.

In some embodiments, a subject is administered any one of the compositions herein (e.g., a composition comprising an RNAi oligonucleotide described herein) either enterally (e.g., orally, by gastric feeding tube, by duodenal feeding tube, via gastrostomy or rectally), parenterally (e.g., subcutaneous injection, intravenous injection or infusion, intra-arterial injection or infusion, intraosseous infusion, intramuscular injection, intracerebral injection, intracerebroventricular injection, intrathecal), topically (e.g., epicutaneous, inhalational, via eye drops, or through a mucous membrane), or by direct injection into a target organ (e.g., the liver of a subject). Typically, oligonucleotides herein are administered intravenously or subcutaneously.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide), or a pharmaceutical composition comprising the oligonucleotide, is administered alone or in combination. In some embodiments, the oligonucleotides herein are administered in combination concurrently, sequentially (in any order), or intermittently. For example, two oligonucleotides may be co-administered concurrently. Alternatively, one oligonucleotide may be administered and followed any amount of time later (e.g., one hour, one day, one week or one month) by the administration of a second oligonucleotide.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide), or a pharmaceutical composition comprising the oligonucleotide, is administered in combination with one or more additional pharmacologically active substances. In some embodiments the additional pharmacologically active substances are selected from e.g., anti-diabetic agents, anti-obesity agents, appetite regulating agents, antihypertensive agents, agents.

In some embodiments, the subject to be treated is a human or non-human primate or other mammalian subject. Other exemplary subjects include domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and animals such as mice, rats, guinea pigs, and hamsters.

Kits

In some embodiments, the disclosure provides a kit comprising an oligonucleotide herein (e.g., an RNAi oligonucleotide), and instructions for use. In some embodiments, the kit comprises an oligonucleotide herein, and a package insert containing instructions for use of the kit and/or any component thereof. In some embodiments, the kit comprises, in a suitable container, an oligonucleotide herein, one or more controls, and various buffers, reagents, enzymes and other standard ingredients well known in the art. In some embodiments, the container comprises at least one vial, well, test tube, flask, bottle, syringe, or other container means, into which the oligonucleotide is placed, and in some instances, suitably aliquoted. In some embodiments where an additional component is provided, the kit contains additional containers into which this component is placed. The kits can also include a means for containing the oligonucleotide and any other reagent in close confinement for commercial sale. Such containers may include injection or blow-molded plastic containers into which the desired vials are retained. Containers and/or kits can include labeling with instructions for use and/or warnings.

In some embodiments, a kit comprises an oligonucleotide herein (e.g., an RNAi oligonucleotide), and a pharmaceutically acceptable carrier, or a pharmaceutical composition comprising the oligonucleotide and instructions for treating or delaying progression of a disease, disorder or condition associated with NR1H3 expression in a subject in need thereof.

Definitions

As used herein, the term “antisense oligonucleotide” encompasses a nucleic acid-based molecule which has a sequence complementary to all or part of the target mRNA, in particular seed sequence thereby capable of forming a duplex with a mRNA. Thus, the term “antisense oligonucleotide”, as used herein, may be referred to as “complementary nucleic acid-based inhibitor”.

As used herein, “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

As used herein, “administer,” “administering,” “administration” and the like refers to providing a substance (e.g., an oligonucleotide) to a subject in a manner that is pharmacologically useful (e.g., to treat a disease, disorder, or condition in the subject).

As used herein, “attenuate,” “attenuating,” “attenuation” and the like refers to reducing or effectively halting. As a non-limiting example, one or more of the treatments herein may reduce or effectively halt the onset or progression of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus in a subject. This attenuation may be exemplified by, for example, a decrease in one or more aspects (e.g., symptoms, tissue characteristics, and cellular, inflammatory, or immunological activity, etc.) of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus, no detectable progression (worsening) of one or more aspects fatty liver disease, or systemic lupus erythematosus, or no detectable aspects of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus in a subject when they might otherwise be expected.

As used herein, “complementary” refers to a structural relationship between two nucleotides (e.g., on two opposing nucleic acids or on opposing regions of a single nucleic acid strand) that permits the two nucleotides to form base pairs with one another. For example, a purine nucleotide of one nucleic acid that is complementary to a pyrimidine nucleotide of an opposing nucleic acid may base pair together by forming hydrogen bonds with one another. In some embodiments, complementary nucleotides can base pair in the Watson-Crick manner or in any other manner that allows for the formation of stable duplexes. In some embodiments, two nucleic acids may have regions of multiple nucleotides that are complementary with each other to form regions of complementarity, as described herein.

As used herein, “deoxyribonucleotide” refers to a nucleotide having a hydrogen in place of a hydroxyl at the 2′ position of its pentose sugar when compared with a ribonucleotide. A modified deoxyribonucleotide is a deoxyribonucleotide having one or more modifications or substitutions of atoms other than at the 2′ position, including modifications or substitutions in or of the sugar, phosphate group or base.

As used herein, “double-stranded oligonucleotide” or “ds oligonucleotide” refers to an oligonucleotide that is substantially in a duplex form. In some embodiments, the complementary base-pairing of duplex region(s) of a double-stranded oligonucleotide is formed between antiparallel sequences of nucleotides of covalently separate nucleic acid strands. In some embodiments, complementary base-pairing of duplex region(s) of a double-stranded oligonucleotide is formed between antiparallel sequences of nucleotides of nucleic acid strands that are covalently linked. In some embodiments, complementary base-pairing of duplex region(s) of a double-stranded oligonucleotide is formed from single nucleic acid strand that is folded (e.g., via a hairpin) to provide complementary antiparallel sequences of nucleotides that base pair together. In some embodiments, a double-stranded oligonucleotide comprises two covalently separate nucleic acid strands that are fully duplexed with one another. However, in some embodiments, a double-stranded oligonucleotide comprises two covalently separate nucleic acid strands that are partially duplexed (e.g., having overhangs at one or both ends). In some embodiments, a double-stranded oligonucleotide comprises antiparallel sequence of nucleotides that are partially complementary, and thus, may have one or more mismatches, which may include internal mismatches or end mismatches.

As used herein, “duplex,” in reference to nucleic acids (e.g., oligonucleotides), refers to a structure formed through complementary base pairing of two antiparallel sequences of nucleotides.

As used herein, “excipient” refers to a non-therapeutic agent that may be included in a composition, for example, to provide or contribute to a desired consistency or stabilizing effect.

As used herein, “hepatocyte” or “hepatocytes” refers to cells of the parenchymal tissues of the liver. These cells make up about 70-85% of the liver's mass and manufacture serum albumin, FBN and the prothrombin group of clotting factors (except for Factors 3 and 4). Markers for hepatocyte lineage cells include, but are not limited to, transthyretin (Ttr), glutamine synthetase (Glul), hepatocyte nuclear factor 1a (Hnf1a) and hepatocyte nuclear factor 4a (Hnf4a). Markers for mature hepatocytes may include, but are not limited to, cytochrome P450 (Cyp3a11), fumarylacetoacetate hydrolase (Fah), glucose 6-phosphate (G6p), albumin (Alb) and OC2-2F8. See, e.g., Huch et al. NATURE (2013); 494: 247-50.

As used herein, a “hepatotoxic agent” refers to a chemical compound, virus or other substance that is itself toxic to the liver or can be processed to form a metabolite that is toxic to the liver. Hepatotoxic agents may include, but are not limited to, carbon tetrachloride (CCl₄), acetaminophen (paracetamol), vinyl chloride, arsenic, chloroform, nonsteroidal anti-inflammatory drugs (such as aspirin and phenylbutazone).

As used herein, the term “NR1H3” refers to the gene which encodes to the protein Liver X receptor alpha, or LXR-alpha. LXR-alpha is a nuclear receptor protein that is encoded by NR1H3 (nuclear receptor subfamily 1, group H, member 3). The term “NR1H3” is intended to refer to all isoforms unless stated otherwise.

As used herein, “labile linker” refers to a linker that can be cleaved (e.g., by acidic pH). A “fairly stable linker” refers to a linker that cannot be readily cleaved.

As used herein, “liver inflammation” or “hepatitis” refers to a physical condition in which the liver becomes swollen, dysfunctional and/or painful, especially as a result of injury or infection, as may be caused by exposure to a hepatotoxic agent. Symptoms may include jaundice (yellowing of the skin or eyes), fatigue, weakness, nausea, vomiting, appetite reduction and weight loss. Liver inflammation, if left untreated, may progress to fibrosis, cirrhosis, liver failure or liver cancer.

As used herein, “liver fibrosis” “Liver Fibrosis” or “fibrosis of the liver” refers to an excessive accumulation in the liver of extracellular matrix proteins, which could include collagens (I, III, and IV), FBN, undulin, elastin, laminin, hyaluronan and proteoglycans resulting from inflammation and liver cell death. Liver fibrosis, if left untreated, may progress to cirrhosis, liver failure or liver cancer.

As used herein, “loop” refers to an unpaired region of a nucleic acid (e.g., oligonucleotide) that is flanked by two antiparallel regions of the nucleic acid that are sufficiently complementary to one another, such that under appropriate hybridization conditions (e.g., in a phosphate buffer, in a cell), the two antiparallel regions, which flank the unpaired region, hybridize to form a duplex (referred to as a “stem”).

As used herein, “Metabolic syndrome’ or “metabolic liver disease” refers to a disorder characterized by a cluster of associated medical conditions and associated pathologies including, but not limited to the following medical conditions: abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, liver fibrosis, and low levels of high-density lipoprotein (HDL) levels. As used herein, the term metabolic syndrome or metabolic liver disease may encompass a wide array of direct and indirect manifestations, diseases and pathologies associated with metabolic syndrome and metabolic liver disease, with an expanded list of conditions used throughout the document.

As used herein, “modified internucleotide linkage” refers to an internucleotide linkage having one or more chemical modifications when compared with a reference internucleotide linkage comprising a phosphodiester bond. In some embodiments, a modified nucleotide is a non-naturally occurring linkage. Typically, a modified internucleotide linkage confers one or more desirable properties to a nucleic acid in which the modified internucleotide linkage is present. For example, a modified internucleotide linkage may improve thermal stability, resistance to degradation, nuclease resistance, solubility, bioavailability, bioactivity, reduced immunogenicity, etc.

As used herein, “modified nucleotide” refers to a nucleotide having one or more chemical modifications when compared with a corresponding reference nucleotide selected from: adenine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, uracil ribonucleotide, adenine deoxyribonucleotide, guanine deoxyribonucleotide, cytosine deoxyribonucleotide and thymidine deoxyribonucleotide. In some embodiments, a modified nucleotide is a non-naturally occurring nucleotide. In some embodiments, a modified nucleotide has one or more chemical modification in its sugar, nucleobase and/or phosphate group. In some embodiments, a modified nucleotide has one or more chemical moieties conjugated to a corresponding reference nucleotide. Typically, a modified nucleotide confers one or more desirable properties to a nucleic acid in which the modified nucleotide is present. For example, a modified nucleotide may improve thermal stability, resistance to degradation, nuclease resistance, solubility, bioavailability, bioactivity, reduced immunogenicity, etc.

As used herein, “nicked tetraloop structure” refers to a structure of a RNAi oligonucleotide that is characterized by separate sense (passenger) and antisense (guide) strands, in which the sense strand has a region of complementarity with the antisense strand, and in which at least one of the strands, generally the sense strand, has a tetraloop configured to stabilize an adjacent stem region formed within the at least one strand.

As used herein, “oligonucleotide” refers to a short nucleic acid (e.g., less than about 100 nucleotides in length). An oligonucleotide may be single-stranded (ss) or double-stranded (ds). An oligonucleotide may or may not have duplex regions. As a set of non-limiting examples, an oligonucleotide may be, but is not limited to, a small interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), dicer substrate interfering RNA (DsiRNA), antisense oligonucleotide, short siRNA or ss siRNA. In some embodiments, a double-stranded (dsRNA) is an RNAi oligonucleotide.

As used herein, “overhang” refers to terminal non-base pairing nucleotide(s) resulting from one strand or region extending beyond the terminus of a complementary strand with which the one strand or region forms a duplex. In some embodiments, an overhang comprises one or more unpaired nucleotides extending from a duplex region at the 5′ terminus or 3′ terminus of an oligonucleotide. In certain embodiments, the overhang is a 3′- or 5′-overhang on the antisense strand or sense strand of an oligonucleotide.

As used herein, “phosphate analog” refers to a chemical moiety that mimics the electrostatic and/or steric properties of a phosphate group. In some embodiments, a phosphate analog is positioned at the 5′ terminal nucleotide of an oligonucleotide in place of a 5′-phosphate, which is often susceptible to enzymatic removal. In some embodiments, a 5′ phosphate analog contains a phosphatase-resistant linkage. Examples of phosphate analogs include, but are not limited to, 5′ phosphonates, such as 5′ methylene phosphonate (5′-MP) and 5′-(E)-vinylphosphonate (5′-VP). In some embodiments, an oligonucleotide has a phosphate analog at a 4′-carbon position of the sugar (referred to as a “4′-phosphate analog”) at a 5′-terminal nucleotide. An example of a 4′-phosphate analog is oxymethylphosphonate, in which the oxygen atom of the oxymethyl group is bound to the sugar moiety (e.g., at its 4′-carbon) or analog thereof. See, e.g., US Provisional Patent Application Nos. 62/383,207 (filed on 2 Sep. 2016) and 62/393,401 (filed on 12 Sep. 2016). Other modifications have been developed for the 5′ end of oligonucleotides (see, e.g., Intl. Patent Application No. WO 2011/133871; U.S. Pat. No. 8,927,513; and Prakash et al. NUCLEIC ACIDS RES. (2015); 43: 2993-3011).

As used herein, “reduced expression” of a gene (e.g., NR1H3) refers to a decrease in the amount or level of RNA transcript (e.g., NR1H3 mRNA) or protein encoded by the gene and/or a decrease in the amount or level of activity of the gene in a cell, a population of cells, a sample, or a subject, when compared to an appropriate reference (e.g., a reference cell, population of cells, sample or subject). For example, the act of contacting a cell with an oligonucleotide herein (e.g., an oligonucleotide comprising an antisense strand having a nucleotide sequence that is complementary to a nucleotide sequence comprising NR1H3 mRNA) may result in a decrease in the amount or level of NR1H3 mRNA, protein and/or activity (e.g., via degradation of NR1H3 mRNA by the RNAi pathway) when compared to a cell that is not treated with the oligonucleotide. Similarly, and as used herein, “reducing expression” refers to an act that results in reduced expression of a gene (e.g., NR1H3).

As used herein, “reduction of NR1H3 expression” refers to a decrease in the amount or level of NR1H3 mRNA, NR1H3 protein and/or NR1H3 activity in a cell, a population of cells, a sample or a subject when compared to an appropriate reference (e.g., a reference cell, population of cells, sample, or subject).

As used herein, “region of complementarity” refers to a sequence of nucleotides of a nucleic acid (e.g., an oligonucleotide) that is sufficiently complementary to an antiparallel sequence of nucleotides to permit hybridization between the two sequences of nucleotides under appropriate hybridization conditions (e.g., in a phosphate buffer, in a cell, etc.). In some embodiments, an oligonucleotide herein comprises a targeting sequence having a region of complementary to a mRNA target sequence.

As used herein, “ribonucleotide” refers to a nucleotide having a ribose as its pentose sugar, which contains a hydroxyl group at its 2′ position. A modified ribonucleotide is a ribonucleotide having one or more modifications or substitutions of atoms other than at the 2′ position, including modifications or substitutions in or of the ribose, phosphate group or base.

As used herein, “RNAi oligonucleotide” refers to either (a) a double-stranded oligonucleotide having a sense strand (passenger) and antisense strand (guide), in which the antisense strand or part of the antisense strand is used by the Argonaute 2 (Ago2) endonuclease in the cleavage of a target mRNA (e.g., NR1H3 mRNA) or (b) a single-stranded oligonucleotide having a single antisense strand, where that antisense strand (or part of that antisense strand) is used by the Ago2 endonuclease in the cleavage of a target mRNA (e.g., NR1H3 mRNA).

As used herein, “strand” refers to a single, contiguous sequence of nucleotides linked together through internucleotide linkages (e.g., phosphodiester linkages or phosphorothioate linkages). In some embodiments, a strand has two free ends (e.g., a 5′ end and a 3′ end).

As used herein, “subject” means any mammal, including mice, rabbits, and humans. In one embodiment, the subject is a human or NHP. Moreover, “individual” or “patient” may be used interchangeably with “subject.”

As used herein, “synthetic” refers to a nucleic acid or other molecule that is artificially synthesized (e.g., using a machine (e.g., a solid-state nucleic acid synthesizer)) or that is otherwise not derived from a natural source (e.g., a cell or organism) that normally produces the molecule.

As used herein, “targeting ligand” refers to a molecule (e.g., a carbohydrate, amino sugar, cholesterol, polypeptide, or lipid) that selectively binds to a cognate molecule (e.g., a receptor) of a tissue or cell of interest and that is conjugatable to another substance for purposes of targeting the other substance to the tissue or cell of interest. For example, in some embodiments, a targeting ligand may be conjugated to an oligonucleotide for purposes of targeting the oligonucleotide to a specific tissue or cell of interest. In some embodiments, a targeting ligand selectively binds to a cell surface receptor. Accordingly, in some embodiments, a targeting ligand when conjugated to an oligonucleotide facilitates delivery of the oligonucleotide into a particular cell through selective binding to a receptor expressed on the surface of the cell and endosomal internalization by the cell of the complex comprising the oligonucleotide, targeting ligand and receptor. In some embodiments, a targeting ligand is conjugated to an oligonucleotide via a linker that is cleaved following or during cellular internalization such that the oligonucleotide is released from the targeting ligand in the cell. In some embodiments, the targeting ligand comprises at least one GalNAc moiety and targets the liver and human liver cells (e.g., human hepatocytes).

As used herein, “tetraloop” refers to a loop that increases stability of an adjacent duplex formed by hybridization of flanking sequences of nucleotides. The increase in stability is detectable as an increase in melting temperature (T_m) of an adjacent stem duplex that is higher than the T_m of the adjacent stem duplex expected, on average, from a set of loops of comparable length consisting of randomly selected sequences of nucleotides. For example, a tetraloop can confer a T_m of at least about 50° C., at least about 55° C., at least about 56° C., at least about 58° C., at least about 60° C., at least about 65° C., or at least about 75° C. in 10 mM Na₂HPO₄ to a hairpin comprising a duplex of at least 2 base pairs (bp) in length. In some embodiments, a tetraloop can confer a Tm of at least about 50° C., at least about 55° C., at least about 56° C., at least about 58° C., at least about 60° C., at least about 65° C., or at least about 75° C. in 10 mM NaH₂PO4 to a hairpin comprising a duplex of at least 2 base pairs (bp) in length. In some embodiments, a tetraloop may stabilize a bp in an adjacent stem duplex by stacking interactions. In addition, interactions among the nucleotides in a tetraloop include, but are not limited to, non-Watson-Crick base pairing, stacking interactions, hydrogen bonding and contact interactions (Cheong et al. NATURE (1990); 346: 680-82; and Heus & Pardi SCIENCE (1991); 253: 191-94). In some embodiments, a tetraloop comprises or consists of 3 to 6 nucleotides and is typically 4 to 5 nucleotides. In certain embodiments, a tetraloop comprises or consists of 3, 4, 5, or 6 nucleotides, which may or may not be modified (e.g., which may or may not be conjugated to a targeting moiety). In one embodiment, a tetraloop consists of 4 nucleotides. Any nucleotide may be used in the tetraloop and standard IUPAC-IUB symbols for such nucleotides may be used as described in Cornish-Bowden NUCLEIC ACIDS RES. (1985); 13: 3021-30. For example, the letter “N” may be used to mean that any base may be in that position, the letter “R” may be used to show that A (adenine) or G (guanine) may be in that position, and “B” may be used to show that C (cytosine), G (guanine), or T (thymine) may be in that position. Examples of tetraloops include the UNCG family of tetraloops (e.g., UUCG), the GNRA family of tetraloops (e.g., GAAA), and the CUUG tetraloop (Woese et al. PROC. NATL. ACAD. SCI. USA (1990); 87: 8467-71; Antao et al. NUCLEIC ACIDS RES. (1991); 19: 5901-05). Examples of DNA tetraloops include the d(GNNA) family of tetraloops (e.g., d(GTTA), the d(GNRA)) family of tetraloops, the d(GNAB) family of tetraloops, the d(CNNG) family of tetraloops, and the d(TNCG) family of tetraloops (e.g., d(TTCG)). See, e.g., Nakano et al. BIOCHEM. (2002); 41: 14281-92; Shinji et al. NIPPON KAGAKKAI KOEN YOKOSHU (2000); 78: 731. In some embodiments, the tetraloop is contained within a nicked tetraloop structure.

As used herein, “treat” or “treating” refers to the act of providing care to a subject in need thereof, for example, by administering a therapeutic agent (e.g., an oligonucleotide herein) to the subject, for purposes of improving the health and/or well-being of the subject with respect to an existing condition (e.g., a disease, disorder) or to prevent or decrease the likelihood of the occurrence of a condition. In some embodiments, treatment involves reducing the frequency or severity of at least one sign, symptom or contributing factor of a condition (e.g., disease, disorder) experienced by a subject.

EXAMPLES

While the disclosure has been described with reference to the specific embodiments set forth in the following Examples, it should be understood by those skilled in the art that various changes may be made, and equivalents may be substituted without departing from the true spirit and scope of the disclosure. Further, the following Examples are offered by way of illustration and are not intended to limit the scope of the disclosure in any manner. In addition, modifications may be made to adapt to a situation, material, composition of matter, process, process step or steps, to the objective, spirit, and scope of the disclosure. All such modifications are intended to be within the scope of the disclosure. Standard techniques well known in the art or the techniques specifically described below were utilized.

Example 1: Preparation of RNAi Oligonucleotides

Oligonucleotide Synthesis and Purification

The oligonucleotides (RNAi oligonucleotides) described in the foregoing Examples are chemically synthesized using methods described herein. Generally, RNAi oligonucleotides are synthesized using solid phase oligonucleotide synthesis methods as described for 19-23mer siRNAs (see, e.g., Scaringe et al. NUCLEIC ACIDS RES. (1990); 18: 5433-41 and Usman et al. J. AM. CHEM. SOC. (1987); 109: 7845-45; see also, U.S. Pat. Nos. 5,804,683; 5,831,071; 5,998,203; 6,008,400; 6,111,086; 6,117,657; 6,353,098; 6,362,323; 6,437,117 and 6,469,158) in addition to using known phosphoramidite synthesis (see, e.g. Hughes and Ellington, COLD SPRING HARB. PERSPECT. BIOL. (2017); 9(1): a023812; Beaucage S. L., Caruthers M. H. Studies on Nucleotide Chemistry V.: Deoxynucleoside Phosphoramidites A New Class of Key Intermediates for Deoxypolynucleotide Synthesis, TETRAHEDRON LETT. (1981); 22: 1859-62. doi:10.1016/S0040-4039(01)90461-7). dsRNAi oligonucleotides having a 19mer core sequence were formatted into constructs having a 25mer sense strand and a 27mer antisense strand to allow for processing by the RNAi machinery. The 19mer core sequence is complementary to a region in the NR1H3 mRNA.

Individual RNA strands were synthesized and HPLC purified according to standard methods (Integrated DNA Technologies; Coralville, Iowa). For example, RNA oligonucleotides were synthesized using solid phase phosphoramidite chemistry, deprotected and desalted on NAP-5 columns (Amersham Pharmacia Biotech; Piscataway, N.J.) using standard techniques (Damha & Olgivie, METHODS MOL. BIOL. (1993); 20: 81-114; Wincott et al. NUCLEIC ACIDS RES. (1995); 23: 2677-84). The oligomers were purified using ion-exchange high performance liquid chromatography (IE-HPLC) on an Amersham Source 15Q column (1.0 cm×25 cm; Amersham Pharmacia Biotech) using a 15 min step-linear gradient. The gradient varied from 90:10 Buffers A:B to 52:48 Buffers A:B, where Buffer A is 100 mM Tris pH 8.5 and Buffer B is 100 mM Tris pH 8.5, 1 M NaCl. Samples were monitored at 260 nm and peaks corresponding to the full-length oligonucleotide species were collected, pooled, desalted on NAP-5 columns, and lyophilized.

The purity of each oligomer was determined by capillary electrophoresis (CE) on a Beckman PACE 5000 (Beckman Coulter, Inc.; Fullerton, Calif.). The CE capillaries have a 100 μm inner diameter and contain ssDNA 100R Gel (Beckman-Coulter). Typically, about 0.6 nmole of oligonucleotide was injected into a capillary, run in an electric field of 444 V/cm, and was detected by UV absorbance at 260 nm. Denaturing Tris-Borate-7 M-urea running buffer was purchased from Beckman-Coulter. Oligoribonucleotides were obtained that were at least 90% pure as assessed by CE for use in experiments described below. Compound identity was verified by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectroscopy on a Voyager DE™ Biospectometry Work Station (Applied Biosystems; Foster City, Calif.) following the manufacturer's recommended protocol. Relative molecular masses of all oligomers were obtained, often within 0.2% of expected molecular mass.

Preparation of Duplexes

Single strand RNA oligomers were resuspended (e.g., at 100 μM concentration) in duplex buffer consisting of 100 mM potassium acetate, 30 mM HEPES, pH 7.5. Complementary sense and antisense strands were mixed in equal molar amounts to yield a final solution of, for example, 50 μM duplex. Samples were heated to 100° C. for 5′ in RNA buffer (IDT) and were allowed to cool to room temperature before use. The RNAi oligonucleotides were stored at −20° C. Single strand RNA oligomers were stored lyophilized or in nuclease-free water at −80° C.

Example 2: Generation of NR1H3-Targeting Double Stranded RNAi Oligonucleotides

Identification of NR1H3 mRNA Target Sequences

Nuclear Receptor Subfamily 1 Group H Member 3 (NR1H3) is a protein that regulates macrophage function, lipid homeostasis, and inflammation. To generate RNAi oligonucleotide inhibitors of NR1H3 expression, a computer-based algorithm was used to computationally identify NR1H3 mRNA target sequences suitable for assaying inhibition of NR1H3 expression by the RNAi pathway. The algorithm provided RNAi oligonucleotide guide (antisense) strand sequences each having a region of complementarity to a suitable NR1H3 target sequence of human NR1H3 mRNA. Some of the guide strand sequences identified by the algorithm were also complementary to the corresponding NR1H3 target sequence of monkey and/or mouse NR1H3 mRNA. NR1H3 RNAi oligonucleotides comprising a region of complementarity to homologous NR1H3 mRNA target sequences with nucleotide sequence similarity are predicted to have the ability to target homologous NR1H3 mRNAs.

RNAi oligonucleotides (formatted as DsiRNA oligonucleotides) were generated as described in Example 1 for evaluation in vitro. Each DsiRNA was generated with the same modification pattern, and each with a unique guide strand having a region of complementarity to a NR1H3 target sequence identified by the algorithm. Modifications for the sense and anti-sense DsiRNA included the following (X— any nucleotide; m—2′-O-methyl modified nucleotide; r—ribosyl modified nucleotide):

Sense Strand:

rXmXrXmXrXrXrXrXrXrXrXrXrXmXrXmXrXrXrXrXrXrXrXXX

Anti-sense Strand:

mXmXmXmXrXrXrXrXrXrXmXrXmXrXrXrXrXrXrXrXrXrXmXrXmXmXmX

In Vitro Cell-Based Assays

The ability of each of the modified DsiRNA in Table 1 to reduce NR1H3 mRNA was measured using in vitro cell-based assays. Briefly, human Huh-7 cells expressing endogenous human NR1H3 gene were transfected with each of the DsiRNAs listed in Table 1 at 1 nM in separate wells of a multi-well cell-culture plate. Cells were maintained for 24 hours following transfection with the modified DsiRNA, and then the amount of remaining NR1H3 mRNA from the transfected cells was determined using and RT-qPCR assay. The assay used the following primers and probe normalized to the geometric mean of two reference genes HPRT1 and SFRS9: Forward-1198 GTTATAACCGGGAAGACTTTGC (SEQ ID NO:1122); Reverse-1326: TGATAGCAATGAGCAAGGCA (SEQ ID NO: 1123); Probe-1253: ATGGCCCTGGAGAACTCGAAGATG (SEQ ID NO:1124). The primer pair was assayed for % remaining RNA as shown in Table 1. DsiRNAs resulting in less than or equal to 10% NR1H3 mRNA remaining in DsiRNA-transfected cells when compared to mock-transfected cells were considered DsiRNA “hits”. The HuH-7 cell-based assay evaluating the ability of the DsiRNAs listed in Table 1 to inhibit NR1H3 expression identified several candidate DsiRNAs.

Taken together, these results show that DsiRNAs designed to target human NR1H3 mRNA inhibit NR1H3 expression in cells, as determined by a reduced amount of NR1H3 mRNA in DsiRNA-transfected cells relative to control cells. These results demonstrate that the nucleotide sequences comprising the DsiRNA are useful for generating RNAi oligonucleotides to inhibit NR1H3 expression. Further, these results demonstrate that multiple NR1H3 mRNA target sequences are suitable for the RNAi-mediated inhibition of NR1H3 expression.

TABLE 1
In Vitro Screening Results
SED ID	SED ID
NO	NO		NR1H3-F1198
(Sense	(Anti-sense		%
Strand)	Strand)	DsiRNA name	remaining	SEM
1	385	NR1H3-764-784-861	8.9	4.43
2	386	NR1H3-766-786-863	16.25	3.11
3	387	NR1H3-789-809-886	15.08	1.03
4	388	NR1H3-790-810-887	18.74	3.03
5	389	NR1H3-791-811-888	40.34	2.62
6	390	NR1H3-792-812-889	32.44	4.47
7	391	NR1H3-793-813-890	33.77	2.89
8	392	NR1H3-795-815-892	10.87	4.86
9	393	NR1H3-796-816-893	14.94	1.85
10	394	NR1H3-797-817-894	45.07	9.79
11	395	NR1H3-798-818-895	17.91	4.71
12	396	NR1H3-799-819-896	17.87	2.13
13	397	NR1H3-802-822-899	8.47	3.71
14	398	NR1H3-803-823-900	26.43	3.01
15	399	NR1H3-804-824-901	13.60	2.34
16	400	NR1H3-806-826-903	47.05	7.86
17	401	NR1H3-808-828-905	14.07	1.86
18	402	NR1H3-809-829-906	37.06	10.23
19	403	NR1H3-810-830-907	27.90	12.22
20	404	NR1H3-811-831-908	41.69	8.58
21	405	NR1H3-813-833-910	29.81	2.83
22	406	NR1H3-844	22.31	3.43
23	407	NR1H3-895-915-992	13.4	2.84
24	408	NR1H3-898-918-995	21.63	3.63
25	409	NR1H3-915-935	23.64	3.59
26	410	NR1H3-917-937	13.58	3.29
27	411	NR1H3-922-942	21.35	3.75
28	412	NR1H3-924-944	32.89	16.44
29	413	NR1H3-925-945	15.74	4.69
30	414	NR1H3-927-947	26.60	5.18
31	415	NR1H3-928-948	14.55	3.21
32	416	NR1H3-929-949	9.89	1.40
33	417	NR1H3-930-950	26.20	3.86
34	418	NR1H3-931-951	27.44	1.62
35	419	NR1H3-932-952	12.31	6.33
36	420	NR1H3-933-953	13.29	1.84
37	421	NR1H3-941-961	10.08	2.10
38	422	NR1H3-944-964	13.78	1.05
39	423	NR1H3-945-965	27.16	2.75
40	424	NR1H3-946-966	15.99	1.88
41	425	NR1H3-947-967	8.63	3.01
42	426	NR1H3-949-969	17.43	1.64
43	427	NR1H3-951-971	9.66	1.70
44	428	NR1H3-952-972	9.92	1.39
45	429	NR1H3-953-973	21.75	4.12
46	430	NR1H3-1151-1171	18.83	2.78
47	431	NR1H3-1153-1173	78.76	9.71
48	432	NR1H3-1154-1174	45.38	5.78
49	433	NR1H3-1155-1175	23.72	2.37
50	434	NR1H3-1156-1176	23.75	2.37
51	435	NR1H3-1157-1177	67.42	6.83
52	436	NR1H3-1158-1178	17.98	2.57
53	437	NR1H3-1159-1179	17.47	2.49
54	438	NR1H3-1160-1180	9.14	1.61
55	439	NR1H3-1161-1181	22.52	2.41
56	440	NR1H3-1162-1182	10.89	1.66
57	441	NR1H3-1163-1183	38.50	7.62
58	442	NR1H3-1164-1184	23.52	9.14
59	443	NR1H3-1165-1185	22.81	3.68
60	444	NR1H3-1166-1186	23.01	4.64
61	445	NR1H3-1167-1187	50.54	10.76
62	446	NR1H3-1169-1189	15.60	2.02
63	447	NR1H3-1170-1190	22.78	5.79
64	448	NR1H3-1171-1191	80.98	9.76
65	449	NR1H3-1173-1193	16.14	4.16
66	450	NR1H3-1175-1195	45.81	7.47
67	451	NR1H3-1176-1196	18.32	4.59
68	452	NR1H3-1177-1197	26.85	5.22
69	453	NR1H3-1178-1198	63.10	17.52
70	454	NR1H3-1179-1199	12.86	1.65
71	455	NR1H3-1180-1200	20.97	4.62
72	456	NR1H3-1181-1201	16.21	4.23
73	457	NR1H3-1182-1202	30.61	5.64
74	458	NR1H3-1183-1203	30.96	6.72
75	459	NR1H3-1184-1204	23.71	6.05
76	460	NR1H3-1185-1205	14.77	1.30
77	461	NR1H3-1186-1206	19.94	6.28
78	462	NR1H3-1187-1207	14.48	1.77
79	463	NR1H3-1188-1208	37.28	3.76
80	464	NR1H3-1190-1210	38.58	4.63
81	465	NR1H3-1191-1211	15.02	2.19
82	466	NR1H3-1192-1212	51.23	7.43
83	467	NR1H3-1193-1213	17.05	3.23
84	468	NR1H3-1194-1214	31.91	6.24
85	469	NR1H3-1196-1216	32.00	9.03
86	470	NR1H3-1197-1217	8.36	2.55
87	471	NR1H3-1198-1218	29.10	4.48
88	472	NR1H3-1199-1219	13.22	2.89
89	473	NR1H3-1200-1220	8.59	2.38
90	474	NR1H3-1203-1223	15.92	3.29
91	475	NR1H3-1204-1224	5.07	0.83
92	476	NR1H3-1207-1227	3.54	2.18
93	477	NR1H3-1211-1231	1.88	1.19
94	478	NR1H3-1212-1232	17.48	7.55
95	479	NR1H3-1213-1233	8.32	4.17
96	480	NR1H3-1214-1234	16.53	1.70
97	481	NR1H3-1215-1235	11.84	1.93
98	482	NR1H3-1216-1236	9.48	1.67
99	483	NR1H3-1217-1237	11.9	2.34
100	484	NR1H3-1218-1238	8.45	1.98
101	485	NR1H3-1219-1239	6.80	1.35
102	486	NR1H3-1220-1240	3.60	1.88
103	487	NR1H3-1222-1242	8.53	1.67
104	488	NR1H3-1223-1243	12.69	1.63
105	489	NR1H3-1224-1244	6.15	2.42
106	490	NR1H3-1225-1245	9.72	3.87
107	491	NR1H3-1226-1246	47.24	5.54
108	492	NR1H3-1227-1247	13.80	2.63
109	493	NR1H3-1228-1248	6.76	1.78
110	494	NR1H3-1229-1249	8.75	2.71
111	495	NR1H3-1232-1252	36.21	3.20
112	496	NR1H3-1233-1253	20.37	2.75
113	497	NR1H3-1234-1254	18.42	1.50
114	498	NR1H3-1235-1255	16.37	1.48
115	499	NR1H3-1236-1256	58.83	6.78
116	500	NR1H3-1237-1257	16.03	2.29
117	501	NR1H3-1238-1258	19.29	5.59
118	502	NR1H3-1241-1261	12.44	2.25
119	503	NR1H3-1242-1262	29.53	10.05
120	504	NR1H3-1243-1263	6.22	5.33
121	505	NR1H3-1244-1264	5.51	0.94
122	506	NR1H3-1245-1265	15.00	2.82
123	507	NR1H3-1246-1266	10.14	2.84
124	508	NR1H3-1247-1267	13.70	3.55
125	509	NR1H3-1248-1268	37.81	4.12
126	510	NR1H3-1250-1270	10.08	2.10
127	511	NR1H3-1251-1271	6.50	0.47
128	512	NR1H3-1252-1272	3.35	0.65
129	513	NR1H3-1253-1273	14.22	1.35
130	514	NR1H3-1256-1276	8.26	1.63
131	515	NR1H3-1258-1278	7.38	1.26
132	516	NR1H3-1259-1279	4.72	1.13
133	517	NR1H3-1261-1281	4.39	1.31
134	518	NR1H3-1262-1282	27.66	5.46
135	519	NR1H3-1265-1285	3.35	1.10
136	520	NR1H3-1266-1286	4.91	0.83
137	521	NR1H3-1267-1287	21.91	4.48
138	522	NR1H3-1268-1288	21.59	3.96
139	523	NR1H3-1269-1289	11.31	1.44
140	524	NR1H3-1270-1290	9.87	5.24
141	525	NR1H3-1271-1291	6.95	1.9
142	526	NR1H3-1272-1292	7.07	0.99
143	527	NR1H3-1273-1293	11.01	3.72
144	528	NR1H3-1275-1295	18.49	2.31
145	529	NR1H3-1276-1296	17.77	3.25
146	530	NR1H3-1277-1297	18.20	1.62
147	531	NR1H3-1278-1298	9.35	1.70
148	532	NR1H3-1279-1299	8.96	1.60
149	533	NR1H3-1280-1300	19.16	3.95
150	534	NR1H3-1281-1301	12.33	1.94
151	535	NR1H3-1282-1302	40.52	7.51
152	536	NR1H3-1283-1303	15.26	7.23
153	537	NR1H3-1284-1304	37.09	9.79
154	538	NR1H3-1285-1305	29.28	4.88
155	539	NR1H3-1286-1306	41.56	4.92
156	540	NR1H3-1288-1308	68.84	4.13
157	541	NR1H3-1289-1309	34.44	10.86
158	542	NR1H3-1290-1310	17.67	3.83
159	543	NR1H3-1291-1311	21.47	2.26
160	544	NR1H3-1292-1312	41.99	7.72
161	545	NR1H3-1293-1313	13.77	1.40
162	546	NR1H3-1294-1314	20.97	3.76
163	547	NR1H3-1295-1315	14.39	3.21
164	548	NR1H3-1296-1316	28.04	10.25
165	549	NR1H3-1297-1317	12.70	2.20
166	550	NR1H3-1338-1358	22.20	4.81
167	551	NR1H3-1339-1359	7.86	1.5
168	552	NR1H3-1340-1360	4.72	1.10
169	553	NR1H3-1341-1361	11.49	4.26
170	554	NR1H3-1342-1362	4.84	1.18
171	555	NR1H3-1343-1363	17.05	4.21
172	556	NR1H3-1344-1364	13.83	6.27
173	557	NR1H3-1345-1365	9.55	1.22
174	558	NR1H3-1346-1366	4.54	1.14
175	559	NR1H3-1347-1367	6.47	1.87
176	560	NR1H3-1377-1443	46.13	5.08
177	561	NR1H3-1379-1445	28.21	2.69
178	562	NR1H3-1383-1449	27.33	3.23
179	563	NR1H3-1384-1450	27.81	4.58
180	564	NR1H3-1385-1451	44.36	4.37
181	565	NR1H3-1387-1453	15.50	2.5
182	566	NR1H3-1388-1454	46.03	6.42
183	567	NR1H3-1391-1457	20.33	2.82
184	568	NR1H3-1393-1459	27.25	2.95
185	569	NR1H3-1394-1460	11.31	2.71
186	570	NR1H3-1395-1461	30.82	3.24
187	571	NR1H3-1396-1462	34.98	4.45
188	572	NR1H3-1397-1463	41.12	4.28
189	573	NR1H3-1398-1464	14.14	2.79
190	574	NR1H3-1399-1465	14.46	2.61
191	575	NR1H3-1400-1466	49.48	5.89
192	576	NR1H3-1401-1467	21.19	3.39
193	577	NR1H3-1402-1468	14.17	2.73
194	578	NR1H3-1403-1469	18.25	1.29
195	579	NR1H3-1404-1470	34.21	2.29
196	580	NR1H3-1406-1472	46.79	7.22
197	581	NR1H3-1407-1473	13.59	2.47
198	582	NR1H3-1408-1474	44.63	5.37
199	583	NR1H3-1410-1476	43.93	9.37
200	584	NR1H3-1411-1477	28.12	4.11
201	585	NR1H3-1412-1478	50.22	11.35
202	586	NR1H3-1413-1479	45.56	6.23
203	587	NR1H3-1414-1480	56.42	9.61
204	588	NR1H3-1415-1481	32.43	10.32
205	589	NR1H3-1416-1482	16.66	2.27
206	590	NR1H3-1417-1483	31.84	4.71
207	591	NR1H3-1418-1484	7.07	0.80
208	592	NR1H3-1419-1485	69.83	8.81
209	593	NR1H3-1420-1486	16.01	5.34
210	594	NR1H3-1421-1487	38.29	6.31
211	595	NR1H3-1422-1488	80.48	13.59
212	596	NR1H3-1423-1489	9.79	1.47
213	597	NR1H3-1424-1490	9.36	1.84
214	598	NR1H3-1425-1491	22.14	3.77
215	599	NR1H3-1426-1492	9.86	2.14
216	600	NR1H3-1427-1493	18.88	6.80
217	601	NR1H3-1428-1494	17.55	5.52
218	602	NR1H3-1429-1495	2.77	1.08
219	603	NR1H3-1430-1496	19.29	3.14
220	604	NR1H3-1431-1497	8.66	3.71
221	605	NR1H3-1432-1498	19.76	3.07
222	606	NR1H3-1433-1499	3.37	2.29
223	607	NR1H3-1434-1500	77.93	11.83
224	608	NR1H3-1435-1501	14.53	5.77
225	609	NR1H3-1436-1502	11.42	2.45
226	610	NR1H3-1437-1503	4.97	1.57
227	611	NR1H3-1438-1504	7.40	1.89
228	612	NR1H3-1439-1505	3.26	0.97
229	613	NR1H3-1440-1506	40.21	5.31
230	614	NR1H3-1442-1508	50.09	3.47
231	615	NR1H3-1443-1509	11.50	5.54
232	616	NR1H3-1444-1510	29.36	15.66
233	617	NR1H3-1445-1511	47.59	6.76
234	618	NR1H3-1446-1512	2.37	0.65
235	619	NR1H3-1447-1513	10.29	4.95
236	620	NR1H3-1448-1514	45.74	4.52
237	621	NR1H3-1449-1515	35.27	4.39
238	622	NR1H3-1450-1516	39.10	5.63
239	623	NR1H3-1451-1517	9.58	2.83
240	624	NR1H3-1452-1518	64.45	15.14
241	625	NR1H3-1453-1519	14.78	2.76
242	626	NR1H3-1454-1520	5.01	2.14
243	627	NR1H3-1455-1521	21.75	3.59
244	628	NR1H3-1456-1522	9.11	2.01
245	629	NR1H3-1457-1523	7.52	3.29
246	630	NR1H3-1459-1525	7.81	1.75
247	631	NR1H3-1460-1526	4.57	1.07
248	632	NR1H3-1461-1527	30.77	4.42
249	633	NR1H3-1462-1528	6.29	1.92
250	634	NR1H3-1463-1529	2.58	0.85
251	635	NR1H3-1465-1531	4.17	1.14
252	636	NR1H3-1466-1532	15.04	1.90
253	637	NR1H3-1468-1534	14.47	1.37
254	638	NR1H3-1469-1535	14.04	2.26
255	639	NR1H3-1471-1537	14.94	1.55
256	640	NR1H3-1472-1538	45.97	3.01
257	641	NR1H3-1473-1539	19.37	8.93
258	642	NR1H3-1474-1540	9.53	2.70
259	643	NR1H3-1475-1541	3.21	1.94
260	644	NR1H3-1476-1542	11.27	4.12
261	645	NR1H3-1477-1543	14.30	2.78
262	646	NR1H3-1478-1544	13.06	3.66
263	647	NR1H3-1479-1545	3.97	0.86
264	648	NR1H3-1480-1546	4.82	1.41
265	649	NR1H3-1481-1547	2.81	0.57
266	650	NR1H3-1483-1549	5.56	1.60
267	651	NR1H3-1484-1550	20.18	2.39
268	652	NR1H3-1485-1551	3.52	2.10
269	653	NR1H3-1486-1552	13.41	1.81
270	654	NR1H3-1487-1553	25.35	3.42
271	655	NR1H3-1488-1554	28.45	6.63
272	656	NR1H3-1489-1555	15.31	5.00
273	657	NR1H3-1491-1557	6.33	1.03
274	658	NR1H3-1492-1558	20.75	4.42
275	659	NR1H3-1494-1560	24.97	4.76
276	660	NR1H3-1505-1571	38.74	5.88
277	661	NR1H3-1507-1573	9.42	2.29
278	662	NR1H3-1508-1574	36.57	6.54
279	663	NR1H3-1509-1575	29.82	5.45
280	664	NR1H3-1510-1576	19.45	3.79
281	665	NR1H3-1511-1577	23.73	3.3
282	666	NR1H3-1512-1578	42.41	7.68
283	667	NR1H3-1513-1579	33.80	5.58
284	668	NR1H3-1514-1580	26.85	4.79
285	669	NR1H3-1515-1581	3.95	0.84
286	670	NR1H3-1516-1582	16.48	3.36
287	671	NR1H3-1517-1583	4.38	1.57
288	672	NR1H3-1518-1584	3.43	1.32
289	673	NR1H3-1519-1585	5.73	1.72
290	674	NR1H3-1520-1586	14.37	1.95
291	675	NR1H3-1521-1587	15.60	9.44
292	676	NR1H3-1522-1588	14.40	3.9
293	677	NR1H3-1523-1589	9.60	2.11
294	678	NR1H3-1525-1591	13.51	4.15
295	679	NR1H3-1526-1592	50.59	16.74
296	680	NR1H3-1527-1593	8.47	4.27
297	681	NR1H3-1528-1594	25.44	3.59
298	682	NR1H3-1529-1595	12.55	2.77
299	683	NR1H3-1530-1596	11.6	3.15
300	684	NR1H3-1531-1597	6.14	2.83
301	685	NR1H3-1532-1598	15.35	4.55
302	686	NR1H3-1533-1599	3.13	3
303	687	NR1H3-1534-1600	8.51	3.07
304	688	NR1H3-1535-1601	1.48	0.67
305	689	NR1H3-1536-1602	30.02	10.69
306	690	NR1H3-1537-1603	17.55	6.31
307	691	NR1H3-1538-1604	21.90	1.81
308	692	NR1H3-1539-1605	28.62	6.45
309	693	NR1H3-1540-1606	19.29	5.08
310	694	NR1H3-1541-1607	10.51	2.94
311	695	NR1H3-1542-1608	8.39	6.98
312	696	NR1H3-1543-1609	5.68	3.86
313	697	NR1H3-1544-1610	23.78	4.02
314	698	NR1H3-1545-1611	3.93	1.19
315	699	NR1H3-1546-1612	11.55	1.89
316	700	NR1H3-1547-1613	16.77	3.13
317	701	NR1H3-1548-1614	10.86	7.45
318	702	NR1H3-1549-1615	33.40	8.27
319	703	NR1H3-1550-1616	13.98	3.23
320	704	NR1H3-1551-1617	32.11	9.43
321	705	NR1H3-1553-1619	43.83	11.06
322	706	NR1H3-1554-1620	5.16	1.29
323	707	NR1H3-1555-1621	89.05	22.10
324	708	NR1H3-1556-1622	33.15	4.79
325	709	NR1H3-1558-1624	15.27	4.11
326	710	NR1H3-1559-1625	15.15	3.47
327	711	NR1H3-1560-1626	34.65	4.83
328	712	NR1H3-1561-1627	63.67	7.04
329	713	NR1H3-1562-1628	16.78	10.54
330	714	NR1H3-1563-1629	26.54	9.20
331	715	NR1H3-1564-1630	34.34	14.27
332	716	NR1H3-1565-1631	89.42	16.51
333	717	NR1H3-1567-1633	66.56	5.80
334	718	NR1H3-1569-1635	39.41	11.96
335	719	NR1H3-1570-1636	25.11	4.45
336	720	NR1H3-1572-1638	24.43	4.3
337	721	NR1H3-1573-1639	13.36	2.16
338	722	NR1H3-1574-1640	82.95	11.20
339	723	NR1H3-1577-1643	35.42	6.60
340	724	NR1H3-1579-1645	18.88	2.81
341	725	NR1H3-1580-1646	21.56	5.67
342	726	NR1H3-1581-1647	4.90	1.52
343	727	NR1H3-1582-1648	10.89	3.83
344	728	NR1H3-1583-1649	13.79	6.45
345	729	NR1H3-1584-1650	16.62	7.10
346	730	NR1H3-1585-1651	5.99	2.91
347	731	NR1H3-1586-1652	3.86	0.94
348	732	NR1H3-1587-1653	4.72	0.90
349	733	NR1H3-1588-1654	2.35	0.39
350	734	NR1H3-1589-1655	47.09	6.4
351	735	NR1H3-1590-1656	12.18	2.49
352	736	NR1H3-1591-1657	7.90	3.08
353	737	NR1H3-1592-1658	13.57	3.13
354	738	NR1H3-1593-1659	31.19	18.86
355	739	NR1H3-1656-1720	31.57	13.68
356	740	NR1H3-1657-1721	21.24	4.73
357	741	NR1H3-1658-1722	15.81	4.89
358	742	NR1H3-1659-1723	12.33	4.79
359	743	NR1H3-1660-1724	22.98	7.43
360	744	NR1H3-1661-1725	9.37	3.58
361	745	NR1H3-1662-1726	8.29	2.01
362	746	NR1H3-1663-1727	4.60	1.56
363	747	NR1H3-1664-1728	16.48	1.97
364	748	NR1H3-1665-1729	17.41	2.6
365	749	NR1H3-1666-1730	23.86	4.49
366	750	NR1H3-1667-1731	23.67	5.80
367	751	NR1H3-1668-1732	27.34	4.76
368	752	NR1H3-1669-1733	9.25	2.46
369	753	NR1H3-1671-1735	5.99	1.88
370	754	NR1H3-1677-1741	28.16	4.53
371	755	NR1H3-1679-1743	10.30	2.96
372	756	NR1H3-1680-1744	13.50	3.80
373	757	NR1H3-1681-1745	12.10	2.74
374	758	NR1H3-1682-1746	17.59	5.47
375	759	NR1H3-1683-1747	17.57	14.50
376	760	NR1H3-1684-1748	3.97	0.47
377	761	NR1H3-1685-1749	7.55	2.88
378	762	NR1H3-1686-1750	8.97	4.18
379	763	NR1H3-1687-1751	16.24	8.75
380	764	NR1H3-1728-1792	6.44	1.49
381	765	NR1H3-1729-1793	8.96	3.52
382	766	NR1H3-1730-1794	15.41	8.06
383	767	NR1H3-1731-1795	5.40	2.04
384	768	NR1H3-1732-1796	3.85	0.85

Example 3: GalNAc-Conjugated NR1H3 RNAi Oligonucleotides Inhibit Human NR1H3 in Vitro

The in vitro screening assay in Example 2 validated the ability of NR1H3-targeting DsiRNA to knockdown NR1H3 mRNA. To further evaluate the ability of NR1H3 RNAi oligonucleotides to inhibit NR1H3 mRNA expression, GalNAc-conjugated NR1H3 oligonucleotides were generated using sequences identified by the algorithm in Example 2.

Specifically, a subset of the DsiRNAs identified by the algorithm were used to generate corresponding double-stranded RNAi oligonucleotides comprising a nicked tetraloop GalNAc-conjugated structure (referred to herein as “GalNAc-conjugated NR1H3 oligonucleotides” or “GalNAc-NR1H3 constructs”) having a 36-mer passenger strand and a 22-mer guide strand (Table 3). Further, two nucleotide sequences comprising the passenger strand and guide strand have a distinct pattern of modified nucleotides and phosphorothioate linkages (sense strand SEQ ID Nos: 945-1032; antisense SEQ ID Nos:1037 and 1086). Three of the nucleotides comprising the tetraloop were each conjugated to a GalNAc moiety (CAS #14131-60-3). The modification pattern of each strand is illustrated below:

Sense Strand: 5′-mX-S-mX-mX-mX-mX-mX-mX-fX-fX-fX-fX[-mX-]16-[ademX-GalNAc]-[ademX-GalNAc]-[ademX-GalNAc]-mX-mX-mX-mX-mX-mX-3′.

Hybridized to:

Antisense Strand: 5′-[MePhosphonate-40-mX]-S-fX-S-fX-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-mX-mX-mX-mX-mX-S-mX-S-mX-3′.

(Modification key: Table 2 and [ademX-GalNAc]=GalNAc-conjugated nucleotide) Or, represented as:

Sense Strand: [mXs][mX][mX][mX][mX][mX][mX][fX][fX][fX][fX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mX][mX][mX][mX][mX][mX]

Hybridized to:

Antisense Strand: [MePhosphonate-4O-mXs][fXs][fX][fX][fX][mX][fX][mX][mX][fX][mX][mX][mX][fX][mX][mX][mX][mX][mX][mXs][mXs][mX]

The remainder of the nucleotide sequences comprising the passenger strand and guide strand have a second distinct pattern of modified nucleotides and phosphorothioate linkages (sense strand SEQ ID Nos: 945-1032; antisense SEQ ID NOs: 1033-1036, 1038-1085 and 1087-1120). Three of the nucleotides comprising the tetraloop were each conjugated to a GalNAc moiety (CAS #14131-60-3). The modification pattern of each strand is illustrated below:Sense Strand: 5′-mX-S-mX-mX-mX-mX-mX-mX-fX-fX-fX-fX[-mX-]16-[ademX-GalNAc]-[ademX-GalNAc]-[ademX-GalNAc]-mX-mX-mX-mX-mX-mX-3′.

Hybridized to:

Antisense Strand: 5′-[MePhosphonate-40-mX]-S-fX-S-fX-S-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-mX-mX-mX-mX-mX-S-mX-S-mX-3′.

(Modification key: Table 2 and [ademX-GalNAc]=GalNAc-conjugated nucleotide) Or, represented as:

Sense Strand: [mXs][mX][mX][mX][mX][mX][mX][fX][fX][fX][fX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mX][mX][mX][mX][mX][mX]

Hybridized to:

Antisense Strand: [MePhosphonate-40-mXs][fXs][fXs][fX][fX][mX][fX][mX][mX][fX][mX][mX][mX][fX][mX][mX][mX][mX][mX][mXs][mXs][mX]

(Modification key: Table 2).
Symbol                Modification/linkage
Key 1
mX                    2′-O-methyl modified nucleotide
fX                    2'-fluoro modified nucleotide
-S-                   phosphorothioate linkage
-                     phosphodiester linkage
[MePhosphonate-4O-mX] 5′-methoxyphosphonate-4′-oxy modified
                      nucleotide
ademA-GalNAc          GalNAc attached to an adenine nucleotide
Key 2
[mXs]                 2′-O-methyl modified nucleotide with a
                      phosphorothioate linkage to the neighboring
                      nucleotide
[fXs]                 2′-fluoro modified nucleotide with a
                      phosphorothioate linkage to the neighboring
                      nucleotide
[mX]                  2′-O-methyl modified nucleotide with
                      phosphodiester linkages to neighboring
                      nucleotides
[fX]                  2′-fluoro modified nucleotide with
                      phosphodiester linkages to neighboring
                      nucleotides

GalNAc-NR1H3 constructs were used to evaluate inhibition efficacy in cells expressing human NR1H3. Specifically, Huh-7 cells were transfected with the GalNAc-NR1H3 constructs using methods described in Example 2. Results are provided in Table 3, which demonstrate successful knock-down of human NR1H3 mRNA with several constructs.

TABLE 3
GalNAc-Conjugated Human NR1H3 RNAi Oligonucleotides
	SED ID
SED ID	NO
NO	(modified
(modified	Anti-
Sense	sense		%
Strand)	Strand)	DsiRNA name	remaining	SEM
945	1033	NR1H3-763-783-860	109.29	17.94
946	1034	NR1H3-765-785-862	57.30	15.34
947	1035	NR1H3-767-787-864	31.55	7.72
948	1036	NR1H3-768-788-865	89.93	18.03
949	1037	NR1H3-769-789-866	18.84	4.39
950	1038	NR1H3-794-814-891	40.26	12.66
951	1039	NR1H3-1152-1172-1249	74.17	12.97
952	1040	NR1H3-1189-1209-1286	47.09	11.14
953	1041	NR1H3-1195-1215-1292	41.72	9.81
954	1042	NR1H3-1200-1220-1297	102.50	25.27
955	1043	NR1H3-1201-1221-1298	28.78	4.63
956	1044	NR1H3-1202-1222-1299	16.81	5.40
957	1045	NR1H3-1203-1223-1300	11.40	3.12
958	1046	NR1H3-1204-1224-1301	10.27	9.33
959	1047	NR1H3-1205-1225-1302	15.93	5.10
960	1048	NR1H3-1206-1226-1303	59.82	14.86
962	1050	NR1H3-1208-1228-1305	10.94	1.83
963	1051	NR1H3-1209-1229-1306	101.62	23.09
964	1052	NR1H3-1210-1230-1307	25.85	6.52
965	1053	NR1H3-1211-1231-1308	29.68	4.19
966	1054	NR1H3-1212-1232-1309	39.90	13.07
967	1055	NR1H3-1213-1233-1310	15.16	4.91
968	1056	NR1H3-1214-1234-1311	25.26	16.03
970	1058	NR1H3-1221-1241-1318	23.77	6.65
973	1061	NR1H3-1249-1269-1346	45.75	8.54
975	1063	NR1H3-1254-1274-1351	36.79	10.59
976	1064	NR1H3-1255-1275-1352	16.79	4.54
977	1065	NR1H3-1256-1276-1353	55.93	16.15
978	1066	NR1H3-1257-1277-1354	90.17	15.01
980	1068	NR1H3-1260-1280-1357	17.80	2.89
981	1069	NR1H3-1261-1281-1358	81.65	24.27
982	1070	NR1H3-1263-1283-1360	15.12	5.37
983	1071	NR1H3-1264-1284-1361	25.69	6.43
986	1074	NR1H3-1405-1471-1502	40.51	10.03
987	1075	NR1H3-1409-1475-1506	43.45	7.797
993	1081	NR1H3-1458-1524-1555	6.54	1.345
995	1083	NR1H3-1464-1530-1561	53.64	10.29
996	1084	NR1H3-1465-1531-1562	33.78	10.83
997	1085	NR1H3-1467-1533-1564	33.29	19.93
998	1086	NR1H3-1469-1535-1566	20.17	7.60
999	1087	NR1H3-1470-1536-1567	34.02	6.95
1002	1088	NR1H3-1480-1546-1577	31.73	6.53
1004	1092	NR1H3-1482-1548-1579	12.18	3.56
1009	1097	NR1H3-1524-1590-1621	28.36	10.49
1018	1106	NR1H3-1594-1660-1691	30.67	13.85
1019	1107	NR1H3-1595-1661-1692	50.80	8.90
1020	1108	NR1H3-1596-1662	56.02	19.49
1022	1110	NR1H3-1670-1734	10.71	5.09
1024	1112	NR1H3-1672-1736	25.94	11.33
1025	1113	NR1H3-1673-1737	53.70	17.23
1026	1114	NR1H3-1674-1738	14.48	2.82
1027	1115	NR1H3-1675-1739-1766	55.04	10.59
1028	1116	NR1H3-1676-1740-1767	33.47	12.90
1029	1117	NR1H3-1678-1742-1769	364.22	31.30

Example 4: RNAi Oligonucleotide Inhibition of NR1H3 Expression in Mice In Vivo

The in vitro screening assays in Examples 2 and 3 validated the ability of NR1H3-targeting oligonucleotides to knock-down target mRNA. To confirm the ability of the RNAi oligonucleotides to knockdown NR1H3 in vivo, an HDI mouse model was used. Two sets of GalNAc-conjugated NR1H3 oligonucleotides were evaluated. Specifically, a set of GalNAc-conjugated NR1H3 oligonucleotides were generated from DsiRNA screened in Example 2 (as shown in Table 4) and the GalNAc-conjugated NR1H3 oligonucleotides from Example 3 (as shown in Table 5). Both sets of constructs were evaluated in mice engineered to transiently express human NR1H3 mRNA in hepatocytes of the mouse liver. Briefly, 6-8-week-old female CD-1 mice (n=4-5) were subcutaneously administered the indicated GalNAc-conjugated NR1H3 oligonucleotides at a dose of 2 mg/kg formulated in PBS. A control group of mice (n=5) were administered only PBS. Three days later (72 hours), the mice were hydrodynamically injected (HDI) with a DNA plasmid encoding the full human NR1H3 gene (25 μg) under control of a ubiquitous cytomegalovirus (CMV) promoter sequence. One day after introduction of the DNA plasmid, liver samples from HDI mice were collected. Total RNA derived from these HDI mice were subjected to qRT-PCR analysis to determine NR1H3 mRNA levels as described in Example 2. mRNA levels were measured for both human and mouse mRNA. The values were normalized for transfection efficiency using the NeoR gene included on the DNA plasmid.

TABLE 4
GalNAc-Conjugated Human NR1H3 RNAi Oligonucleotides for HDI
screen
	Unmodified	Unmodified	Modified	Modified
	Sense Strand	Antisense	Sense Strand	Antisense
	(SED ID	strand	(SED ID	strand
	NO)	(SED ID NO)	NO)	(SED ID NO)
NR1H3-1207-	823	911	961	1049
1227
NR1H3-1220-	824	912	969	1057
1240
NR1H3-1224-	825	913	971	1059
1244
NR1H3-1244-	826	914	972	1060
1264
NR1H3-1252-	827	915	974	1062
1272
NR1H3-1259-	828	916	979	1067
1279
NR1H3-1265-	829	917	984	1072
1285
NR1H3-1266-	830	918	985	1073
1286
NR1H3-1429-	831	919	988	1076
1495
NR1H3-1433-	832	920	989	1077
1499
NR1H3-1437-	833	921	990	1078
1503
NR1H3-1439-	834	922	991	1079
1505
NR1H3-1446-	835	923	992	1080
1512
NR1H3-1463-	836	924	994	1082
1529
NR1H3-1475-	837	925	1000	1088
1541
NR1H3-1479-	838	926	1001	1089
1545
NR1H3-1481-	839	927	1003	1091
1547
NR1H3-1485-	840	928	1005	1093
1551
NR1H3-1515-	1537	929	1006	1094
1581
NR1H3-1517-	842	930	1007	1095
1583
NR1H3-1518-	843	931	1008	1096
1584
NR1H3-1533-	844	932	1010	1098
1599
NR1H3-1535-	845	933	1011	1099
1601
NR1H3-1545-	846	934	1012	1100
1611
NR1H3-1554-	847	935	1013	1101
1620
NR1H3-1581-	848	936	1014	1102
1647
NR1H3-1586-	849	937	1015	1103
1652
NR1H3-1587-	850	938	1016	1104
1653
NR1H3-1588-	851	939	1017	1105
1654
NR1H3-1663-	852	940	1021	1109
1727
NR1H3-1671-	853	941	1023	1111
1735
NR1H3-1684-	854	942	1030	1118
1748
NR1H3-1731-	855	943	1031	1119
1795
NR1H3-1732-	856	944	1032	1120
1796

TABLE 5
GalNAc-Conjugated Human NR1H3 RNAi Oligonucleotides for HDI
screen
	Unmodified	Unmodified	Modified	Modified
	Sense Strand	Antisense	Sense Strand	Antisense
	(SED ID	strand	(SED ID	strand
	NO)	(SED ID NO)	NO)	(SED ID NO)
NR1H3-763-	769	857	945	1033
783-860
NR1H3-765-	770	858	946	1034
785-862
NR1H3-767-	771	859	947	1035
787-864
NR1H3-768-	772	860	948	1036
788-865
NR1H3-769-	773	861	949	1037
789-866
NR1H3-794-	774	862	950	1038
814-891
NR1H3-1152-	775	863	951	1039
1172-1249
NR1H3-1189-	776	864	952	1040
1209-1286
NR1H3-1195-	777	865	953	1041
1215-1292
NR1H3-1200-	778	866	954	1042
1220-1297
NR1H3-1201-	779	867	955	1043
1221-1298
NR1H3-1202-	780	868	956	1044
1222-1299
NR1H3-1203-	781	869	957	1045
1223-1300
NR1H3-1204-	782	870	958	1046
1224-1301
NR1H3-1205-	783	871	959	1047
1225-1302
NR1H3-1206-	784	872	960	1048
1226-1303
NR1H3-1208-	785	873	962	1050
1228-1305
NR1H3-1209-	786	874	963	1051
1229-1306
NR1H3-1210-	787	875	964	1052
1230-1307
NR1H3-1211-	788	876	965	1053
1231-1308
NR1H3-1212-	789	877	966	1054
1232-1309
NR1H3-1213-	790	878	967	1055
1233-1310
NR1H3-1214-	791	879	968	1056
1234-1311
NR1H3-1221-	792	880	970	1058
124 1-13 18
NR1H3-1249-	793	881	973	1061
1269-1346
NR1H3-1254-	794	882	975	1063
1274-1351
NR1H3-1255-	795	883	976	1064
1275-1352
NR1H3-1256-	796	884	977	1065
1276-1353
NR1H3-1257-	797	885	978	1066
1277-1354
NR1H3-1260-	798	886	980	1068
1280-1357
NR1H3-1261-	799	887	981	1069
128 1-13 58
NR1H3-1263-	800	888	982	1070
1283-1360
NR1H3-1264-	801	889	983	1071
1284-1361
NR1H3-1405-	802	890	986	1074
1471-1502
NR1H3-1409-	803	891	987	1075
1475-1506
NR1H3-1458-	804	892	993	1081
1524-1555
NR1H3-1464-	805	893	995	1083
1530-1561
NR1H3-1465-	806	894	996	1084
1531-1562
NR1H3-1467-	807	895	997	1085
1533-1564
NR1H3-1469-	808	896	998	1086
1535-1566
NR1H3-1470-	809	897	999	1087
1536-1567
NR1H3-1480-	810	898	1002	1090
1546-1577
NR1H3-1482-	811	899	1004	1092
1548-1579
NR1H3-1524-	812	900	1009	1097
1590-1621
NR1H3-1594-	813	901	1018	1106
1660-1691
NR1H3-1595-	814	902	1019	1107
1661-1692
NR1H3-1596-	815	903	1020	1108
1662
NR1H3-1670-	816	904	1022	1110
1734
NR1H3-1672-	817	905	1024	1112
1736
NR1H3-1673-	818	906	1025	1113
1737
NR1H3-1674-	819	907	1026	1114
1738
NR1H3-1675-	820	908	1027	1115
1739-1766
NR1H3-1676-	821	909	1028	1116
1740-1767
NR1H3-1678-	822	910	1029	1117
1742-1769

The results in FIG. 1B and FIG. 2 demonstrate that GalNAc-conjugated NR1H3 oligonucleotides designed to target human NR1H3 mRNA successfully inhibited human NR1H3 mRNA expression in HDI mice, as determined by a reduction in the amount of human NR1H3 mRNA expression in liver samples from HDI mice treated with GalNAc-conjugated NR1H3 oligonucleotides relative to control HDI mice treated with only PBS. Benchmark controls (NR1H3-769 and NR1H3-1469), which were selected from a prior sequence screening, were used to confirm successful knock-down.

The GalNAc-conjugated NR1H3 oligonucleotides tested in FIG. 1B and FIG. 2 were further validated in repeat assays as shown in FIGS. 3 and 4 using constructs from Table 4 and Table 5. The assays verified knock-down efficiency of each GalNAc-conjugated NR1H3 oligonucleotide, and four constructs were selected for further analysis in non-human primates (NHP).

Example 5: RNAi Oligonucleotide Inhibition of NR1H3 Expression in Non-human Primates In Vivo

Effective GalNAc-NR1H3 constructs identified in the HDI mouse studies were assayed for targeting efficiency in non-human primates. Specifically, GalNAc-conjugated NR1H3 oligonucleotides listed in Table 6 were evaluated in non-naïve cynomolgus monkeys (Macaca fascicularis).

TABLE 6
GalNAc Constructs evaluated in non-human primate
	Modified Sense	Modified
	strand	Antisense strand
	(SED ID NO)	(SED ID NO)
NR1H3-1209-1229-	963	1051
1306
NR1H3-1210-1230-	964	1052
1307
NR1H3-1515-1581	1006	1094
NR1H3-1594-1660-	1018	1106
1691

In this study, the monkeys were grouped so that their mean body weights (about 5.4 kg) were comparable between the control and experimental groups. Each cohort contained at least two female and at least two male subjects. The GalNAc-conjugated NR1H3 oligonucleotides were administered subcutaneously at a dose of 1 or 4 mg/kg on Study Day 0, 28, 56, and 112 as outlined in FIG. 5. Blood samples and liver biopsies were collected as outlined in Table 7 and FIG. 5.

TABLE 7
Treatment plan for NHP study
	Dose
	(mg/	Dos-		DP	Blood	Liver
Group	kg)	ing	GalXC	Number	Collection	Biopsy	N
A	N/A	sc	PBS	N/A	−8, 0, 14,	−8, 28,	5
					28, 56, 112	56, 112
B	1	sc	NR1H3-1209-	DP18987P:	−8, 0, 14,	28, 56,	5
			1229-1306	DP18986G	28, 56, 112	112
C	4	sc	NR1H3-1209-	DP18987P:	−8, 0, 14,	−8, 28,	5
			1229-1306	DP18986G	28, 56, 112	56, 112
D	1	sc	NR1H3-1210-	DP18989P:	−8, 0, 14,	28, 56,	5
			1230-1307	DP18988G	28, 56, 112	112
E	4	sc	NR1H3-1210-	DP18989P:	−8, 0, 14,	−8, 28,	5
			1230-1307	DP18988G	28, 56, 112	56, 112
F	1	sc	NR1H3-1515-	DP20645P:	−8, 0, 14,	28, 56,	5
			1581	DP20644G	28, 56, 112	112
G	4	sc	NR1H3-1515-	DP20645P:	−8, 0, 14,	−8, 28,	5
			1581	DP20644G	28, 56, 112	56, 112
H	1	sc	NR1H3-1594-	DP19040P:	−8, 0, 14,	28, 56,	4
			1660-1691	DP19039G	28, 56, 112	112
I	4	sc	NR1H3-1594-	DP19040P:	−8, 0, 14,	−8, 28,	5
			1660-1691	DP19039G	28, 56, 112	56, 112

At each time point, total RNA derived from the liver biopsy samples was subjected to qRT-PCR analysis to measure NR1H3 mRNA in oligonucleotide-treated monkeys relative to those treated with a comparable volume of PBS. To normalize the data, the measurements were made relative to the reference gene, PPIB (Rh02802984_m1 (Taqman)). The following SYBR assays purchased from Integrated DNA Technologies were used to evaluate gene expressions: Forward-942: GTCTCTGTGCAGGAGATAGTTG (SEQ ID NO: 1517), Reverse-1399: GGAGGCTCACCAGTTTCATTA (SEQ ID NO: 1518). As shown in Table 8 (Day 28), treating NHPs with the GalNAc-conjugated NR1H3 oligonucleotides listed in Table 6 inhibited NR1H3 expression in the liver, as determined by a reduced amount of NR1H3 mRNA in liver samples from oligonucleotide-treated NHPs relative to NHPs treated with PBS. Days 56 and 112 were also measured (Table 8). These results demonstrate that treating NHPs with the GalNAc-conjugated NR1H3 oligonucleotides reduces the amount of NR1H3 mRNA in the liver in a dose dependent manner.

TABLE 8
NR1H3 mRNA remaining after treatment with the indicated
NR1H3-GalNAc in the liver from the oligonucleotide-treated NHP
	NR1H3 Gene Expression (% Time-Matched PBS)
		−1209	−1210	−1515	−1594
		1	4	1	4	1	4	1	4
		mg/	mg/	mg/	mg/	mg/	mg/	mg/	mg/
	PBS	kg	kg	kg	kg	kg	kg	kg	kg
Day 28
Animal 1	107.3	58.6	35.6	60.1	45.1	95.8	55.4	111.6	80.4
Animal 2	116.6	62.4	27.8	48.5	34.7	101.3	NS	108.3	103.6
Animal 3	122.1	79.4	44.5	73.8	35.7	111.8	74.1	145.5	45.9
Animal 4	77.4	78.5	50.5	65.1	27.5	70.0	45.1	195.4	73.2
Animal 5	76.6	89.2	37.4	77.5	45.2	78.9	34.9	NS	68.5
Average	100.0	73.6	39.2	65.0	37.6	91.6	52.4	140.2	74.3
SEM	9.7	5.7	3.9	5.1	3.4	7.6	8.4	20.2	9.3
Day 56
Animal 1	96.7	72.9	29.0	43.7	39.0	59.7	30.0	67.7	78.2
Animal 2	115.0	60.1	29.7	75.9	32.1	68.7	NS	85.1	103.4
Animal 3	87.1	52.7	32.6	36.8	40.4	48.1	45.0	104.3	70.0
Animal 4	103.4	34.9	45.0	51.9	26.9	43.6	37.3	76.2	72.1
Animal 5	97.8	45.9	32.3	55.9	36.0	47.1	31.1	NS	72.4
Average	100.0	53.3	33.7	52.8	34.9	53.4	35.9	83.3	79.2
SEM	4.6	6.4	2.9	6.6	2.5	4.7	3.4	7.8	6.2
Day 112
Animal 1	113.2	44.2	27.3	34.4	33.1	52.8	46.8	56.6	34.8
Animal 2	106.6	56.2	21.7	42.8	33.0	36.2	NS	57.9	31.2
Animal 3	100.2	59.6	22.1	33.4	29.6	46.2	45.7	48.5	44.2
Animal 4	103.1	47.8	45.0	44.9	33.1	44.1	44.9	65.7	32.1
Animal 5	77.0	55.9	34.4	45.3	32.1	52.6	37.6	NS	33.6
Average	100.0	52.7	30.1	40.2	32.2	46.4	43.8	57.2	35.2
SEM	6.2	2.9	4.4	2.6	0.7	3.1	2.1	3.5	2.3
NS = no sample

To confirm if the GalNAc conjugated NR1H3 were specific targeting NR1H3, both NR1H3 and NR1H2 expression was evaluated in liver samples. Non-human primates treated with 4 mg/kg of GalNAc-conjugated NR1H3 were assayed for expression at days 0, 28, 56, and 112 in the liver for knock-down (KD) of NR1H3 mRNA in (Table 9), and NR1H2 (Table 10). The results demonstrate that the constructs are specific to NR1H3 and do not have significant off target effects for NR1H2.

TABLE 9
NR1H3 mRNA remaining after treatment with the indicated
NR1H3-GalNAc in NHP
	NR1H3 Gene Expression (% Time Matched PBS)
	4 mg/kg
	PBS	−1209	−1210	−1515	−1594
	Day −6
Animal 1	65.8	136.6	204.3	103.8	NS
Animal 2	102.4	78.1	113.3	49.3	80.3
Animal 3	86.1	101.0	150.2	94.0	104.3
Animal 4	137.3	89.9	155.0	82.8	109.7
Animal 5	108.4	90.8	92.5	83.1	124.2
Average	100.0	99.3	143.1	82.6	104.6
SEM	11.9	10.0	19.2	9.2	9.1
	Day 28
Animal 1	107.3	35.6	45.1	55.4	80.4
Animal 2	116.6	27.8	34.7	NS	103.6
Animal 3	122.1	44.5	35.7	74.1	45.9
Animal 4	77.4	50.5	27.5	45.1	73.2
Animal 5	76.6	37.4	45.2	34.9	68.5
Average	100.0	39.2	37.6	52.4	74.3
SEM	9.7	3.9	3.4	8.4	9.3
	Day 56
Animal 1	96.7	29.0	39.0	30.0	78.2
Animal 2	115.0	29.7	32.1	NS	103.4
Animal 3	87.1	32.6	40.4	45.0	70.0
Animal 4	103.4	45.0	26.9	37.3	72.1
Animal 5	97.8	32.3	36.0	31.1	72.4
Average	100.0	33.7	34.9	35.9	79.2
SEM	4.6	2.9	2.5	3.4	6.2
	Day 112
Animal 1	113.2	27.3	33.1	46.8	34.8
Animal 2	106.6	21.7	33.0	NS	31.2
Animal 3	100.2	22.1	29.6	45.7	44.2
Animal 4	103.1	45.0	33.1	44.9	32.1
Animal 5	77.0	34.4	32.1	37.6	33.6
Average	100.0	30.1	32.2	43.8	35.2
SEM	6.2	4.4	0.7	2.1	2.3
NS = no sample

TABLE 10
NR1H2 mRNA remaining after treatment with the indicated
NR1H3-GalNAc in NHP
	NR1H2 Gene Expression (% Time Matched PBS)
	4 mg/kg
	PBS	−1209	−1210	−1515	−1594
	Day −6
Animal 1	119.7	84	324.9	79.8	NS
Animal 2	96.3	107.5	116.1	89.3	175.9
Animal 3	105.7	86.2	106.6	103	151.1
Animal 4	82.1	105.7	672	127.9	113.2
Animal 5	96.3	134.9	126.7	101.6	113.9
Average	100.0	103.7	269.3	100.3	138.5
SEM	6.2	9.2	108.5	8.1	15.3
	Day 28
Animal 1	101	80.2	122.2	102.7	117.5
Animal 2	123.3	80.9	103.7	NS	130
Animal 3	111.8	78.1	107.3	87.8	61.2
Animal 4	88.5	120.4	113.7	98.3	80.2
Animal 5	75.3	129.4	102.7	97.1	75.4
Average	100.0	97.8	109.9	96.5	92.9
SEM	8.4	11.2	3.6	3.1	13.1
	Day 56
Animal 1	118.5	127.9	119.2	90.9	88.5
Animal 2	118.4	98.6	99.6	NS	112
Animal 3	90.9	91	131.8	76.3	103
Animal 4	88.5	115.4	117.8	100.7	121.1
Animal 5	83.8	107.6	87.1	85.5	119.4
Average	100.0	108.1	111.1	88.4	108.8
SEM	7.6	6.4	7.9	5.1	6.0
	Day 112
Animal 1	105.6	114.2	107.9	95.6	89.6
Animal 2	108.5	81.5	106.8	NS	80.8
Animal 3	119.1	76.7	118.4	90.5	96.8
Animal 4	100.4	121.1	97.2	95.4	98.6
Animal 5	66.4	99.1	104.8	111.9	98.1
Average	100.0	98.5	107.0	98.4	92.8
SEM	8.9	8.7	3.4	4.7	3.4

Taken together, these results show that GalNAc-conjugated NR1H3 oligonucleotides designed to target human NR1H3 mRNA inhibit total NR1H3 expression in vivo (as determined by the reduction of the amount of NR1H3 mRNA).

Example 6

In order to determine the effect of hepatic NR1H3 knockdown on liver and plasma triglycerides and total plasma cholesterol, C57B1 mice fed a high fat, high fructose, high cholesterol (HFFC-NASH) diet were administrated a NR1H3 GalNac siRNA probe specifically designed to reduce NR1H3 expression in mice. The compound was administrated by subcutaneous injection 3 mg/kg once a week for 4 weeks. The respective vehicle treated groups (chow and HFFC-NASH diet) were treated with PBS.

As seen in Table 11, hepatocyte specific knockdown (KD) of murine NR1H3-specific GalNac siRNA led to a significant decrease in murine NR1H3 transcript expression in the liver of treated animals as compared to vehicle. Treatment leading to such hepatic NR1H3 mRNA reduction in turn induced reductions in liver triglycerides, plasma triglyceride and plasma total cholesterol. Furthermore, genes involved in hepatic de novo lipogenesis (fatty acid synthase (Fasn) and Acetyl-CoA carboxylase 2 (Acc2)) were decreased by treatment with the murine NR1H3-specific GalNac siRNA. In conclusion, hepatocyte-specific knockdown of NR1H3 mRNA in a mouse model for NAFLD led to significant improvement in NASH related dyslipidemia.

TABLE 11
			NASH	p-value
			diet/NR1H3	NASH/
	CHOW diet	NASH	KD	NASH
	AVG ± ST.	AVG ± ST.	AVG ± ST.	NR1H3
	DEV.	DEV.	DEV.	KD
Liver	9.39 ± 2.88	47.00 ± 12.56	19.39 ± 11.07	<0.0001
triglycerides
mg/g liver
Plasma	1.31 ± 0.31	0.86 ± 0.21	0.46 ± 0.11	0.0036
triglycerides
mM
Plasma total	2.06 ± 0.21	4.19 ± 0.54	3.37 ± 0.67	0.0145
cholesterol
mM
NR1H3	100 ± 5.27	106.19 ± 8.75	43.88 ± 6.27	<0.0001
mRNA
expression
Fasn mRNA	100 ± 44.53	56.60 ± 27.23	17.58 ± 6.06	0.0327
expression
Acc2 mRNA	100 ± 20.30	43.34 ± 21.89	12.21 ± 4.31	0.0034
expression

Example 7: GalNAc-Conjugated siRNA Targeting NR1H3 for Knock Down in Obese Rhesus Monkeys Fed a High Cholesterol Diet

A GalNAc-conjugated NR1H3 oligonucleotide (sense strand SEQ ID NO: 964 antisense strand SEQ ID NO: 1052) was administered to obese rhesus monkeys fed a high cholesterol diet (0.06% cholesterol). Eight obese rhesus monkeys fed a high cholesterol diet (0.06% cholesterol) for more than 4 years, and with a body weight ranging from 8-25 kg, were dosed with 4 mg/kg lead at weeks 0, 4 and 8 and study was terminated at week 12. A liver biopsy (week −3) and an ultrasound scan of the liver (week −1) were performed prior to dosing of the animals. Liver enzymes and plasma lipids were determined prior to dosing and every 2 weeks posttreatment to assess potential adverse effects. At the end of the study, liver and plasma samples were collected to measure the effect of NR1H3a knock down on lipid and cholesterol metabolism, hepatic genes involved in these pathways, as well as liver histology.

At the end of the study NR1H3a mRNA in the liver was decreased 50%. mRNA is calculated as A/A Ct levels relative to 18s gene expression in each sample. As NR1H3a is expressed in other liver cells, e.g. the Kupffer cells, a full knockdown of NR1H3a was not expected from a liver homogenate.

The plasma levels of liver enzymes and plasma levels of lipids are presented in Table 12. During the treatment period, there was no change in the plasma level of alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT) or total bilirubin (TB), while a small increase was observed in aspartate aminotransferase (AST) after 8 and 10 weeks of treatment. During the treatment period, there was no change in the plasma level total cholesterol (TC) or low-density lipoprotein cholesterol (LDL C), while a significant increase in high-density lipoprotein cholesterol (HDL C) was observed already after 2 weeks of treatment. After 12 weeks of treatment a significant decrease in plasma triglycerides (TG) was observed. In Table 12, data represent mean±standard error of the mean. Baseline is the average of measures from week −4 to week 0 (pre-dose). Statistics are done relative to baseline: One-Way ANOVA. P*<0.05 P**<0.01, P***<0.001.

TABLE 12
Liver enzymes and plasma lipids in response to NR1H3a KD in obese rhesus
monkeys.
						Plasma
					Plasma	Total
	AST	ALT	GGT	TBili	TG	Cholesterol	HDL-C	LDL-C
	(IU/L)	(IU/L)	(IU/L)	(mg/dL)	(mg/dL)	(mg/dL)	(mg/dL)	(mg/dL)
Baseline	31.9 ± 1.5	55.6 ± 7.1	55.1 ± 4.2	0.21 ± 0.01	110 ± 19	206 ± 21.9	80 ± 4.6	107 ± 17.3
Week 2	32.9 ± 2.9	58.4 ± 6.2	55.6 ± 5.2	0.17 ± 0.03	84.9 ± 10.3	209 ± 20	98 ± 6.0**	98 ± 14.5
Week 4	36.6 ± 4.1	68.9 ± 9.3	58.0 ± 3.8	0.18 ± 0.02	103 ± 20.2	210 ± 15	107 ± 4.3***	101 ± 10.8
Week 6	38.5 ± 3.2	66.3 ± 6.0	49.9 ± 3.2	0.23 ± 0.02	74.1 ± 6.7	208 ± 16	102 ± 6.4**	98 ± 9.8
Week 8	42.5 ± 2.5***	70.4 ± 9.0	54.1 ± 4.5	0.15 ± 0.02*	93.3 ± 18.0	211 ± 14	105 ± 6.2**	104 ± 9.4
Week 10	39.5 ± 2.8**	58.5 ± 3.7	60.0 ± 3.3	0.17 ± 0.02	91.6 ± 12.4	219 ± 15	107 ± 4.9**	105 ± 10.4
Week 12	36.1 ± 2.1	59.3 ± 7.0	62.8 ± 3.5	0.16 ± 0.02*	84.9 ± 17.2*	214 ± 14	108 ± 4.3**	116 ± 11.1

The effect of NR1H3a knock down on liver triglycerides and liver cholesterol is presented in Table 13. No significant change in liver triglycerides or cholesterol was observed. However, a tendency (p=0.055, paired t-test) towards a decrease in liver stiffness as measured by FibroScan™ was observed in response to hepatic NR1H3a knock down. In Table 13 data represent mean±standard error of the mean analyzed by a paired t-test. One monkey was excluded from the FibroScan™ analysis as it was not fully sedated during the second scan.

TABLE 13
TG and cholesterol levels and FibroScan ™ liver
stiffness in obese rhesus monkeys
	Baseline	Week 13-14
Liver triglycerides (mg/dL)	40.9 ± 6.6	40.0 ± 5.5
Liver cholesterol (mg/dL)	42.6 ± 3.9	41.4 ± 3.0
Liver stiffness kPa	5.7 ± 0.5	4.3 ± 0.2

From the study, it can be concluded that knockdown of NR1H3a in hepatocytes does not cause hepatic cholesterol accumulation in obese monkeys fed a high cholesterol diet. An increased in plasma HDL C was observed 2 weeks after dosing, while a lowering of plasma TG was observed at week 12. No effect on liver TG was observed but none of the monkeys had steatosis at the start of the study. However, a tendency toward a decrease in liver stiffness was observed in response to hepatic NR1H3a knockdown.

List of Embodiments

Embodiment 1. An RNAi oligonucleotide 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 antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 2. The RNAi oligonucleotide of embodiment 1, wherein the sense strand is 15 to 50 nucleotides in length.

Embodiment 3. The RNAi oligonucleotide of embodiments 1 or 2, wherein the sense strand is 18 to 36 nucleotides in length.

Embodiment 4. The RNAi oligonucleotide of any one of embodiments 1 to 3, wherein the antisense strand is 15 to 30 nucleotides in length.

Embodiment 5. The RNAi oligonucleotide of any one of embodiments 1 to 4, wherein the antisense strand is 22 nucleotides in length and wherein antisense strand and the sense strand form a duplex region of at least 19 nucleotides in length, optionally at least 20 nucleotides in length.

Embodiment 6. The RNAi oligonucleotide of any one of embodiments 1 to 5, wherein the region of complementarity is at least 19 contiguous nucleotides in length, optionally at least 20 nucleotides in length.

Embodiment 7. The RNAi oligonucleotide of any one of embodiments 1 to 6, wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein S1 is complementary to S2, and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length.

Embodiment 8. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 15 to 50 nucleotides in length and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 9. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 15 to 50 nucleotides in length and an antisense strand of 15 to 30 nucleotides in length, 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: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 10. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 15 to 50 nucleotides in length 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: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 11. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 18 to 36 nucleotides in length 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: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 12. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 18 to 36 nucleotides in length and an antisense strand of 22 nucleotides in length, 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: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 13. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 18 to 36 nucleotides in length and an antisense strand of 22 nucleotides in length, wherein the sense strand and the antisense strand form a duplex region, wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein S1 is complementary to S2, and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 14. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 36 nucleotides in length and an antisense strand of 22 nucleotides in length, wherein the sense strand and the antisense strand form a duplex region, wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein S1 is complementary to S2, and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 15. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 36 nucleotides in length and an antisense strand of 22 nucleotides in length, wherein the sense strand and the antisense strand form a duplex region of at least 19 nucleotides in length, optionally 20 nucleotides in length, wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein S1 is complementary to S2, and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 16. The RNAi oligonucleotide of any one of embodiments 7 and 13-15, wherein L is a triloop or a tetraloop.

Embodiment 17. The RNAi oligonucleotide of embodiment 16, wherein L is a tetraloop.

Embodiment 18. The RNAi oligonucleotide of embodiment 17, wherein the tetraloop comprises the sequence 5′-GAAA-3′.

Embodiment 19. The RNAi oligonucleotide of any one of embodiments 16-18, wherein the S1 and S2 are 1-10 nucleotides in length and have the same length.

Embodiment 20. The RNAi oligonucleotide of embodiment 19, wherein S1 and S2 are 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9 nucleotides, or 10 nucleotides in length.

Embodiment 21. The RNAi oligonucleotide of embodiment 20, wherein S1 and S2 are 6 nucleotides in length.

Embodiment 22. The RNAi oligonucleotide of any one of embodiments 16 to 21, wherein the stem-loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1121).

Embodiment 23. The RNAi oligonucleotide of any one of embodiments 1 to 22, wherein the antisense strand comprises a 3′-overhang sequence of one or more nucleotides in length.

Embodiment 24. The RNAi oligonucleotide of embodiment 23, wherein the 3′-overhang sequence is 2 nucleotides in length, optionally wherein the 3′-overhang sequence is GG.

Embodiment 25. The RNAi oligonucleotide of any one of the preceding embodiments, wherein the oligonucleotide comprises at least one modified nucleotide.

Embodiment 26. The RNAi oligonucleotide of embodiment 25, wherein the modified nucleotide comprises a 2′-modification.

Embodiment 27. The RNAi oligonucleotide of embodiment 26, wherein the 2′-modification is a modification selected from 2′-aminoethyl, 2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid.

Embodiment 28. The RNAi oligonucleotide of any one of embodiments 25 to 27, wherein all nucleotides comprising the oligonucleotide are modified, optionally wherein the modification is a 2′-modification selected from 2′-fluoro and 2′-O-methyl.

Embodiment 29. The RNAi oligonucleotide of any one of embodiments 25-28, wherein about 10-15%, 10%, 11%, 12%, 13%, 14%, or 15% of the nucleotides of the sense strand comprise a 2′-fluoro modification.

Embodiment 30. The RNAi oligonucleotide of any one of embodiments 25-29, wherein about 25-35%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the antisense strand comprise a 2′-fluoro modification.

Embodiment 31. The RNAi oligonucleotide of any one of embodiments 25-30, wherein about 25-35%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the oligonucleotide comprise a 2′-fluoro modification

Embodiment 32. The RNAi oligonucleotide of any one of embodiments 25-31, wherein the sense strand comprises 36 nucleotides with positions 1-36 from 5′ to 3′, wherein positions 8-11 comprise a 2′-fluoro modification.

Embodiment 33. The RNAi oligonucleotide of any one of embodiments 25-32, wherein 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.

Embodiment 34. The RNAi oligonucleotide of any one of embodiments 25-33, wherein the remaining nucleotides comprise a 2′-O-methyl modification.

Embodiment 35. The RNAi oligonucleotide of any one of the preceding embodiments, wherein the oligonucleotide comprises at least one modified internucleotide linkage.

Embodiment 36. The RNAi oligonucleotide of embodiment 35, wherein the at least one modified internucleotide linkage is a phosphorothioate linkage.

Embodiment 37. The RNAi oligonucleotide of any one of the preceding embodiments, wherein the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog.

Embodiment 38. The RNAi oligonucleotide of embodiment 37, wherein the phosphate analog is oxymethylphosphonate, vinylphosphonate or malonylphosphonate, optionally wherein the phosphate analog is a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy.

Embodiment 39. The RNAi oligonucleotide of any one of the preceding embodiments, wherein at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands.

Embodiment 40. The RNAi oligonucleotide of embodiment 39, wherein each targeting ligand comprises a carbohydrate, amino sugar, cholesterol, polypeptide or lipid.

Embodiment 41. The RNAi oligonucleotide of embodiment 39, wherein each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety.

Embodiment 42. The RNAi oligonucleotide of embodiment 35, wherein the GalNAc moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety.

Embodiment 43. The RNAi oligonucleotide of any one of embodiments 16 to 38, wherein up to 4 nucleotides of L of the stem-loop are each conjugated to a monovalent GalNAc moiety.

Embodiment 44. The RNAi oligonucleotide of any one of embodiments 1 to 43, wherein the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 769-856 or 1519-1552.

Embodiment 45. The RNAi oligonucleotide of any one of embodiments 1 to 44, wherein the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 857-944.

Embodiment 46. The RNAi oligonucleotide of any one of embodiments 1 to 45, 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.

Embodiment 47. The RNAi oligonucleotide of any one of embodiments 1 to 46, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 786, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 874.

Embodiment 48. The RNAi oligonucleotide of any one of embodiments 1 to 46, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 787, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 875.

Embodiment 49. The RNAi oligonucleotide of any one of embodiments 1 to 46, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1537, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 929.

Embodiment 50. The RNAi oligonucleotide of any one of embodiments 1 to 46, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 813, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 901.

Embodiment 51. An RNAi oligonucleotide 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 all nucleotides comprising the sense strand and antisense strand are modified, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 52. An RNAi oligonucleotide 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 all nucleotides comprising the sense strand and antisense strand are modified, wherein the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 53. An RNAi oligonucleotide 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 all nucleotides comprising the sense strand and antisense strand are modified, wherein the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 54. An RNAi oligonucleotide 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 all nucleotides comprising the sense strand and the antisense strand are modified, wherein the antisense strand and the sense strand comprise one or more 2′-fluoro and 2′-O-methyl modified nucleotides and at least one phosphorothioate linkage, wherein the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 55. The RNAi oligonucleotide of any one of embodiments 1-54, wherein the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 945-1032.

Embodiment 56. The RNAi oligonucleotide of any one of embodiments 1-55, wherein the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 1033-1120.

Embodiment 57. The RNAi oligonucleotide of any one of embodiments 1-56, 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.

Embodiment 58. The RNAi oligonucleotide of any one of embodiments 1-57, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 963 and 1051, respectively.

Embodiment 59. The RNAi oligonucleotide of any one of embodiments 1-57, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 964 and 1052, respectively.

Embodiment 60. The RNAi oligonucleotide of any one of embodiments 1-57, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 1006 and 1094, respectively.

Embodiment 61. The RNAi oligonucleotide of any one of embodiments 1-57, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 1018 and 1106, respectively.

Embodiment 62. An RNAi oligonucleotide for inhibiting expression of NR1H3, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a NR1H3 RNA transcript, wherein the sense strand comprises the sequence and all of the modifications of 5′-mCs-mU-mC-mA-mA-mG-mG-fA-fU-fU-fU-mC-mA-mG-mU-mU-mA-mU-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 963), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-40-mUs]-fUs-fAs-fU-fA-mA-fC-mU-mG-fA-mA-mA-mU-fC-mC-mU-mU-mG-mA-mGs-mGs-mG-3′ (SEQ ID NO: 1051), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

Embodiment 63. An RNAi oligonucleotide for inhibiting expression of NR1H3, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a NR1H3 RNA transcript, wherein the sense strand comprises the sequence and all of the modifications of 5′-mUs-mC-mA-mA-mG-mG-mA-fU-fU-fU-fC-mA-mG-mU-mU-mA-mU-mA-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 964) and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-40-mUs]-fUs-fUs-fA-fU-mA-fA-mC-mU-fG-mA-mA-mA-fU-mC-mC-mU-mU-mG-mAs-mGs-mG-3′ (SEQ ID NO: 1052), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

Embodiment 64. An RNAi oligonucleotide for inhibiting expression of NR1H3, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a NR1H3 RNA transcript, wherein the sense strand comprises the sequence and all of the modifications of 5′-mAs-mG-mC-mA-mG-mC-mG-fU-fC-fC-fA-mC-mU-mC-mA-mG-mA-mG-mC-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1006), and wherein the antisense strand comprises the sequence and all of the modifications of 5′[MePhosphonate-40-mUs]-fGs-fCs-fU-fC-mU-fG-mA-mG-fU-mG-mG-mA-fC-mG-mC-mU-mG-mC-mUs-mGs-mG-3′ (SEQ ID NO: 1094), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

Embodiment 65. A double stranded RNAi oligonucleotide (dsRNAi) for inhibiting expression of NR1H3, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a NR1H3 RNA transcript, wherein the sense strand comprises the sequence and all of the modifications of 5′-mAs-mU-mG-mU-mG-mC-mA-fC-fG-fA-fA-mU-mG-mA-mC-mU-mG-mU-mU-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1018), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fAs-fAs-fC-fA-mG-fU-mC-mA-fU-mU-mC-mG-fU-mG-mC-mA-mC-mA-mUs-mGs-mG-3′ (SEQ ID NO: 1106), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

Embodiment 66. A method for treating a subject having a disease, disorder or condition associated with NR1H3 expression, the method comprising administering to the subject a therapeutically effective amount of the RNAi oligonucleotide of any one of the preceding embodiments, or pharmaceutical composition thereof, thereby treating the subject.

Embodiment 67. A pharmaceutical composition comprising the RNAi oligonucleotide of any one of embodiments 1 to 65, and a pharmaceutically acceptable carrier, delivery agent or excipient.

Embodiment 68. A method of delivering an oligonucleotide to a subject, the method comprising administering pharmaceutical composition of embodiment 67 to the subject.

Embodiment 69. A method for reducing NR1H3 expression in a cell, a population of cells or a subject, the method comprising the step of:

• • i. contacting the cell or the population of cells with the RNAi oligonucleotide of any one of embodiments 1 to 65, or the pharmaceutical composition of embodiment 67; or
  • ii. administering to the subject the RNAi oligonucleotide of any one of embodiments 1 to 65, or the pharmaceutical composition of embodiment 67.

Embodiment 70. The method of embodiment 69, wherein reducing NR1H3 expression comprises reducing an amount or level of NR1H3 mRNA, an amount or level of NR1H3 protein, or both.

Embodiment 71. The method of embodiment 69 or 70, wherein the subject has a disease, disorder or condition associated with NR1H3 expression.

Embodiment 72. The method of embodiment 66 or 71, wherein the disease, disorder or condition associated with NR1H3 expression is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus.

Embodiment 73. The method of any one of embodiments 66 and 69 to 72, wherein the RNAi oligonucleotide, or pharmaceutical composition, is administered in combination with a second composition or therapeutic agent.

Embodiment 74. A method for treating a subject having a disease, disorder or condition associated with NR1H3 expression, the method comprising administering to the subject a therapeutically effective amount of an RNAi 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: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 75. A method for treating a subject having a disease, disorder or condition associated with NR1H3 expression, the method comprising administering to the subject a therapeutically effective amount of an RNAi oligonucleotide comprising a sense strand and an antisense strand selected from a row set forth in Table 4 or Table 5, or pharmaceutical composition thereof, thereby treating the subject.

Embodiment 76. A method for treating a subject having a disease, disorder or condition associated with NR1H3 expression, the method comprising administering to the subject a therapeutically effective amount of an RNAi oligonucleotide comprising a sense strand and an antisense strand, 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.

Embodiment 77. The method of embodiment 76, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 786, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 874.

Embodiment 78. The method of embodiment 76, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 787, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 875.

Embodiment 79. The method of embodiment 76, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1537, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 929.

Embodiment 80. The method of embodiment 76, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 813, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 901.

Embodiment 81. A method for treating a subject having a disease, disorder or condition associated with NR1H3 expression, the method comprising administering to the subject a therapeutically effective amount of an RNAi oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand 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.

Embodiment 82. The method of embodiment 81, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 963, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1051.

Embodiment 83. The method of embodiment 81, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 964, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1052.

Embodiment 84. The method of embodiment 81, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1006, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1094.

Embodiment 85. The method of embodiment 81, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1018, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1106.

Embodiment 86. The method of any one of embodiments 74 to 85, wherein the disease, disorder or condition associated with NR1H3 expression is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus.

Embodiment 87. Use of the RNAi oligonucleotide of any one of embodiments 1 to 65, or the pharmaceutical composition of embodiment 67, in the manufacture of a medicament for the treatment of a disease, disorder or condition associated with NR1H3 expression, optionally for the treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus.

Embodiment 88. The RNAi oligonucleotide of any one of embodiments 1 to 65, or the pharmaceutical composition of embodiment 67, for use, or adaptable for use, in the treatment of a disease, disorder or condition associated with NR1H3 expression, optionally for the treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus.

Embodiment 89. A kit comprising the RNAi oligonucleotide of any one of embodiments 1 to 65, an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administration to a subject having a disease, disorder or condition associated with NR1H3 expression.

Embodiment 90. The use of embodiment 87, the RNAi oligonucleotide or pharmaceutical composition for use, or adaptable for use, of embodiment 88, or the kit of embodiment 89, wherein the disease, disorder or condition associated with NR1H3 expression is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus.

Embodiment 91. 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, SEQ ID NOs: 1125-1511, SEQ ID NOs: 769-856, SEQ ID NOs: 1519-1552 or SEQ ID NOs: 945-1032; 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, SEQ ID NOs 1512-1515, or SEQ ID NOs: 1033-1120.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety.

				SEQ
Name	Species	Description	Sequence	ID NO
NR1H3-764-	Artificial	25 mer sense	UGUCCUGUCAGAAGAACAGAUCC	1
784-861	Sequence	strand	GC
NR1H3-766-	Artificial	25 mer sense	UCCUGUCAGAAGAACAGAUACGC	2
786-863	Sequence	strand	CU
NR1H3-789-	Artificial	25 mer sense	CUGAAGAAACUGAAGCGGCAAG	3
809-886	Sequence	strand	AGG
NR1H3-790-	Artificial	25 mer sense	UGAAGAAACUGAAGCGGCAAGA	4
810-887	Sequence	strand	GGA
NR1H3-791-	Artificial	25 mer sense	GAAGAAACUGAAGCGGCAAAAG	5
811-888	Sequence	strand	GAG
NR1H3-792-	Artificial	25 mer sense	AAGAAACUGAAGCGGCAAGAGG	6
812-889	Sequence	strand	AGG
NR1H3-793-	Artificial	25 mer sense	AGAAACUGAAGCGGCAAGAAGA	7
813-890	Sequence	strand	GGA
NR1H3-795-	Artificial	25 mer sense	AAACUGAAGCGGCAAGAGGAGG	8
815-892	Sequence	strand	AAC
NR1H3-796-	Artificial	25 mer sense	AACUGAAGCGGCAAGAGGAAGA	9
816-893	Sequence	strand	ACA
NR1H3-797-	Artificial	25 mer sense	ACUGAAGCGGCAAGAGGAGAAA	10
817-894	Sequence	strand	CAG
NR1H3-798-	Artificial	25 mer sense	CUGAAGCGGCAAGAGGAGGAAC	11
818-895	Sequence	strand	AGG
NR1H3-799-	Artificial	25 mer sense	UGAAGCGGCAAGAGGAGGAACA	12
819-896	Sequence	strand	GGC
NR1H3-802-	Artificial	25 mer sense	AGCGGCAAGAGGAGGAACAAGC	13
822-899	Sequence	strand	UCA
NR1H3-803-	Artificial	25 mer sense	GCGGCAAGAGGAGGAACAGACUC	14
823-900	Sequence	strand	AU
NR1H3-804-	Artificial	25 mer sense	CGGCAAGAGGAGGAACAGGAUC	15
824-901	Sequence	strand	AUG
NR1H3-806-	Artificial	25 mer sense	GCAAGAGGAGGAACAGGCUAAU	16
826-903	Sequence	strand	GCC
NR1H3-808-	Artificial	25 mer sense	AAGAGGAGGAACAGGCUCAAGCC	17
828-905	Sequence	strand	AC
NR1H3-809-	Artificial	25 mer sense	AGAGGAGGAACAGGCUCAUACCA	18
829-906	Sequence	strand	CA
NR1H3-810-	Artificial	25 mer sense	GAGGAGGAACAGGCUCAUGACAC	19
830-907	Sequence	strand	AU
NR1H3-811-	Artificial	25 mer sense	AGGAGGAACAGGCUCAUGCAACA	20
831-908	Sequence	strand	UC
NR1H3-813-	Artificial	25 mer sense	GAGGAACAGGCUCAUGCCAAAUC	21
833-910	Sequence	strand	CU
NR1H3-844	Artificial	25 mer sense	CCAGGGCUUCCUCACCCCCACAA	22
	Sequence	strand	AU
NR1H3-895-	Artificial	25 mer sense	UGGGCAUGAUCGAGAAGCUAGU	23
915-992	Sequence	strand	CGC
NR1H3-898-	Artificial	25 mer sense	GCAUGAUCGAGAAGCUCGUAGCU	24
918-995	Sequence	strand	GC
NR1H3-915-	Artificial	25 mer sense	GUCGCUGCCCAGCAACAGUAUAA	25
935	Sequence	strand	CC
NR1H3-917-	Artificial	25 mer sense	CGCUGCCCAGCAACAGUGUAACC	26
937	Sequence	strand	GG
NR1H3-922-	Artificial	25 mer sense	CCCAGCAACAGUGUAACCGACGC	27
942	Sequence	strand	UC
NR1H3-924-	Artificial	25 mer sense	CAGCAACAGUGUAACCGGCACUC	28
944	Sequence	strand	CU
NR1H3-925-	Artificial	25 mer sense	AGCAACAGUGUAACCGGCGAUCC	29
945	Sequence	strand	UU
NR1H3-927-	Artificial	25 mer sense	CAACAGUGUAACCGGCGCUACUU	30
947	Sequence	strand	UU
NR1H3-928-	Artificial	25 mer sense	AACAGUGUAACCGGCGCUCAUUU	31
948	Sequence	strand	UC
NR1H3-929-	Artificial	25 mer sense	ACAGUGUAACCGGCGCUCCAUUU	32
949	Sequence	strand	CU
NR1H3-930-	Artificial	25 mer sense	CAGUGUAACCGGCGCUCCUAUUC	33
950	Sequence	strand	UG
NR1H3-931-	Artificial	25 mer sense	AGUGUAACCGGCGCUCCUUAUCU	34
951	Sequence	strand	GA
NR1H3-932-	Artificial	25 mer sense	GUGUAACCGGCGCUCCUUUACUG	35
952	Sequence	strand	AC
NR1H3-933-	Artificial	25 mer sense	UGUAACCGGCGCUCCUUUUAUGA	36
953	Sequence	strand	CC
NR1H3-941-	Artificial	25 mer sense	GCGCUCCUUUUCUGACCGGAUUC	37
961	Sequence	strand	GA
NR1H3-944-	Artificial	25 mer sense	CUCCUUUUCUGACCGGCUUAGAG	38
964	Sequence	strand	UC
NR1H3-945-	Artificial	25 mer sense	UCCUUUUCUGACCGGCUUCAAGU	39
965	Sequence	strand	CA
NR1H3-946-	Artificial	25 mer sense	CCUUUUCUGACCGGCUUCGAGUC	40
966	Sequence	strand	AC
NR1H3-947-	Artificial	25 mer sense	CUUUUCUGACCGGCUUCGAAUCA	41
967	Sequence	strand	CG
NR1H3-949-	Artificial	25 mer sense	UUUCUGACCGGCUUCGAGUAACG	42
969	Sequence	strand	CC
NR1H3-951-	Artificial	25 mer sense	UCUGACCGGCUUCGAGUCAAGCC	43
971	Sequence	strand	UU
NR1H3-952-	Artificial	25 mer sense	CUGACCGGCUUCGAGUCACACCU	44
972	Sequence	strand	UG
NR1H3-953-	Artificial	25 mer sense	UGACCGGCUUCGAGUCACGACUU	45
973	Sequence	strand	GG
NR1H3-1151-	Artificial	25 mer sense	GGUGAUGCUUCUGGAGACAACUC	46
1171	Sequence	strand	GG
NR1H3-1153-	Artificial	25 mer sense	UGAUGCUUCUGGAGACAUCACGG	47
1173	Sequence	strand	AG
NR1H3-1154-	Artificial	25 mer sense	GAUGCUUCUGGAGACAUCUAGG	48
1174	Sequence	strand	AGG
NR1H3-1155-	Artificial	25 mer sense	AUGCUUCUGGAGACAUCUCAGAG	49
1175	Sequence	strand	GU
NR1H3-1156-	Artificial	25 mer sense	UGCUUCUGGAGACAUCUCGAAGG	50
1176	Sequence	strand	UA
NR1H3-1157-	Artificial	25 mer sense	GCUUCUGGAGACAUCUCGGAGGU	51
1177	Sequence	strand	AC
NR1H3-1158-	Artificial	25 mer sense	CUUCUGGAGACAUCUCGGAAGUA	52
1178	Sequence	strand	CA
NR1H3-1159-	Artificial	25 mer sense	UUCUGGAGACAUCUCGGAGAUAC	53
1179	Sequence	strand	AA
NR1H3-1160-	Artificial	25 mer sense	UCUGGAGACAUCUCGGAGGAACA	54
1180	Sequence	strand	AC
NR1H3-1161-	Artificial	25 mer sense	CUGGAGACAUCUCGGAGGUACAA	55
1181	Sequence	strand	CC
NR1H3-1162-	Artificial	25 mer sense	UGGAGACAUCUCGGAGGUAAAA	56
1182	Sequence	strand	CCC
NR1H3-1163-	Artificial	25 mer sense	GGAGACAUCUCGGAGGUACAACC	57
1183	Sequence	strand	CU
NR1H3-1164-	Artificial	25 mer sense	GAGACAUCUCGGAGGUACAACCC	58
1184	Sequence	strand	UG
NR1H3-1165-	Artificial	25 mer sense	AGACAUCUCGGAGGUACAAACCU	59
1185	Sequence	strand	GG
NR1H3-1166-	Artificial	25 mer sense	GACAUCUCGGAGGUACAACACUG	60
1186	Sequence	strand	GG
NR1H3-1167-	Artificial	25 mer sense	ACAUCUCGGAGGUACAACCAUGG	61
1187	Sequence	strand	GA
NR1H3-1169-	Artificial	25 mer sense	AUCUCGGAGGUACAACCCUAGGA	62
1189	Sequence	strand	GU
NR1H3-1170-	Artificial	25 mer sense	UCUCGGAGGUACAACCCUGAGAG	63
1190	Sequence	strand	UG
NR1H3-1171-	Artificial	25 mer sense	CUCGGAGGUACAACCCUGGAAGU	64
1191	Sequence	strand	GA
NR1H3-1173-	Artificial	25 mer sense	CGGAGGUACAACCCUGGGAAUGA	65
1193	Sequence	strand	GA
NR1H3-1175-	Artificial	25 mer sense	GAGGUACAACCCUGGGAGUAAG	66
1195	Sequence	strand	AGU
NR1H3-1176-	Artificial	25 mer sense	AGGUACAACCCUGGGAGUGAGA	67
1196	Sequence	strand	GUA
NR1H3-1177-	Artificial	25 mer sense	GGUACAACCCUGGGAGUGAAAG	68
1197	Sequence	strand	UAU
NR1H3-1178-	Artificial	25 mer sense	GUACAACCCUGGGAGUGAGAGU	69
1198	Sequence	strand	AUC
NR1H3-1179-	Artificial	25 mer sense	UACAACCCUGGGAGUGAGAAUA	70
1199	Sequence	strand	UCA
NR1H3-1180-	Artificial	25 mer sense	ACAACCCUGGGAGUGAGAGAAUC	71
1200	Sequence	strand	AC
NR1H3-1181-	Artificial	25 mer sense	CAACCCUGGGAGUGAGAGUAUCA	72
1201	Sequence	strand	CC
NR1H3-1182-	Artificial	25 mer sense	AACCCUGGGAGUGAGAGUAACAC	73
1202	Sequence	strand	CU
NR1H3-1183-	Artificial	25 mer sense	ACCCUGGGAGUGAGAGUAUAACC	74
1203	Sequence	strand	UU
NR1H3-1184-	Artificial	25 mer sense	CCCUGGGAGUGAGAGUAUCACCU	75
1204	Sequence	strand	UC
NR1H3-1185-	Artificial	25 mer sense	CCUGGGAGUGAGAGUAUCAACU	76
1205	Sequence	strand	UCC
NR1H3-1186-	Artificial	25 mer sense	CUGGGAGUGAGAGUAUCACAUU	77
1206	Sequence	strand	CCU
NR1H3-1187-	Artificial	25 mer sense	UGGGAGUGAGAGUAUCACCAUCC	78
1207	Sequence	strand	UC
NR1H3-1188-	Artificial	25 mer sense	GGGAGUGAGAGUAUCACCUACCU	79
1208	Sequence	strand	CA
NR1H3-1190-	Artificial	25 mer sense	GAGUGAGAGUAUCACCUUCAUCA	80
1210	Sequence	strand	AG
NR1H3-1191-	Artificial	25 mer sense	AGUGAGAGUAUCACCUUCCACAA	81
1211	Sequence	strand	GG
NR1H3-1192-	Artificial	25 mer sense	GUGAGAGUAUCACCUUCCUAAAG	82
1212	Sequence	strand	GA
NR1H3-1193-	Artificial	25 mer sense	UGAGAGUAUCACCUUCCUCAAGG	83
1213	Sequence	strand	AU
NR1H3-1194-	Artificial	25 mer sense	GAGAGUAUCACCUUCCUCAAGGA	84
1214	Sequence	strand	UU
NR1H3-1196-	Artificial	25 mer sense	GAGUAUCACCUUCCUCAAGAAUU	85
1216	Sequence	strand	UC
NR1H3-1197-	Artificial	25 mer sense	AGUAUCACCUUCCUCAAGGAUUU	86
1217	Sequence	strand	CA
NR1H3-1198-	Artificial	25 mer sense	GUAUCACCUUCCUCAAGGAAUUC	87
1218	Sequence	strand	AG
NR1H3-1199-	Artificial	25 mer sense	UAUCACCUUCCUCAAGGAUAUCA	88
1219	Sequence	strand	GU
NR1H3-1200-	Artificial	25 mer sense	AUCACCUUCCUCAAGGAUUACAG	89
1220	Sequence	strand	UU
NR1H3-1203-	Artificial	25 mer sense	ACCUUCCUCAAGGAUUUCAAUUA	90
1223	Sequence	strand	UA
NR1H3-1204-	Artificial	25 mer sense	CCUUCCUCAAGGAUUUCAGAUAU	91
1224	Sequence	strand	AA
NR1H3-1207-	Artificial	25 mer sense	UCCUCAAGGAUUUCAGUUAAAAC	92
1227	Sequence	strand	CG
NR1H3-1211-	Artificial	25 mer sense	CAAGGAUUUCAGUUAUAACAGG	93
1231	Sequence	strand	GAA
NR1H3-1212-	Artificial	25 mer sense	AAGGAUUUCAGUUAUAACCAGG	94
1232	Sequence	strand	AAG
NR1H3-1213-	Artificial	25 mer sense	AGGAUUUCAGUUAUAACCGAGA	95
1233	Sequence	strand	AGA
NR1H3-1214-	Artificial	25 mer sense	GGAUUUCAGUUAUAACCGGAAA	96
1234	Sequence	strand	GAC
NR1H3-1215-	Artificial	25 mer sense	GAUUUCAGUUAUAACCGGGAAG	97
1235	Sequence	strand	ACU
NR1H3-1216-	Artificial	25 mer sense	AUUUCAGUUAUAACCGGGAAGA	98
1236	Sequence	strand	CUU
NR1H3-1217-	Artificial	25 mer sense	UUUCAGUUAUAACCGGGAAAAC	99
1237	Sequence	strand	UUU
NR1H3-1218-	Artificial	25 mer sense	UUCAGUUAUAACCGGGAAGACU	100
1238	Sequence	strand	UUG
NR1H3-1219-	Artificial	25 mer sense	UCAGUUAUAACCGGGAAGAAUU	101
1239	Sequence	strand	UGC
NR1H3-1220-	Artificial	25 mer sense	CAGUUAUAACCGGGAAGACAUU	102
1240	Sequence	strand	GCC
NR1H3-1222-	Artificial	25 mer sense	GUUAUAACCGGGAAGACUUAGCC	103
1242	Sequence	strand	AA
NR1H3-1223-	Artificial	25 mer sense	UUAUAACCGGGAAGACUUUACCA	104
1243	Sequence	strand	AA
NR1H3-1224-	Artificial	25 mer sense	UAUAACCGGGAAGACUUUGACA	105
1244	Sequence	strand	AAG
NR1H3-1225-	Artificial	25 mer sense	AUAACCGGGAAGACUUUGCAAA	106
1245	Sequence	strand	AGC
NR1H3-1226-	Artificial	25 mer sense	UAACCGGGAAGACUUUGCCAAAG	107
1246	Sequence	strand	CA
NR1H3-1227-	Artificial	25 mer sense	AACCGGGAAGACUUUGCCAAAGC	108
1247	Sequence	strand	AG
NR1H3-1228-	Artificial	25 mer sense	ACCGGGAAGACUUUGCCAAAGCA	109
1248	Sequence	strand	GG
NR1H3-1229-	Artificial	25 mer sense	CCGGGAAGACUUUGCCAAAACAG	110
1249	Sequence	strand	GG
NR1H3-1232-	Artificial	25 mer sense	GGAAGACUUUGCCAAAGCAAGGC	111
1252	Sequence	strand	UG
NR1H3-1233-	Artificial	25 mer sense	GAAGACUUUGCCAAAGCAGAGCU	112
1253	Sequence	strand	GC
NR1H3-1234-	Artificial	25 mer sense	AAGACUUUGCCAAAGCAGGACUG	113
1254	Sequence	strand	CA
NR1H3-1235-	Artificial	25 mer sense	AGACUUUGCCAAAGCAGGGAUGC	114
1255	Sequence	strand	AA
NR1H3-1236-	Artificial	25 mer sense	GACUUUGCCAAAGCAGGGCAGCA	115
1256	Sequence	strand	AG
NR1H3-1237-	Artificial	25 mer sense	ACUUUGCCAAAGCAGGGCUACAA	116
1257	Sequence	strand	GU
NR1H3-1238-	Artificial	25 mer sense	CUUUGCCAAAGCAGGGCUGAAAG	117
1258	Sequence	strand	UG
NR1H3-1241-	Artificial	25 mer sense	UGCCAAAGCAGGGCUGCAAAUGG	118
1261	Sequence	strand	AA
NR1H3-1242-	Artificial	25 mer sense	GCCAAAGCAGGGCUGCAAGAGGA	119
1262	Sequence	strand	AU
NR1H3-1243-	Artificial	25 mer sense	CCAAAGCAGGGCUGCAAGUAGAA	120
1263	Sequence	strand	UU
NR1H3-1244-	Artificial	25 mer sense	CAAAGCAGGGCUGCAAGUGAAA	121
1264	Sequence	strand	UUC
NR1H3-1245-	Artificial	25 mer sense	AAAGCAGGGCUGCAAGUGGAAU	122
1265	Sequence	strand	UCA
NR1H3-1246-	Artificial	25 mer sense	AAGCAGGGCUGCAAGUGGAAUU	123
1266	Sequence	strand	CAU
NR1H3-1247-	Artificial	25 mer sense	AGCAGGGCUGCAAGUGGAAAUC	124
1267	Sequence	strand	AUC
NR1H3-1248-	Artificial	25 mer sense	GCAGGGCUGCAAGUGGAAUACA	125
1268	Sequence	strand	UCA
NR1H3-1250-	Artificial	25 mer sense	AGGGCUGCAAGUGGAAUUCAUC	126
1270	Sequence	strand	AAC
NR1H3-1251-	Artificial	25 mer sense	GGGCUGCAAGUGGAAUUCAACA	127
1271	Sequence	strand	ACC
NR1H3-1252-	Artificial	25 mer sense	GGCUGCAAGUGGAAUUCAUAAA	128
1272	Sequence	strand	CCC
NR1H3-1253-	Artificial	25 mer sense	GCUGCAAGUGGAAUUCAUCAACC	129
1273	Sequence	strand	CC
NR1H3-1256-	Artificial	25 mer sense	GCAAGUGGAAUUCAUCAACACCA	130
1276	Sequence	strand	UC
NR1H3-1258-	Artificial	25 mer sense	AAGUGGAAUUCAUCAACCCAAUC	131
1278	Sequence	strand	UU
NR1H3-1259-	Artificial	25 mer sense	AGUGGAAUUCAUCAACCCCAUCU	132
1279	Sequence	strand	UC
NR1H3-1261-	Artificial	25 mer sense	UGGAAUUCAUCAACCCCAUAUUC	133
1281	Sequence	strand	GA
NR1H3-1262-	Artificial	25 mer sense	GGAAUUCAUCAACCCCAUCAUCG	134
1282	Sequence	strand	AG
NR1H3-1265-	Artificial	25 mer sense	AUUCAUCAACCCCAUCUUCAAGU	135
1285	Sequence	strand	UC
NR1H3-1266-	Artificial	25 mer sense	UUCAUCAACCCCAUCUUCGAGUU	136
1286	Sequence	strand	CU
NR1H3-1267-	Artificial	25 mer sense	UCAUCAACCCCAUCUUCGAAUUC	137
1287	Sequence	strand	UC
NR1H3-1268-	Artificial	25 mer sense	CAUCAACCCCAUCUUCGAGAUCU	138
1288	Sequence	strand	CC
NR1H3-1269-	Artificial	25 mer sense	AUCAACCCCAUCUUCGAGUACUC	139
1289	Sequence	strand	CA
NR1H3-1270-	Artificial	25 mer sense	UCAACCCCAUCUUCGAGUUAUCC	140
1290	Sequence	strand	AG
NR1H3-1271-	Artificial	25 mer sense	CAACCCCAUCUUCGAGUUCACCA	141
1291	Sequence	strand	GG
NR1H3-1272-	Artificial	25 mer sense	AACCCCAUCUUCGAGUUCUACAG	142
1292	Sequence	strand	GG
NR1H3-1273-	Artificial	25 mer sense	ACCCCAUCUUCGAGUUCUCAAGG	143
1293	Sequence	strand	GC
NR1H3-1275-	Artificial	25 mer sense	CCCAUCUUCGAGUUCUCCAAGGC	144
1295	Sequence	strand	CA
NR1H3-1276-	Artificial	25 mer sense	CCAUCUUCGAGUUCUCCAGAGCC	145
1296	Sequence	strand	AU
NR1H3-1277-	Artificial	25 mer sense	CAUCUUCGAGUUCUCCAGGACCA	146
1297	Sequence	strand	UG
NR1H3-1278-	Artificial	25 mer sense	AUCUUCGAGUUCUCCAGGGACAU	147
1298	Sequence	strand	GA
NR1H3-1279-	Artificial	25 mer sense	UCUUCGAGUUCUCCAGGGCAAUG	148
1299	Sequence	strand	AA
NR1H3-1280-	Artificial	25 mer sense	CUUCGAGUUCUCCAGGGCCAUGA	149
1300	Sequence	strand	AU
NR1H3-1281-	Artificial	25 mer sense	UUCGAGUUCUCCAGGGCCAAGAA	150
1301	Sequence	strand	UG
NR1H3-1282-	Artificial	25 mer sense	UCGAGUUCUCCAGGGCCAUAAAU	151
1302	Sequence	strand	GA
NR1H3-1283-	Artificial	25 mer sense	CGAGUUCUCCAGGGCCAUGAAUG	152
1303	Sequence	strand	AG
NR1H3-1284-	Artificial	25 mer sense	GAGUUCUCCAGGGCCAUGAAUGA	153
1304	Sequence	strand	GC
NR1H3-1285-	Artificial	25 mer sense	AGUUCUCCAGGGCCAUGAAAGAG	154
1305	Sequence	strand	CU
NR1H3-1286-	Artificial	25 mer sense	GUUCUCCAGGGCCAUGAAUAAGC	155
1306	Sequence	strand	UG
NR1H3-1288-	Artificial	25 mer sense	UCUCCAGGGCCAUGAAUGAACUG	156
1308	Sequence	strand	CA
NR1H3-1289-	Artificial	25 mer sense	CUCCAGGGCCAUGAAUGAGAUGC	157
1309	Sequence	strand	AA
NR1H3-1290-	Artificial	25 mer sense	UCCAGGGCCAUGAAUGAGCAGCA	158
1310	Sequence	strand	AC
NR1H3-1291-	Artificial	25 mer sense	CCAGGGCCAUGAAUGAGCUACAA	159
1311	Sequence	strand	CU
NR1H3-1292-	Artificial	25 mer sense	CAGGGCCAUGAAUGAGCUGAAAC	160
1312	Sequence	strand	UC
NR1H3-1293-	Artificial	25 mer sense	AGGGCCAUGAAUGAGCUGCAACU	161
1313	Sequence	strand	CA
NR1H3-1294-	Artificial	25 mer sense	GGGCCAUGAAUGAGCUGCAACUC	162
1314	Sequence	strand	AA
NR1H3-1295-	Artificial	25 mer sense	GGCCAUGAAUGAGCUGCAAAUCA	163
1315	Sequence	strand	AU
NR1H3-1296-	Artificial	25 mer sense	GCCAUGAAUGAGCUGCAACACAA	164
1316	Sequence	strand	UG
NR1H3-1297-	Artificial	25 mer sense	CCAUGAAUGAGCUGCAACUAAAU	165
1317	Sequence	strand	GA
NR1H3-1338-	Artificial	25 mer sense	CUCAUUGCUAUCAGCAUCUACUC	166
1358	Sequence	strand	UG
NR1H3-1339-	Artificial	25 mer sense	UCAUUGCUAUCAGCAUCUUAUCU	167
1359	Sequence	strand	GC
NR1H3-1340-	Artificial	25 mer sense	CAUUGCUAUCAGCAUCUUCACUG	168
1360	Sequence	strand	CA
NR1H3-1341-	Artificial	25 mer sense	AUUGCUAUCAGCAUCUUCUAUGC	169
1361	Sequence	strand	AG
NR1H3-1342-	Artificial	25 mer sense	UUGCUAUCAGCAUCUUCUCAGCA	170
1362	Sequence	strand	GA
NR1H3-1343-	Artificial	25 mer sense	UGCUAUCAGCAUCUUCUCUACAG	171
1363	Sequence	strand	AC
NR1H3-1344-	Artificial	25 mer sense	GCUAUCAGCAUCUUCUCUGAAGA	172
1364	Sequence	strand	CC
NR1H3-1345-	Artificial	25 mer sense	CUAUCAGCAUCUUCUCUGCAGAC	173
1365	Sequence	strand	CG
NR1H3-1346-	Artificial	25 mer sense	UAUCAGCAUCUUCUCUGCAAACC	174
1366	Sequence	strand	GG
NR1H3-1347-	Artificial	25 mer sense	AUCAGCAUCUUCUCUGCAGACCG	175
1367	Sequence	strand	GC
NR1H3-1377-	Artificial	25 mer sense	GUGCAGGACCAGCUCCAGGAAGA	176
1443	Sequence	strand	GA
NR1H3-1379-	Artificial	25 mer sense	GCAGGACCAGCUCCAGGUAAAGA	177
1445	Sequence	strand	GG
NR1H3-1383-	Artificial	25 mer sense	GACCAGCUCCAGGUAGAGAAGCU	178
1449	Sequence	strand	GC
NR1H3-1384-	Artificial	25 mer sense	ACCAGCUCCAGGUAGAGAGACUG	179
1450	Sequence	strand	CA
NR1H3-1385-	Artificial	25 mer sense	CCAGCUCCAGGUAGAGAGGAUGC	180
1451	Sequence	strand	AG
NR1H3-1387-	Artificial	25 mer sense	AGCUCCAGGUAGAGAGGCUACAG	181
1453	Sequence	strand	CA
NR1H3-1388-	Artificial	25 mer sense	GCUCCAGGUAGAGAGGCUGAAGC	182
1454	Sequence	strand	AC
NR1H3-1391-	Artificial	25 mer sense	CCAGGUAGAGAGGCUGCAGAACA	183
1457	Sequence	strand	CA
NR1H3-1393-	Artificial	25 mer sense	AGGUAGAGAGGCUGCAGCAAAC	184
1459	Sequence	strand	AUA
NR1H3-1394-	Artificial	25 mer sense	GGUAGAGAGGCUGCAGCACACAU	185
1460	Sequence	strand	AU
NR1H3-1395-	Artificial	25 mer sense	GUAGAGAGGCUGCAGCACAAAU	186
1461	Sequence	strand	AUG
NR1H3-1396-	Artificial	25 mer sense	UAGAGAGGCUGCAGCACACAUAU	187
1462	Sequence	strand	GU
NR1H3-1397-	Artificial	25 mer sense	AGAGAGGCUGCAGCACACAAAUG	188
1463	Sequence	strand	UG
NR1H3-1398-	Artificial	25 mer sense	GAGAGGCUGCAGCACACAUAUGU	189
1464	Sequence	strand	GG
NR1H3-1399-	Artificial	25 mer sense	AGAGGCUGCAGCACACAUAAGUG	190
1465	Sequence	strand	GA
NR1H3-1400-	Artificial	25 mer sense	GAGGCUGCAGCACACAUAUAUGG	191
1466	Sequence	strand	AA
NR1H3-1401-	Artificial	25 mer sense	AGGCUGCAGCACACAUAUGAGGA	192
1467	Sequence	strand	AG
NR1H3-1402-	Artificial	25 mer sense	GGCUGCAGCACACAUAUGUAGAA	193
1468	Sequence	strand	GC
NR1H3-1403-	Artificial	25 mer sense	GCUGCAGCACACAUAUGUGAAAG	194
1469	Sequence	strand	CC
NR1H3-1404-	Artificial	25 mer sense	CUGCAGCACACAUAUGUGGAAGC	195
1470	Sequence	strand	CC
NR1H3-1406-	Artificial	25 mer sense	GCAGCACACAUAUGUGGAAACCC	196
1472	Sequence	strand	UG
NR1H3-1407-	Artificial	25 mer sense	CAGCACACAUAUGUGGAAGACCU	197
1473	Sequence	strand	GC
NR1H3-1408-	Artificial	25 mer sense	AGCACACAUAUGUGGAAGCACUG	198
1474	Sequence	strand	CA
NR1H3-1410-	Artificial	25 mer sense	CACACAUAUGUGGAAGCCCAGCA	199
1476	Sequence	strand	UG
NR1H3-1411-	Artificial	25 mer sense	ACACAUAUGUGGAAGCCCUACAU	200
1477	Sequence	strand	GC
NR1H3-1412-	Artificial	25 mer sense	CACAUAUGUGGAAGCCCUGAAUG	201
1478	Sequence	strand	CC
NR1H3-1413-	Artificial	25 mer sense	ACAUAUGUGGAAGCCCUGCAUGC	202
1479	Sequence	strand	CU
NR1H3-1414-	Artificial	25 mer sense	CAUAUGUGGAAGCCCUGCAAGCC	203
1480	Sequence	strand	UA
NR1H3-1415-	Artificial	25 mer sense	AUAUGUGGAAGCCCUGCAUACCU	204
1481	Sequence	strand	AC
NR1H3-1416-	Artificial	25 mer sense	UAUGUGGAAGCCCUGCAUGACUA	205
1482	Sequence	strand	CG
NR1H3-1417-	Artificial	25 mer sense	AUGUGGAAGCCCUGCAUGCAUAC	206
1483	Sequence	strand	GU
NR1H3-1418-	Artificial	25 mer sense	UGUGGAAGCCCUGCAUGCCAACG	207
1484	Sequence	strand	UC
NR1H3-1419-	Artificial	25 mer sense	GUGGAAGCCCUGCAUGCCUACGU	208
1485	Sequence	strand	CU
NR1H3-1420-	Artificial	25 mer sense	UGGAAGCCCUGCAUGCCUAAGUC	209
1486	Sequence	strand	UC
NR1H3-1421-	Artificial	25 mer sense	GGAAGCCCUGCAUGCCUACAUCU	210
1487	Sequence	strand	CC
NR1H3-1422-	Artificial	25 mer sense	GAAGCCCUGCAUGCCUACGACUC	211
1488	Sequence	strand	CA
NR1H3-1423-	Artificial	25 mer sense	AAGCCCUGCAUGCCUACGUAUCC	212
1489	Sequence	strand	AU
NR1H3-1424-	Artificial	25 mer sense	AGCCCUGCAUGCCUACGUCACCA	213
1490	Sequence	strand	UC
NR1H3-1425-	Artificial	25 mer sense	GCCCUGCAUGCCUACGUCUACAU	214
1491	Sequence	strand	CC
NR1H3-1426-	Artificial	25 mer sense	CCCUGCAUGCCUACGUCUCAAUC	215
1492	Sequence	strand	CA
NR1H3-1427-	Artificial	25 mer sense	CCUGCAUGCCUACGUCUCCAUCC	216
1493	Sequence	strand	AC
NR1H3-1428-	Artificial	25 mer sense	CUGCAUGCCUACGUCUCCAACCA	217
1494	Sequence	strand	CC
NR1H3-1429-	Artificial	25 mer sense	UGCAUGCCUACGUCUCCAUACAC	218
1495	Sequence	strand	CA
NR1H3-1430-	Artificial	25 mer sense	GCAUGCCUACGUCUCCAUCAACC	219
1496	Sequence	strand	AU
NR1H3-1431-	Artificial	25 mer sense	CAUGCCUACGUCUCCAUCCACCA	220
1497	Sequence	strand	UC
NR1H3-1432-	Artificial	25 mer sense	AUGCCUACGUCUCCAUCCAACAU	221
1498	Sequence	strand	CC
NR1H3-1433-	Artificial	25 mer sense	UGCCUACGUCUCCAUCCACAAUC	222
1499	Sequence	strand	CC
NR1H3-1434-	Artificial	25 mer sense	GCCUACGUCUCCAUCCACCAUCC	223
1500	Sequence	strand	CC
NR1H3-1435-	Artificial	25 mer sense	CCUACGUCUCCAUCCACCAACCC	224
1501	Sequence	strand	CA
NR1H3-1436-	Artificial	25 mer sense	CUACGUCUCCAUCCACCAUACCC	225
1502	Sequence	strand	AU
NR1H3-1437-	Artificial	25 mer sense	UACGUCUCCAUCCACCAUCACCA	226
1503	Sequence	strand	UG
NR1H3-1438-	Artificial	25 mer sense	ACGUCUCCAUCCACCAUCCACAU	227
1504	Sequence	strand	GA
NR1H3-1439-	Artificial	25 mer sense	CGUCUCCAUCCACCAUCCCAAUG	228
1505	Sequence	strand	AC
NR1H3-1440-	Artificial	25 mer sense	GUCUCCAUCCACCAUCCCCAUGA	229
1506	Sequence	strand	CC
NR1H3-1442-	Artificial	25 mer sense	CUCCAUCCACCAUCCCCAUAACC	230
1508	Sequence	strand	GA
NR1H3-1443-	Artificial	25 mer sense	UCCAUCCACCAUCCCCAUGACCG	231
1509	Sequence	strand	AC
NR1H3-1444-	Artificial	25 mer sense	CCAUCCACCAUCCCCAUGAACGA	232
1510	Sequence	strand	CU
NR1H3-1445-	Artificial	25 mer sense	CAUCCACCAUCCCCAUGACAGAC	233
1511	Sequence	strand	UG
NR1H3-1446-	Artificial	25 mer sense	AUCCACCAUCCCCAUGACCAACU	234
1512	Sequence	strand	GA
NR1H3-1447-	Artificial	25 mer sense	UCCACCAUCCCCAUGACCGACUG	235
1513	Sequence	strand	AU
NR1H3-1448-	Artificial	25 mer sense	CCACCAUCCCCAUGACCGAAUGA	236
1514	Sequence	strand	UG
NR1H3-1449-	Artificial	25 mer sense	CACCAUCCCCAUGACCGACAGAU	237
1515	Sequence	strand	GU
NR1H3-1450-	Artificial	25 mer sense	ACCAUCCCCAUGACCGACUAAUG	238
1516	Sequence	strand	UU
NR1H3-1451-	Artificial	25 mer sense	CCAUCCCCAUGACCGACUGAUGU	239
1517	Sequence	strand	UC
NR1H3-1452-	Artificial	25 mer sense	CAUCCCCAUGACCGACUGAAGUU	240
1518	Sequence	strand	CC
NR1H3-1453-	Artificial	25 mer sense	AUCCCCAUGACCGACUGAUAUUC	241
1519	Sequence	strand	CC
NR1H3-1454-	Artificial	25 mer sense	UCCCCAUGACCGACUGAUGAUCC	242
1520	Sequence	strand	CA
NR1H3-1455-	Artificial	25 mer sense	CCCCAUGACCGACUGAUGUACCC	243
1521	Sequence	strand	AC
NR1H3-1456-	Artificial	25 mer sense	CCCAUGACCGACUGAUGUUACCA	244
1522	Sequence	strand	CG
NR1H3-1457-	Artificial	25 mer sense	CCAUGACCGACUGAUGUUCACAC	245
1523	Sequence	strand	GG
NR1H3-1459-	Artificial	25 mer sense	AUGACCGACUGAUGUUCCCACGG	246
1525	Sequence	strand	AU
NR1H3-1460-	Artificial	25 mer sense	UGACCGACUGAUGUUCCCAAGGA	247
1526	Sequence	strand	UG
NR1H3-1461-	Artificial	25 mer sense	GACCGACUGAUGUUCCCACAGAU	248
1527	Sequence	strand	GC
NR1H3-1462-	Artificial	25 mer sense	ACCGACUGAUGUUCCCACGAAUG	249
1528	Sequence	strand	CU
NR1H3-1463-	Artificial	25 mer sense	CCGACUGAUGUUCCCACGGAUGC	250
1529	Sequence	strand	UA
NR1H3-1465-	Artificial	25 mer sense	GACUGAUGUUCCCACGGAUACUA	251
1531	Sequence	strand	AU
NR1H3-1466-	Artificial	25 mer sense	ACUGAUGUUCCCACGGAUGAUAA	252
1532	Sequence	strand	UG
NR1H3-1468-	Artificial	25 mer sense	UGAUGUUCCCACGGAUGCUAAUG	253
1534	Sequence	strand	AA
NR1H3-1469-	Artificial	25 mer sense	GAUGUUCCCACGGAUGCUAAUGA	254
1535	Sequence	strand	AA
NR1H3-1471-	Artificial	25 mer sense	UGUUCCCACGGAUGCUAAUAAAA	255
1537	Sequence	strand	CU
NR1H3-1472-	Artificial	25 mer sense	GUUCCCACGGAUGCUAAUGAAAC	256
1538	Sequence	strand	UG
NR1H3-1473-	Artificial	25 mer sense	UUCCCACGGAUGCUAAUGAAACU	257
1539	Sequence	strand	GG
NR1H3-1474-	Artificial	25 mer sense	UCCCACGGAUGCUAAUGAAACUG	258
1540	Sequence	strand	GU
NR1H3-1475-	Artificial	25 mer sense	CCCACGGAUGCUAAUGAAAAUGG	259
1541	Sequence	strand	UG
NR1H3-1476-	Artificial	25 mer sense	CCACGGAUGCUAAUGAAACAGGU	260
1542	Sequence	strand	GA
NR1H3-1477-	Artificial	25 mer sense	CACGGAUGCUAAUGAAACUAGU	261
1543	Sequence	strand	GAG
NR1H3-1478-	Artificial	25 mer sense	ACGGAUGCUAAUGAAACUGAUG	262
1544	Sequence	strand	AGC
NR1H3-1479-	Artificial	25 mer sense	CGGAUGCUAAUGAAACUGGAGA	263
1545	Sequence	strand	GCC
NR1H3-1480-	Artificial	25 mer sense	GGAUGCUAAUGAAACUGGUAAG	264
1546	Sequence	strand	CCU
NR1H3-1481-	Artificial	25 mer sense	GAUGCUAAUGAAACUGGUGAGC	265
1547	Sequence	strand	CUC
NR1H3-1483-	Artificial	25 mer sense	UGCUAAUGAAACUGGUGAGACU	266
1549	Sequence	strand	CCG
NR1H3-1484-	Artificial	25 mer sense	GCUAAUGAAACUGGUGAGCAUCC	267
1550	Sequence	strand	GG
NR1H3-1485-	Artificial	25 mer sense	CUAAUGAAACUGGUGAGCCACCG	268
1551	Sequence	strand	GA
NR1H3-1486-	Artificial	25 mer sense	UAAUGAAACUGGUGAGCCUACG	269
1552	Sequence	strand	GAC
NR1H3-1487-	Artificial	25 mer sense	AAUGAAACUGGUGAGCCUCAGG	270
1553	Sequence	strand	ACC
NR1H3-1488-	Artificial	25 mer sense	AUGAAACUGGUGAGCCUCCAGAC	271
1554	Sequence	strand	CC
NR1H3-1489-	Artificial	25 mer sense	UGAAACUGGUGAGCCUCCGAACC	272
1555	Sequence	strand	CU
NR1H3-1491-	Artificial	25 mer sense	AAACUGGUGAGCCUCCGGAACCU	273
1557	Sequence	strand	GA
NR1H3-1492-	Artificial	25 mer sense	AACUGGUGAGCCUCCGGACACUG	274
1558	Sequence	strand	AG
NR1H3-1494-	Artificial	25 mer sense	CUGGUGAGCCUCCGGACCCAGAG	275
1560	Sequence	strand	CA
NR1H3-1505-	Artificial	25 mer sense	CCGGACCCUGAGCAGCGUCAACU	276
1571	Sequence	strand	CA
NR1H3-1507-	Artificial	25 mer sense	GGACCCUGAGCAGCGUCCAAUCA	277
1573	Sequence	strand	GA
NR1H3-1508-	Artificial	25 mer sense	GACCCUGAGCAGCGUCCACACAG	278
1574	Sequence	strand	AG
NR1H3-1509-	Artificial	25 mer sense	ACCCUGAGCAGCGUCCACUAAGA	279
1575	Sequence	strand	GC
NR1H3-1510-	Artificial	25 mer sense	CCCUGAGCAGCGUCCACUCAGAG	280
1576	Sequence	strand	CA
NR1H3-1511-	Artificial	25 mer sense	CCUGAGCAGCGUCCACUCAAAGC	281
1577	Sequence	strand	AA
NR1H3-1512-	Artificial	25 mer sense	CUGAGCAGCGUCCACUCAGAGCA	282
1578	Sequence	strand	AG
NR1H3-1513-	Artificial	25 mer sense	UGAGCAGCGUCCACUCAGAACAA	283
1579	Sequence	strand	GU
NR1H3-1514-	Artificial	25 mer sense	GAGCAGCGUCCACUCAGAGAAAG	284
1580	Sequence	strand	UG
NR1H3-1515-	Artificial	25 mer sense	AGCAGCGUCCACUCAGAGCAAGU	285
1581	Sequence	strand	GU
NR1H3-1516-	Artificial	25 mer sense	GCAGCGUCCACUCAGAGCAAGUG	286
1582	Sequence	strand	UU
NR1H3-1517-	Artificial	25 mer sense	CAGCGUCCACUCAGAGCAAAUGU	287
1583	Sequence	strand	UU
NR1H3-1518-	Artificial	25 mer sense	AGCGUCCACUCAGAGCAAGAGUU	288
1584	Sequence	strand	UG
NR1H3-1519-	Artificial	25 mer sense	GCGUCCACUCAGAGCAAGUAUUU	289
1585	Sequence	strand	GC
NR1H3-1520-	Artificial	25 mer sense	CGUCCACUCAGAGCAAGUGAUUG	290
1586	Sequence	strand	CA
NR1H3-1521-	Artificial	25 mer sense	GUCCACUCAGAGCAAGUGUAUGC	291
1587	Sequence	strand	AC
NR1H3-1522-	Artificial	25 mer sense	UCCACUCAGAGCAAGUGUUAGCA	292
1588	Sequence	strand	CU
NR1H3-1523-	Artificial	25 mer sense	CCACUCAGAGCAAGUGUUUACAC	293
1589	Sequence	strand	UG
NR1H3-1525-	Artificial	25 mer sense	ACUCAGAGCAAGUGUUUGCACUG	294
1591	Sequence	strand	CG
NR1H3-1526-	Artificial	25 mer sense	CUCAGAGCAAGUGUUUGCAAUGC	295
1592	Sequence	strand	GU
NR1H3-1527-	Artificial	25 mer sense	UCAGAGCAAGUGUUUGCACAGCG	296
1593	Sequence	strand	UC
NR1H3-1528-	Artificial	25 mer sense	CAGAGCAAGUGUUUGCACUACGU	297
1594	Sequence	strand	CU
NR1H3-1529-	Artificial	25 mer sense	AGAGCAAGUGUUUGCACUGAGU	298
1595	Sequence	strand	CUG
NR1H3-1530-	Artificial	25 mer sense	GAGCAAGUGUUUGCACUGCAUCU	299
1596	Sequence	strand	GC
NR1H3-1531-	Artificial	25 mer sense	AGCAAGUGUUUGCACUGCGACUG	300
1597	Sequence	strand	CA
NR1H3-1532-	Artificial	25 mer sense	GCAAGUGUUUGCACUGCGUAUGC	301
1598	Sequence	strand	AGA
NR1H3-1533-	Artificial	25 mer sense	CAAGUGUUUGCACUGCGUCAGC	302
1599	Sequence	strand	GG
NR1H3-1534-	Artificial	25 mer sense	AAGUGUUUGCACUGCGUCUACAG	303
1600	Sequence	strand	GA
NR1H3-1535-	Artificial	25 mer sense	AGUGUUUGCACUGCGUCUGAAG	304
1601	Sequence	strand	GAC
NR1H3-1536-	Artificial	25 mer sense	GUGUUUGCACUGCGUCUGCAGGA	305
1602	Sequence	strand	CA
NR1H3-1537-	Artificial	25 mer sense	UGUUUGCACUGCGUCUGCAAGAC	306
1603	Sequence	strand	AA
NR1H3-1538-	Artificial	25 mer sense	GUUUGCACUGCGUCUGCAGAACA	307
1604	Sequence	strand	AA
NR1H3-1539-	Artificial	25 mer sense	UUUGCACUGCGUCUGCAGGACAA	308
1605	Sequence	strand	AA
NR1H3-1540-	Artificial	25 mer sense	UUGCACUGCGUCUGCAGGAAAAA	309
1606	Sequence	strand	AA
NR1H3-1541-	Artificial	25 mer sense	UGCACUGCGUCUGCAGGACAAAA	310
1607	Sequence	strand	AG
NR1H3-1542-	Artificial	25 mer sense	GCACUGCGUCUGCAGGACAAAAA	311
1608	Sequence	strand	GC
NR1H3-1543-	Artificial	25 mer sense	CACUGCGUCUGCAGGACAAAAAG	312
1609	Sequence	strand	CU
NR1H3-1544-	Artificial	25 mer sense	ACUGCGUCUGCAGGACAAAAAGC	313
1610	Sequence	strand	UC
NR1H3-1545-	Artificial	25 mer sense	CUGCGUCUGCAGGACAAAAAGCU	314
1611	Sequence	strand	CC
NR1H3-1546-	Artificial	25 mer sense	UGCGUCUGCAGGACAAAAAACUC	315
1612	Sequence	strand	CC
NR1H3-1547-	Artificial	25 mer sense	GCGUCUGCAGGACAAAAAGAUCC	316
1613	Sequence	strand	CA
NR1H3-1548-	Artificial	25 mer sense	CGUCUGCAGGACAAAAAGCACCC	317
1614	Sequence	strand	AC
NR1H3-1549-	Artificial	25 mer sense	GUCUGCAGGACAAAAAGCUACCA	318
1615	Sequence	strand	CC
NR1H3-1550-	Artificial	25 mer sense	UCUGCAGGACAAAAAGCUCACAC	319
1616	Sequence	strand	CG
NR1H3-1551-	Artificial	25 mer sense	CUGCAGGACAAAAAGCUCCAACC	320
1617	Sequence	strand	GC
NR1H3-1553-	Artificial	25 mer sense	GCAGGACAAAAAGCUCCCAACGC	321
1619	Sequence	strand	UG
NR1H3-1554-	Artificial	25 mer sense	CAGGACAAAAAGCUCCCACAGCU	322
1620	Sequence	strand	GC
NR1H3-1555-	Artificial	25 mer sense	AGGACAAAAAGCUCCCACCACUG	323
1621	Sequence	strand	CU
NR1H3-1556-	Artificial	25 mer sense	GGACAAAAAGCUCCCACCGAUGC	324
1622	Sequence	strand	UC
NR1H3-1558-	Artificial	25 mer sense	ACAAAAAGCUCCCACCGCUACUC	325
1624	Sequence	strand	UC
NR1H3-1559-	Artificial	25 mer sense	CAAAAAGCUCCCACCGCUGAUCU	326
1625	Sequence	strand	CU
NR1H3-1560-	Artificial	25 mer sense	AAAAAGCUCCCACCGCUGCACUC	327
1626	Sequence	strand	UG
NR1H3-1561-	Artificial	25 mer sense	AAAAGCUCCCACCGCUGCUAUCU	328
1627	Sequence	strand	GA
NR1H3-1562-	Artificial	25 mer sense	AAAGCUCCCACCGCUGCUCACUG	329
1628	Sequence	strand	AG
NR1H3-1563-	Artificial	25 mer sense	AAGCUCCCACCGCUGCUCUAUGA	330
1629	Sequence	strand	GA
NR1H3-1564-	Artificial	25 mer sense	AGCUCCCACCGCUGCUCUCAGAG	331
1630	Sequence	strand	AU
NR1H3-1565-	Artificial	25 mer sense	GCUCCCACCGCUGCUCUCUAAGA	332
1631	Sequence	strand	UC
NR1H3-1567-	Artificial	25 mer sense	UCCCACCGCUGCUCUCUGAAAUC	333
1633	Sequence	strand	UG
NR1H3-1569-	Artificial	25 mer sense	CCACCGCUGCUCUCUGAGAACUG	334
1635	Sequence	strand	GG
NR1H3-1570-	Artificial	25 mer sense	CACCGCUGCUCUCUGAGAUAUGG	335
1636	Sequence	strand	GA
NR1H3-1572-	Artificial	25 mer sense	CCGCUGCUCUCUGAGAUCUAGGA	336
1638	Sequence	strand	UG
NR1H3-1573-	Artificial	25 mer sense	CGCUGCUCUCUGAGAUCUGAGAU	337
1639	Sequence	strand	GU
NR1H3-1574-	Artificial	25 mer sense	GCUGCUCUCUGAGAUCUGGAAUG	338
1640	Sequence	strand	UG
NR1H3-1577-	Artificial	25 mer sense	GCUCUCUGAGAUCUGGGAUAUGC	339
1643	Sequence	strand	AC
NR1H3-1579-	Artificial	25 mer sense	UCUCUGAGAUCUGGGAUGUACAC	340
1645	Sequence	strand	GA
NR1H3-1580-	Artificial	25 mer sense	CUCUGAGAUCUGGGAUGUGAAC	341
1646	Sequence	strand	GAA
NR1H3-1581-	Artificial	25 mer sense	UCUGAGAUCUGGGAUGUGCACG	342
1647	Sequence	strand	AAU
NR1H3-1582-	Artificial	25 mer sense	CUGAGAUCUGGGAUGUGCAAGA	343
1648	Sequence	strand	AUG
NR1H3-1583-	Artificial	25 mer sense	UGAGAUCUGGGAUGUGCACAAA	344
1649	Sequence	strand	UGA
NR1H3-1584-	Artificial	25 mer sense	GAGAUCUGGGAUGUGCACGAAU	345
1650	Sequence	strand	GAC
NR1H3-1585-	Artificial	25 mer sense	AGAUCUGGGAUGUGCACGAAUG	346
1651	Sequence	strand	ACU
NR1H3-1586-	Artificial	25 mer sense	GAUCUGGGAUGUGCACGAAAGA	347
1652	Sequence	strand	CUG
NR1H3-1587-	Artificial	25 mer sense	AUCUGGGAUGUGCACGAAUAAC	348
1653	Sequence	strand	UGU
NR1H3-1588-	Artificial	25 mer sense	UCUGGGAUGUGCACGAAUGACU	349
1654	Sequence	strand	GUU
NR1H3-1589-	Artificial	25 mer sense	CUGGGAUGUGCACGAAUGAAUG	350
1655	Sequence	strand	UUC
NR1H3-1590-	Artificial	25 mer sense	UGGGAUGUGCACGAAUGACAGU	351
1656	Sequence	strand	UCU
NR1H3-1591-	Artificial	25 mer sense	GGGAUGUGCACGAAUGACUAUU	352
1657	Sequence	strand	CUG
NR1H3-1592-	Artificial	25 mer sense	GGAUGUGCACGAAUGACUGAUC	353
1658	Sequence	strand	UGU
NR1H3-1593-	Artificial	25 mer sense	GAUGUGCACGAAUGACUGUACU	354
1659	Sequence	strand	GUC
NR1H3-1656-	Artificial	25 mer sense	UGGUGGCUGCCUCCUAGAAAUGG	355
1720	Sequence	strand	AA
NR1H3-1657-	Artificial	25 mer sense	GGUGGCUGCCUCCUAGAAGAGGA	356
1721	Sequence	strand	AC
NR1H3-1658-	Artificial	25 mer sense	GUGGCUGCCUCCUAGAAGUAGAA	357
1722	Sequence	strand	CA
NR1H3-1659-	Artificial	25 mer sense	UGGCUGCCUCCUAGAAGUGAAAC	358
1723	Sequence	strand	AG
NR1H3-1660-	Artificial	25 mer sense	GGCUGCCUCCUAGAAGUGGAACA	359
1724	Sequence	strand	GA
NR1H3-1661-	Artificial	25 mer sense	GCUGCCUCCUAGAAGUGGAACAG	360
1725	Sequence	strand	AC
NR1H3-1662-	Artificial	25 mer sense	CUGCCUCCUAGAAGUGGAAAAGA	361
1726	Sequence	strand	CU
NR1H3-1663-	Artificial	25 mer sense	UGCCUCCUAGAAGUGGAACAGAC	362
1727	Sequence	strand	UG
NR1H3-1664-	Artificial	25 mer sense	GCCUCCUAGAAGUGGAACAAACU	363
1728	Sequence	strand	GA
NR1H3-1665-	Artificial	25 mer sense	CCUCCUAGAAGUGGAACAGACUG	364
1729	Sequence	strand	AG
NR1H3-1666-	Artificial	25 mer sense	CUCCUAGAAGUGGAACAGAAUG	365
1730	Sequence	strand	AGA
NR1H3-1667-	Artificial	25 mer sense	UCCUAGAAGUGGAACAGACAGA	366
1731	Sequence	strand	GAA
NR1H3-1668-	Artificial	25 mer sense	CCUAGAAGUGGAACAGACUAAG	367
1732	Sequence	strand	AAG
NR1H3-1669-	Artificial	25 mer sense	CUAGAAGUGGAACAGACUGAGA	368
1733	Sequence	strand	AGG
NR1H3-1671-	Artificial	25 mer sense	AGAAGUGGAACAGACUGAGAAG	369
1735	Sequence	strand	GGC
NR1H3-1677-	Artificial	25 mer sense	GGAACAGACUGAGAAGGGCAAA	370
1741	Sequence	strand	CAU
NR1H3-1679-	Artificial	25 mer sense	AACAGACUGAGAAGGGCAAACA	371
1743	Sequence	strand	UUC
NR1H3-1680-	Artificial	25 mer sense	ACAGACUGAGAAGGGCAAAAAU	372
1744	Sequence	strand	UCC
NR1H3-1681-	Artificial	25 mer sense	CAGACUGAGAAGGGCAAACAUUC	373
1745	Sequence	strand	CU
NR1H3-1682-	Artificial	25 mer sense	AGACUGAGAAGGGCAAACAAUCC	374
1746	Sequence	strand	UG
NR1H3-1683-	Artificial	25 mer sense	GACUGAGAAGGGCAAACAUACCU	375
1747	Sequence	strand	GG
NR1H3-1684-	Artificial	25 mer sense	ACUGAGAAGGGCAAACAUUACU	376
1748	Sequence	strand	GGG
NR1H3-1685-	Artificial	25 mer sense	CUGAGAAGGGCAAACAUUCAUG	377
1749	Sequence	strand	GGA
NR1H3-1686-	Artificial	25 mer sense	UGAGAAGGGCAAACAUUCCAGG	378
1750	Sequence	strand	GAG
NR1H3-1687-	Artificial	25 mer sense	GAGAAGGGCAAACAUUCCUAGG	379
1751	Sequence	strand	AGC
NR1H3-1728-	Artificial	25 mer sense	CCCGUGGCAUUAAAAGAGAAUCA	380
1792	Sequence	strand	AA
NR1H3-1729-	Artificial	25 mer sense	CCGUGGCAUUAAAAGAGAGACA	381
1793	Sequence	strand	AAG
NR1H3-1730-	Artificial	25 mer sense	CGUGGCAUUAAAAGAGAGUAAA	382
1794	Sequence	strand	AGG
NR1H3-1731-	Artificial	25 mer sense	GUGGCAUUAAAAGAGAGUCAAA	383
1795	Sequence	strand	GGG
NR1H3-1732-	Artificial	25 mer sense	UGGCAUUAAAAGAGAGUCAAAG	384
1796	Sequence	strand	GGU
NR1H3-764-	Artificial	27 mer	GCGGAUCUGUUCUUCUGACAGGA	385
784-861	Sequence	antisense	CACA
		strand
NR1H3-766-	Artificial	27 mer	AGGCGUAUCUGUUCUUCUGACAG	386
786-863	Sequence	antisense	GACA
		strand
NR1H3-789-	Artificial	27 mer	CCUCUUGCCGCUUCAGUUUCUUC	387
809-886	Sequence	antisense	AGGC
		strand
NR1H3-790-	Artificial	27 mer	UCCUCUUGCCGCUUCAGUUUCUU	388
810-887	Sequence	antisense	CAGG
		strand
NR1H3-791-	Artificial	27 mer	CUCCUUUUGCCGCUUCAGUUUCU	389
811-888	Sequence	antisense	UCAG
		strand
NR1H3-792-	Artificial	27 mer	CCUCCUCUUGCCGCUUCAGUUUC	390
812-889	Sequence	antisense	UUCA
		strand
NR1H3-793-	Artificial	27 mer	UCCUCUUCUUGCCGCUUCAGUUU	391
813-890	Sequence	antisense	CUUC
		strand
NR1H3-795-	Artificial	27 mer	GUUCCUCCUCUUGCCGCUUCAGU	392
815-892	Sequence	antisense	UUCU
		strand
NR1H3-796-	Artificial	27 mer	UGUUCUUCCUCUUGCCGCUUCAG	393
816-893	Sequence	antisense	UUUC
		strand
NR1H3-797-	Artificial	27 mer	CUGUUUCUCCUCUUGCCGCUUCA	394
817-894	Sequence	antisense	GUUU
		strand
NR1H3-798-	Artificial	27 mer	CCUGUUCCUCCUCUUGCCGCUUC	395
818-895	Sequence	antisense	AGUU
		strand
NR1H3-799-	Artificial	27 mer	GCCUGUUCCUCCUCUUGCCGCUU	396
819-896	Sequence	antisense	CAGU
		strand
NR1H3-802-	Artificial	27 mer	UGAGCUUGUUCCUCCUCUUGCCG	397
822-899	Sequence	antisense	CUUC
		strand
NR1H3-803-	Artificial	27 mer	AUGAGUCUGUUCCUCCUCUUGCC	398
823-900	Sequence	antisense	GCUU
		strand
NR1H3-804-	Artificial	27 mer	CAUGAUCCUGUUCCUCCUCUUGC	399
824-901	Sequence	antisense	CGCU
		strand
NR1H3-806-	Artificial	27 mer	GGCAUUAGCCUGUUCCUCCUCUU	400
826-903	Sequence	antisense	GCCG
		strand
NR1H3-808-	Artificial	27 mer	GUGGCUUGAGCCUGUUCCUCCUC	401
828-905	Sequence	antisense	UUGC
		strand
NR1H3-809-	Artificial	27 mer	UGUGGUAUGAGCCUGUUCCUCCU	402
829-906	Sequence	antisense	CUUG
		strand
NR1H3-810-	Artificial	27 mer	AUGUGUCAUGAGCCUGUUCCUCC	403
830-907	Sequence	antisense	UCUU
		strand
NR1H3-811-	Artificial	27 mer	GAUGUUGCAUGAGCCUGUUCCUC	404
831-908	Sequence	antisense	CUCU
		strand
NR1H3-813-	Artificial	27 mer	AGGAUUUGGCAUGAGCCUGUUCC	405
833-910	Sequence	antisense	UCCU
		strand
NR1H3-844	Artificial	27 mer	AUUUGUGGGGGUGAGGAAGCCC	406
	Sequence	antisense	UGGGG
		strand
NR1H3-895-	Artificial	27 mer	GCGACUAGCUUCUCGAUCAUGCC	407
915-992	Sequence	antisense	CAGU
		strand
NR1H3-898-	Artificial	27 mer	GCAGCUACGAGCUUCUCGAUCAU	408
918-995	Sequence	antisense	GCCC
		strand
NR1H3-915-	Artificial	27 mer	GGUUAUACUGUUGCUGGGCAGC	409
935	Sequence	antisense	GACGA
		strand
NR1H3-917-	Artificial	27 mer	CCGGUUACACUGUUGCUGGGCAG	410
937	Sequence	antisense	CGAC
		strand
NR1H3-922-	Artificial	27 mer	GAGCGUCGGUUACACUGUUGCUG	411
942	Sequence	antisense	GGCA
		strand
NR1H3-924-	Artificial	27 mer	AGGAGUGCCGGUUACACUGUUGC	412
944	Sequence	antisense	UGGG
		strand
NR1H3-925-	Artificial	27 mer	AAGGAUCGCCGGUUACACUGUUG	413
945	Sequence	antisense	CUGG
		strand
NR1H3-927-	Artificial	27 mer	AAAAGUAGCGCCGGUUACACUGU	414
947	Sequence	antisense	UGCU
		strand
NR1H3-928-	Artificial	27 mer	GAAAAUGAGCGCCGGUUACACUG	415
948	Sequence	antisense	UUGC
		strand
NR1H3-929-	Artificial	27 mer	AGAAAUGGAGCGCCGGUUACACU	416
949	Sequence	antisense	GUUG
		strand
NR1H3-930-	Artificial	27 mer	CAGAAUAGGAGCGCCGGUUACAC	417
950	Sequence	antisense	UGUU
		strand
NR1H3-931-	Artificial	27 mer	UCAGAUAAGGAGCGCCGGUUACA	418
951	Sequence	antisense	CUGU
		strand
NR1H3-932-	Artificial	27 mer	GUCAGUAAAGGAGCGCCGGUUAC	419
952	Sequence	antisense	ACUG
		strand
NR1H3-933-	Artificial	27 mer	GGUCAUAAAAGGAGCGCCGGUU	420
953	Sequence	antisense	ACACU
		strand
NR1H3-941-	Artificial	27 mer	UCGAAUCCGGUCAGAAAAGGAGC	421
961	Sequence	antisense	GCCG
		strand
NR1H3-944-	Artificial	27 mer	GACUCUAAGCCGGUCAGAAAAGG	422
964	Sequence	antisense	AGCG
		strand
NR1H3-945-	Artificial	27 mer	UGACUUGAAGCCGGUCAGAAAA	423
965	Sequence	antisense	GGAGC
		strand
NR1H3-946-	Artificial	27 mer	GUGACUCGAAGCCGGUCAGAAAA	424
966	Sequence	antisense	GGAG
		strand
NR1H3-947-	Artificial	27 mer	CGUGAUUCGAAGCCGGUCAGAAA	425
967	Sequence	antisense	AGGA
		strand
NR1H3-949-	Artificial	27 mer	GGCGUUACUCGAAGCCGGUCAGA	426
969	Sequence	antisense	AAAG
		strand
NR1H3-951-	Artificial	27 mer	AAGGCUUGACUCGAAGCCGGUCA	427
971	Sequence	antisense	GAAA
		strand
NR1H3-952-	Artificial	27 mer	CAAGGUGUGACUCGAAGCCGGUC	428
972	Sequence	antisense	AGAA
		strand
NR1H3-953-	Artificial	27 mer	CCAAGUCGUGACUCGAAGCCGGU	429
973	Sequence	antisense	CAGA
		strand
NR1H3-1151-	Artificial	27 mer	CCGAGUUGUCUCCAGAAGCAUCA	430
1171	Sequence	antisense	CCUG
		strand
NR1H3-1153-	Artificial	27 mer	CUCCGUGAUGUCUCCAGAAGCAU	431
1173	Sequence	antisense	CACC
		strand
NR1H3-1154-	Artificial	27 mer	CCUCCUAGAUGUCUCCAGAAGCA	432
1174	Sequence	antisense	UCAC
		strand
NR1H3-1155-	Artificial	27 mer	ACCUCUGAGAUGUCUCCAGAAGC	433
1175	Sequence	antisense	AUCA
		strand
NR1H3-1156-	Artificial	27 mer	UACCUUCGAGAUGUCUCCAGAAG	434
1176	Sequence	antisense	CAUC
		strand
NR1H3-1157-	Artificial	27 mer	GUACCUCCGAGAUGUCUCCAGAA	435
1177	Sequence	antisense	GCAU
		strand
NR1H3-1158-	Artificial	27 mer	UGUACUUCCGAGAUGUCUCCAGA	436
1178	Sequence	antisense	AGCA
		strand
NR1H3-1159-	Artificial	27 mer	UUGUAUCUCCGAGAUGUCUCCAG	437
1179	Sequence	antisense	AAGC
		strand
NR1H3-1160-	Artificial	27 mer	GUUGUUCCUCCGAGAUGUCUCCA	438
1180	Sequence	antisense	GAAG
		strand
NR1H3-1161-	Artificial	27 mer	GGUUGUACCUCCGAGAUGUCUCC	439
1181	Sequence	antisense	AGAA
		strand
NR1H3-1162-	Artificial	27 mer	GGGUUUUACCUCCGAGAUGUCUC	440
1182	Sequence	antisense	CAGA
		strand
NR1H3-1163-	Artificial	27 mer	AGGGUUGUACCUCCGAGAUGUCU	441
1183	Sequence	antisense	CCAG
		strand
NR1H3-1164-	Artificial	27 mer	CAGGGUUGUACCUCCGAGAUGUC	442
1184	Sequence	antisense	UCCA
		strand
NR1H3-1165-	Artificial	27 mer	CCAGGUUUGUACCUCCGAGAUGU	443
1185	Sequence	antisense	CUCC
		strand
NR1H3-1166-	Artificial	27 mer	CCCAGUGUUGUACCUCCGAGAUG	444
1186	Sequence	antisense	UCUC
		strand
NR1H3-1167-	Artificial	27 mer	UCCCAUGGUUGUACCUCCGAGAU	445
1187	Sequence	antisense	GUCU
		strand
NR1H3-1169-	Artificial	27 mer	ACUCCUAGGGUUGUACCUCCGAG	446
1189	Sequence	antisense	AUGU
		strand
NR1H3-1170-	Artificial	27 mer	CACUCUCAGGGUUGUACCUCCGA	447
1190	Sequence	antisense	GAUG
		strand
NR1H3-1171-	Artificial	27 mer	UCACUUCCAGGGUUGUACCUCCG	448
1191	Sequence	antisense	AGAU
		strand
NR1H3-1173-	Artificial	27 mer	UCUCAUUCCCAGGGUUGUACCUC	449
1193	Sequence	antisense	CGAG
		strand
NR1H3-1175-	Artificial	27 mer	ACUCUUACUCCCAGGGUUGUACC	450
1195	Sequence	antisense	UCCG
		strand
NR1H3-1176-	Artificial	27 mer	UACUCUCACUCCCAGGGUUGUAC	451
1196	Sequence	antisense	CUCC
		strand
NR1H3-1177-	Artificial	27 mer	AUACUUUCACUCCCAGGGUUGUA	452
1197	Sequence	antisense	CCUC
		strand
NR1H3-1178-	Artificial	27 mer	GAUACUCUCACUCCCAGGGUUGU	453
1198	Sequence	antisense	ACCU
		strand
NR1H3-1179-	Artificial	27 mer	UGAUAUUCUCACUCCCAGGGUUG	454
1199	Sequence	antisense	UACC
		strand
NR1H3-1180-	Artificial	27 mer	GUGAUUCUCUCACUCCCAGGGUU	455
1200	Sequence	antisense	GUAC
		strand
NR1H3-1181-	Artificial	27 mer	GGUGAUACUCUCACUCCCAGGGU	456
1201	Sequence	antisense	UGUA
		strand
NR1H3-1182-	Artificial	27 mer	AGGUGUUACUCUCACUCCCAGGG	457
1202	Sequence	antisense	UUGU
		strand
NR1H3-1183-	Artificial	27 mer	AAGGUUAUACUCUCACUCCCAGG	458
1203	Sequence	antisense	GUUG
		strand
NR1H3-1184-	Artificial	27 mer	GAAGGUGAUACUCUCACUCCCAG	459
1204	Sequence	antisense	GGUU
		strand
NR1H3-1185-	Artificial	27 mer	GGAAGUUGAUACUCUCACUCCCA	460
1205	Sequence	antisense	GGGU
		strand
NR1H3-1186-	Artificial	27 mer	AGGAAUGUGAUACUCUCACUCCC	461
1206	Sequence	antisense	AGGG
		strand
NR1H3-1187-	Artificial	27 mer	GAGGAUGGUGAUACUCUCACUCC	462
1207	Sequence	antisense	CAGG
		strand
NR1H3-1188-	Artificial	27 mer	UGAGGUAGGUGAUACUCUCACUC	463
1208	Sequence	antisense	CCAG
		strand
NR1H3-1190-	Artificial	27 mer	CUUGAUGAAGGUGAUACUCUCAC	464
1210	Sequence	antisense	UCCC
		strand
NR1H3-1191-	Artificial	27 mer	CCUUGUGGAAGGUGAUACUCUCA	465
1211	Sequence	antisense	CUCC
		strand
NR1H3-1192-	Artificial	27 mer	UCCUUUAGGAAGGUGAUACUCUC	466
1212	Sequence	antisense	ACUC
		strand
NR1H3-1193-	Artificial	27 mer	AUCCUUGAGGAAGGUGAUACUC	467
1213	Sequence	antisense	UCACU
		strand
NR1H3-1194-	Artificial	27 mer	AAUCCUUGAGGAAGGUGAUACU	468
1214	Sequence	antisense	CUCAC
		strand
NR1H3-1196-	Artificial	27 mer	GAAAUUCUUGAGGAAGGUGAUA	469
1216	Sequence	antisense	CUCUC
		strand
NR1H3-1197-	Artificial	27 mer	UGAAAUCCUUGAGGAAGGUGAU	470
1217	Sequence	antisense	ACUCU
		strand
NR1H3-1198-	Artificial	27 mer	CUGAAUUCCUUGAGGAAGGUGA	471
1218	Sequence	antisense	UACUC
		strand
NR1H3-1199-	Artificial	27 mer	ACUGAUAUCCUUGAGGAAGGUG	472
1219	Sequence	antisense	AUACU
		strand
NR1H3-1200-	Artificial	27 mer	AACUGUAAUCCUUGAGGAAGGU	473
1220	Sequence	antisense	GAUAC
		strand
NR1H3-1203-	Artificial	27 mer	UAUAAUUGAAAUCCUUGAGGAA	474
1223	Sequence	antisense	GGUGA
		strand
NR1H3-1204-	Artificial	27 mer	UUAUAUCUGAAAUCCUUGAGGA	475
1224	Sequence	antisense	AGGUG
		strand
NR1H3-1207-	Artificial	27 mer	CGGUUUUAACUGAAAUCCUUGA	476
1227	Sequence	antisense	GGAAG
		strand
NR1H3-1211-	Artificial	27 mer	UUCCCUGUUAUAACUGAAAUCCU	477
1231	Sequence	antisense	UGAG
		strand
NR1H3-1212-	Artificial	27 mer	CUUCCUGGUUAUAACUGAAAUCC	478
1232	Sequence	antisense	UUGA
		strand
NR1H3-1213-	Artificial	27 mer	UCUUCUCGGUUAUAACUGAAAUC	479
1233	Sequence	antisense	CUUG
		strand
NR1H3-1214-	Artificial	27 mer	GUCUUUCCGGUUAUAACUGAAA	480
1234	Sequence	antisense	UCCUU
		strand
NR1H3-1215-	Artificial	27 mer	AGUCUUCCCGGUUAUAACUGAAA	481
1235	Sequence	antisense	UCCU
		strand
NR1H3-1216-	Artificial	27 mer	AAGUCUUCCCGGUUAUAACUGAA	482
1236	Sequence	antisense	AUCC
		strand
NR1H3-1217-	Artificial	27 mer	AAAGUUUUCCCGGUUAUAACUG	483
1237	Sequence	antisense	AAAUC
		strand
NR1H3-1218-	Artificial	27 mer	CAAAGUCUUCCCGGUUAUAACUG	484
1238	Sequence	antisense	AAAU
		strand
NR1H3-1219-	Artificial	27 mer	GCAAAUUCUUCCCGGUUAUAACU	485
1239	Sequence	antisense	GAAA
		strand
NR1H3-1220-	Artificial	27 mer	GGCAAUGUCUUCCCGGUUAUAAC	486
1240	Sequence	antisense	UGAA
		strand
NR1H3-1222-	Artificial	27 mer	UUGGCUAAGUCUUCCCGGUUAUA	487
1242	Sequence	antisense	ACUG
		strand
NR1H3-1223-	Artificial	27 mer	UUUGGUAAAGUCUUCCCGGUUA	488
1243	Sequence	antisense	UAACU
		strand
NR1H3-1224-	Artificial	27 mer	CUUUGUCAAAGUCUUCCCGGUUA	489
1244	Sequence	antisense	UAAC
		strand
NR1H3-1225-	Artificial	27 mer	GCUUUUGCAAAGUCUUCCCGGUU	490
1245	Sequence	antisense	AUAA
		strand
NR1H3-1226-	Artificial	27 mer	UGCUUUGGCAAAGUCUUCCCGGU	491
1246	Sequence	antisense	UAUA
		strand
NR1H3-1227-	Artificial	27 mer	CUGCUUUGGCAAAGUCUUCCCGG	492
1247	Sequence	antisense	UUAU
		strand
NR1H3-1228-	Artificial	27 mer	CCUGCUUUGGCAAAGUCUUCCCG	493
1248	Sequence	antisense	GUUA
		strand
NR1H3-1229-	Artificial	27 mer	CCCUGUUUUGGCAAAGUCUUCCC	494
1249	Sequence	antisense	GGUU
		strand
NR1H3-1232-	Artificial	27 mer	CAGCCUUGCUUUGGCAAAGUCUU	495
1252	Sequence	antisense	CCCG
		strand
NR1H3-1233-	Artificial	27 mer	GCAGCUCUGCUUUGGCAAAGUCU	496
1253	Sequence	antisense	UCCC
		strand
NR1H3-1234-	Artificial	27 mer	UGCAGUCCUGCUUUGGCAAAGUC	497
1254	Sequence	antisense	UUCC
		strand
NR1H3-1235-	Artificial	27 mer	UUGCAUCCCUGCUUUGGCAAAGU	498
1255	Sequence	antisense	CUUC
		strand
NR1H3-1236-	Artificial	27 mer	CUUGCUGCCCUGCUUUGGCAAAG	499
1256	Sequence	antisense	UCUU
		strand
NR1H3-1237-	Artificial	27 mer	ACUUGUAGCCCUGCUUUGGCAAA	500
1257	Sequence	antisense	GUCU
		strand
NR1H3-1238-	Artificial	27 mer	CACUUUCAGCCCUGCUUUGGCAA	501
1258	Sequence	antisense	AGUC
		strand
NR1H3-1241-	Artificial	27 mer	UUCCAUUUGCAGCCCUGCUUUGG	502
1261	Sequence	antisense	CAAA
		strand
NR1H3-1242-	Artificial	27 mer	AUUCCUCUUGCAGCCCUGCUUUG	503
1262	Sequence	antisense	GCAA
		strand
NR1H3-1243-	Artificial	27 mer	AAUUCUACUUGCAGCCCUGCUUU	504
1263	Sequence	antisense	GGCA
		strand
NR1H3-1244-	Artificial	27 mer	GAAUUUCACUUGCAGCCCUGCUU	505
1264	Sequence	antisense	UGGC
		strand
NR1H3-1245-	Artificial	27 mer	UGAAUUCCACUUGCAGCCCUGCU	506
1265	Sequence	antisense	UUGG
		strand
NR1H3-1246-	Artificial	27 mer	AUGAAUUCCACUUGCAGCCCUGC	507
1266	Sequence	antisense	UUUG
		strand
NR1H3-1247-	Artificial	27 mer	GAUGAUUUCCACUUGCAGCCCUG	508
1267	Sequence	antisense	CUUU
		strand
NR1H3-1248-	Artificial	27 mer	UGAUGUAUUCCACUUGCAGCCCU	509
1268	Sequence	antisense	GCUU
		strand
NR1H3-1250-	Artificial	27 mer	GUUGAUGAAUUCCACUUGCAGCC	510
1270	Sequence	antisense	CUGC
		strand
NR1H3-1251-	Artificial	27 mer	GGUUGUUGAAUUCCACUUGCAGC	511
1271	Sequence	antisense	CCUG
		strand
NR1H3-1252-	Artificial	27 mer	GGGUUUAUGAAUUCCACUUGCA	512
1272	Sequence	antisense	GCCCU
		strand
NR1H3-1253-	Artificial	27 mer	GGGGUUGAUGAAUUCCACUUGC	513
1273	Sequence	antisense	AGCCC
		strand
NR1H3-1256-	Artificial	27 mer	GAUGGUGUUGAUGAAUUCCACU	514
1276	Sequence	antisense	UGCAG
		strand
NR1H3-1258-	Artificial	27 mer	AAGAUUGGGUUGAUGAAUUCCA	515
1278	Sequence	antisense	CUUGC
		strand
NR1H3-1259-	Artificial	27 mer	GAAGAUGGGGUUGAUGAAUUCC	516
1279	Sequence	antisense	ACUUG
		strand
NR1H3-1261-	Artificial	27 mer	UCGAAUAUGGGGUUGAUGAAUU	517
1281	Sequence	antisense	CCACU
		strand
NR1H3-1262-	Artificial	27 mer	CUCGAUGAUGGGGUUGAUGAAU	518
1282	Sequence	antisense	UCCAC
		strand
NR1H3-1265-	Artificial	27 mer	GAACUUGAAGAUGGGGUUGAUG	519
1285	Sequence	antisense	AAUUC
		strand
NR1H3-1266-	Artificial	27 mer	AGAACUCGAAGAUGGGGUUGAU	520
1286	Sequence	antisense	GAAUU
		strand
NR1H3-1267-	Artificial	27 mer	GAGAAUUCGAAGAUGGGGUUGA	521
1287	Sequence	antisense	UGAAU
		strand
NR1H3-1268-	Artificial	27 mer	GGAGAUCUCGAAGAUGGGGUUG	522
1288	Sequence	antisense	AUGAA
		strand
NR1H3-1269-	Artificial	27 mer	UGGAGUACUCGAAGAUGGGGUU	523
1289	Sequence	antisense	GAUGA
		strand
NR1H3-1270-	Artificial	27 mer	CUGGAUAACUCGAAGAUGGGGU	524
1290	Sequence	antisense	UGAUG
		strand
NR1H3-1271-	Artificial	27 mer	CCUGGUGAACUCGAAGAUGGGG	525
1291	Sequence	antisense	UUGAU
		strand
NR1H3-1272-	Artificial	27 mer	CCCUGUAGAACUCGAAGAUGGGG	526
1292	Sequence	antisense	UUGA
		strand
NR1H3-1273-	Artificial	27 mer	GCCCUUGAGAACUCGAAGAUGGG	527
1293	Sequence	antisense	GUUG
		strand
NR1H3-1275-	Artificial	27 mer	UGGCCUUGGAGAACUCGAAGAU	528
1295	Sequence	antisense	GGGGU
		strand
NR1H3-1276-	Artificial	27 mer	AUGGCUCUGGAGAACUCGAAGA	529
1296	Sequence	antisense	UGGGG
		strand
NR1H3-1277-	Artificial	27 mer	CAUGGUCCUGGAGAACUCGAAGA	530
1297	Sequence	antisense	UGGG
		strand
NR1H3-1278-	Artificial	27 mer	UCAUGUCCCUGGAGAACUCGAAG	531
1298	Sequence	antisense	AUGG
		strand
NR1H3-1279-	Artificial	27 mer	UUCAUUGCCCUGGAGAACUCGAA	532
1299	Sequence	antisense	GAUG
		strand
NR1H3-1280-	Artificial	27 mer	AUUCAUGGCCCUGGAGAACUCGA	533
1300	Sequence	antisense	AGAU
		strand
NR1H3-1281-	Artificial	27 mer	CAUUCUUGGCCCUGGAGAACUCG	534
1301	Sequence	antisense	AAGA
		strand
NR1H3-1282-	Artificial	27 mer	UCAUUUAUGGCCCUGGAGAACUC	535
1302	Sequence	antisense	GAAG
		strand
NR1H3-1283-	Artificial	27 mer	CUCAUUCAUGGCCCUGGAGAACU	536
1303	Sequence	antisense	CGAA
		strand
NR1H3-1284-	Artificial	27 mer	GCUCAUUCAUGGCCCUGGAGAAC	537
1304	Sequence	antisense	UCGA
		strand
NR1H3-1285-	Artificial	27 mer	AGCUCUUUCAUGGCCCUGGAGAA	538
1305	Sequence	antisense	CUCG
		strand
NR1H3-1286-	Artificial	27 mer	CAGCUUAUUCAUGGCCCUGGAGA	539
1306	Sequence	antisense	ACUC
		strand
NR1H3-1288-	Artificial	27 mer	UGCAGUUCAUUCAUGGCCCUGGA	540
1308	Sequence	antisense	GAAC
		strand
NR1H3-1289-	Artificial	27 mer	UUGCAUCUCAUUCAUGGCCCUGG	541
1309	Sequence	antisense	AGAA
		strand
NR1H3-1290-	Artificial	27 mer	GUUGCUGCUCAUUCAUGGCCCUG	542
1310	Sequence	antisense	GAGA
		strand
NR1H3-1291-	Artificial	27 mer	AGUUGUAGCUCAUUCAUGGCCCU	543
1311	Sequence	antisense	GGAG
		strand
NR1H3-1292-	Artificial	27 mer	GAGUUUCAGCUCAUUCAUGGCCC	544
1312	Sequence	antisense	UGGA
		strand
NR1H3-1293-	Artificial	27 mer	UGAGUUGCAGCUCAUUCAUGGCC	545
1313	Sequence	antisense	CUGG
		strand
NR1H3-1294-	Artificial	27 mer	UUGAGUUGCAGCUCAUUCAUGGC	546
1314	Sequence	antisense	CCUG
		strand
NR1H3-1295-	Artificial	27 mer	AUUGAUUUGCAGCUCAUUCAUG	547
1315	Sequence	antisense	GCCCU
		strand
NR1H3-1296-	Artificial	27 mer	CAUUGUGUUGCAGCUCAUUCAUG	548
1316	Sequence	antisense	GCCC
		strand
NR1H3-1297-	Artificial	27 mer	UCAUUUAGUUGCAGCUCAUUCAU	549
1317	Sequence	antisense	GGCC
		strand
NR1H3-1338-	Artificial	27 mer	CAGAGUAGAUGCUGAUAGCAAU	550
1358	Sequence	antisense	GAGCA
		strand
NR1H3-1339-	Artificial	27 mer	GCAGAUAAGAUGCUGAUAGCAA	551
1359	Sequence	antisense	UGAGC
		strand
NR1H3-1340-	Artificial	27 mer	UGCAGUGAAGAUGCUGAUAGCA	552
1360	Sequence	antisense	AUGAG
		strand
NR1H3-1341-	Artificial	27 mer	CUGCAUAGAAGAUGCUGAUAGC	553
1361	Sequence	antisense	AAUGA
		strand
NR1H3-1342-	Artificial	27 mer	UCUGCUGAGAAGAUGCUGAUAG	554
1362	Sequence	antisense	CAAUG
		strand
NR1H3-1343-	Artificial	27 mer	GUCUGUAGAGAAGAUGCUGAUA	555
1363	Sequence	antisense	GCAAU
		strand
NR1H3-1344-	Artificial	27 mer	GGUCUUCAGAGAAGAUGCUGAU	556
1364	Sequence	antisense	AGCAA
		strand
NR1H3-1345-	Artificial	27 mer	CGGUCUGCAGAGAAGAUGCUGA	557
1365	Sequence	antisense	UAGCA
		strand
NR1H3-1346-	Artificial	27 mer	CCGGUUUGCAGAGAAGAUGCUG	558
1366	Sequence	antisense	AUAGC
		strand
NR1H3-1347-	Artificial	27 mer	GCCGGUCUGCAGAGAAGAUGCUG	559
1367	Sequence	antisense	AUAG
		strand
NR1H3-1377-	Artificial	27 mer	UCUCUUCCUGGAGCUGGUCCUGC	560
1443	Sequence	antisense	ACGU
		strand
NR1H3-1379-	Artificial	27 mer	CCUCUUUACCUGGAGCUGGUCCU	561
1445	Sequence	antisense	GCAC
		strand
NR1H3-1383-	Artificial	27 mer	GCAGCUUCUCUACCUGGAGCUGG	562
1449	Sequence	antisense	UCCU
		strand
NR1H3-1384-	Artificial	27 mer	UGCAGUCUCUCUACCUGGAGCUG	563
1450	Sequence	antisense	GUCC
		strand
NR1H3-1385-	Artificial	27 mer	CUGCAUCCUCUCUACCUGGAGCU	564
1451	Sequence	antisense	GGUC
		strand
NR1H3-1387-	Artificial	27 mer	UGCUGUAGCCUCUCUACCUGGAG	565
1453	Sequence	antisense	CUGG
		strand
NR1H3-1388-	Artificial	27 mer	GUGCUUCAGCCUCUCUACCUGGA	566
1454	Sequence	antisense	GCUG
		strand
NR1H3-1391-	Artificial	27 mer	UGUGUUCUGCAGCCUCUCUACCU	567
1457	Sequence	antisense	GGAG
		strand
NR1H3-1393-	Artificial	27 mer	UAUGUUUGCUGCAGCCUCUCUAC	568
1459	Sequence	antisense	CUGG
		strand
NR1H3-1394-	Artificial	27 mer	AUAUGUGUGCUGCAGCCUCUCUA	569
1460	Sequence	antisense	CCUG
		strand
NR1H3-1395-	Artificial	27 mer	CAUAUUUGUGCUGCAGCCUCUCU	570
1461	Sequence	antisense	ACCU
		strand
NR1H3-1396-	Artificial	27 mer	ACAUAUGUGUGCUGCAGCCUCUC	571
1462	Sequence	antisense	UACC
		strand
NR1H3-1397-	Artificial	27 mer	CACAUUUGUGUGCUGCAGCCUCU	572
1463	Sequence	antisense	CUAC
		strand
NR1H3-1398-	Artificial	27 mer	CCACAUAUGUGUGCUGCAGCCUC	573
1464	Sequence	antisense	UCUA
		strand
NR1H3-1399-	Artificial	27 mer	UCCACUUAUGUGUGCUGCAGCCU	574
1465	Sequence	antisense	CUCU
		strand
NR1H3-1400-	Artificial	27 mer	UUCCAUAUAUGUGUGCUGCAGCC	575
1466	Sequence	antisense	UCUC
		strand
NR1H3-1401-	Artificial	27 mer	CUUCCUCAUAUGUGUGCUGCAGC	576
1467	Sequence	antisense	CUCU
		strand
NR1H3-1402-	Artificial	27 mer	GCUUCUACAUAUGUGUGCUGCAG	577
1468	Sequence	antisense	CCUC
		strand
NR1H3-1403-	Artificial	27 mer	GGCUUUCACAUAUGUGUGCUGCA	578
1469	Sequence	antisense	GCCU
		strand
NR1H3-1404-	Artificial	27 mer	GGGCUUCCACAUAUGUGUGCUGC	579
1470	Sequence	antisense	AGCC
		strand
NR1H3-1406-	Artificial	27 mer	CAGGGUUUCCACAUAUGUGUGCU	580
1472	Sequence	antisense	GCAG
		strand
NR1H3-1407-	Artificial	27 mer	GCAGGUCUUCCACAUAUGUGUGC	581
1473	Sequence	antisense	UGCA
		strand
NR1H3-1408-	Artificial	27 mer	UGCAGUGCUUCCACAUAUGUGUG	582
1474	Sequence	antisense	CUGC
		strand
NR1H3-1410-	Artificial	27 mer	CAUGCUGGGCUUCCACAUAUGUG	583
1476	Sequence	antisense	UGCU
		strand
NR1H3-1411-	Artificial	27 mer	GCAUGUAGGGCUUCCACAUAUGU	584
1477	Sequence	antisense	GUGC
		strand
NR1H3-1412-	Artificial	27 mer	GGCAUUCAGGGCUUCCACAUAUG	585
1478	Sequence	antisense	UGUG
		strand
NR1H3-1413-	Artificial	27 mer	AGGCAUGCAGGGCUUCCACAUAU	586
1479	Sequence	antisense	GUGU
		strand
NR1H3-1414-	Artificial	27 mer	UAGGCUUGCAGGGCUUCCACAUA	587
1480	Sequence	antisense	UGUG
		strand
NR1H3-1415-	Artificial	27 mer	GUAGGUAUGCAGGGCUUCCACAU	588
1481	Sequence	antisense	AUGU
		strand
NR1H3-1416-	Artificial	27 mer	CGUAGUCAUGCAGGGCUUCCACA	589
1482	Sequence	antisense	UAUG
		strand
NR1H3-1417-	Artificial	27 mer	ACGUAUGCAUGCAGGGCUUCCAC	590
1483	Sequence	antisense	AUAU
		strand
NR1H3-1418-	Artificial	27 mer	GACGUUGGCAUGCAGGGCUUCCA	591
1484	Sequence	antisense	CAUA
		strand
NR1H3-1419-	Artificial	27 mer	AGACGUAGGCAUGCAGGGCUUCC	592
1485	Sequence	antisense	ACAU
		strand
NR1H3-1420-	Artificial	27 mer	GAGACUUAGGCAUGCAGGGCUUC	593
1486	Sequence	antisense	CACA
		strand
NR1H3-1421-	Artificial	27 mer	GGAGAUGUAGGCAUGCAGGGCU	594
1487	Sequence	antisense	UCCAC
		strand
NR1H3-1422-	Artificial	27 mer	UGGAGUCGUAGGCAUGCAGGGC	595
1488	Sequence	antisense	UUCCA
		strand
NR1H3-1423-	Artificial	27 mer	AUGGAUACGUAGGCAUGCAGGG	596
1489	Sequence	antisense	CUUCC
		strand
NR1H3-1424-	Artificial	27 mer	GAUGGUGACGUAGGCAUGCAGG	597
1490	Sequence	antisense	GCUUC
		strand
NR1H3-1425-	Artificial	27 mer	GGAUGUAGACGUAGGCAUGCAG	598
1491	Sequence	antisense	GGCUU
		strand
NR1H3-1426-	Artificial	27 mer	UGGAUUGAGACGUAGGCAUGCA	599
1492	Sequence	antisense	GGGCU
		strand
NR1H3-1427-	Artificial	27 mer	GUGGAUGGAGACGUAGGCAUGC	600
1493	Sequence	antisense	AGGGC
		strand
NR1H3-1428-	Artificial	27 mer	GGUGGUUGGAGACGUAGGCAUG	601
1494	Sequence	antisense	CAGGG
		strand
NR1H3-1429-	Artificial	27 mer	UGGUGUAUGGAGACGUAGGCAU	602
1495	Sequence	antisense	GCAGG
		strand
NR1H3-1430-	Artificial	27 mer	AUGGUUGAUGGAGACGUAGGCA	603
1496	Sequence	antisense	UGCAG
		strand
NR1H3-1431-	Artificial	27 mer	GAUGGUGGAUGGAGACGUAGGC	604
1497	Sequence	antisense	AUGCA
		strand
NR1H3-1432-	Artificial	27 mer	GGAUGUUGGAUGGAGACGUAGG	605
1498	Sequence	antisense	CAUGC
		strand
NR1H3-1433-	Artificial	27 mer	GGGAUUGUGGAUGGAGACGUAG	606
1499	Sequence	antisense	GCAUG
		strand
NR1H3-1434-	Artificial	27 mer	GGGGAUGGUGGAUGGAGACGUA	607
1500	Sequence	antisense	GGCAU
		strand
NR1H3-1435-	Artificial	27 mer	UGGGGUUGGUGGAUGGAGACGU	608
1501	Sequence	antisense	AGGCA
		strand
NR1H3-1436-	Artificial	27 mer	AUGGGUAUGGUGGAUGGAGACG	609
1502	Sequence	antisense	UAGGC
		strand
NR1H3-1437-	Artificial	27 mer	CAUGGUGAUGGUGGAUGGAGAC	610
1503	Sequence	antisense	GUAGG
		strand
NR1H3-1438-	Artificial	27 mer	UCAUGUGGAUGGUGGAUGGAGA	611
1504	Sequence	antisense	CGUAG
		strand
NR1H3-1439-	Artificial	27 mer	GUCAUUGGGAUGGUGGAUGGAG	612
1505	Sequence	antisense	ACGUA
		strand
NR1H3-1440-	Artificial	27 mer	GGUCAUGGGGAUGGUGGAUGGA	613
1506	Sequence	antisense	GACGU
		strand
NR1H3-1442-	Artificial	27 mer	UCGGUUAUGGGGAUGGUGGAUG	614
1508	Sequence	antisense	GAGAC
		strand
NR1H3-1443-	Artificial	27 mer	GUCGGUCAUGGGGAUGGUGGAU	615
1509	Sequence	antisense	GGAGA
		strand
NR1H3-1444-	Artificial	27 mer	AGUCGUUCAUGGGGAUGGUGGA	616
1510	Sequence	antisense	UGGAG
		strand
NR1H3-1445-	Artificial	27 mer	CAGUCUGUCAUGGGGAUGGUGG	617
1511	Sequence	antisense	AUGGA
		strand
NR1H3-1446-	Artificial	27 mer	UCAGUUGGUCAUGGGGAUGGUG	618
1512	Sequence	antisense	GAUGG
		strand
NR1H3-1447-	Artificial	27 mer	AUCAGUCGGUCAUGGGGAUGGU	619
1513	Sequence	antisense	GGAUG
		strand
NR1H3-1448-	Artificial	27 mer	CAUCAUUCGGUCAUGGGGAUGG	620
1514	Sequence	antisense	UGGAU
		strand
NR1H3-1449-	Artificial	27 mer	ACAUCUGUCGGUCAUGGGGAUG	621
1515	Sequence	antisense	GUGGA
		strand
NR1H3-1450-	Artificial	27 mer	AACAUUAGUCGGUCAUGGGGAU	622
1516	Sequence	antisense	GGUGG
		strand
NR1H3-1451-	Artificial	27 mer	GAACAUCAGUCGGUCAUGGGGA	623
1517	Sequence	antisense	UGGUG
		strand
NR1H3-1452-	Artificial	27 mer	GGAACUUCAGUCGGUCAUGGGG	624
1518	Sequence	antisense	AUGGU
		strand
NR1H3-1453-	Artificial	27 mer	GGGAAUAUCAGUCGGUCAUGGG	625
1519	Sequence	antisense	GAUGG
		strand
NR1H3-1454-	Artificial	27 mer	UGGGAUCAUCAGUCGGUCAUGG	626
1520	Sequence	antisense	GGAUG
		strand
NR1H3-1455-	Artificial	27 mer	GUGGGUACAUCAGUCGGUCAUG	627
1521	Sequence	antisense	GGGAU
		strand
NR1H3-1456-	Artificial	27 mer	CGUGGUAACAUCAGUCGGUCAUG	628
1522	Sequence	antisense	GGGA
		strand
NR1H3-1457-	Artificial	27 mer	CCGUGUGAACAUCAGUCGGUCAU	629
1523	Sequence	antisense	GGGG
		strand
NR1H3-1459-	Artificial	27 mer	AUCCGUGGGAACAUCAGUCGGUC	630
1525	Sequence	antisense	AUGG
		strand
NR1H3-1460-	Artificial	27 mer	CAUCCUUGGGAACAUCAGUCGGU	631
1526	Sequence	antisense	CAUG
		strand
NR1H3-1461-	Artificial	27 mer	GCAUCUGUGGGAACAUCAGUCGG	632
1527	Sequence	antisense	UCAU
		strand
NR1H3-1462-	Artificial	27 mer	AGCAUUCGUGGGAACAUCAGUCG	633
1528	Sequence	antisense	GUCA
		strand
NR1H3-1463-	Artificial	27 mer	UAGCAUCCGUGGGAACAUCAGUC	634
1529	Sequence	antisense	GGUC
		strand
NR1H3-1465-	Artificial	27 mer	AUUAGUAUCCGUGGGAACAUCA	635
1531	Sequence	antisense	GUCGG
		strand
NR1H3-1466-	Artificial	27 mer	CAUUAUCAUCCGUGGGAACAUCA	636
1532	Sequence	antisense	GUCG
		strand
NR1H3-1468-	Artificial	27 mer	UUCAUUAGCAUCCGUGGGAACAU	637
1534	Sequence	antisense	CAGU
		strand
NR1H3-1469-	Artificial	27 mer	UUUCAUUAGCAUCCGUGGGAACA	638
1535	Sequence	antisense	UCAG
		strand
NR1H3-1471-	Artificial	27 mer	AGUUUUAUUAGCAUCCGUGGGA	639
1537	Sequence	antisense	ACAUC
		strand
NR1H3-1472-	Artificial	27 mer	CAGUUUCAUUAGCAUCCGUGGGA	640
1538	Sequence	antisense	ACAU
		strand
NR1H3-1473-	Artificial	27 mer	CCAGUUUCAUUAGCAUCCGUGGG	641
1539	Sequence	antisense	AACA
		strand
NR1H3-1474-	Artificial	27 mer	ACCAGUUUCAUUAGCAUCCGUGG	642
1540	Sequence	antisense	GAAC
		strand
NR1H3-1475-	Artificial	27 mer	CACCAUUUUCAUUAGCAUCCGUG	643
1541	Sequence	antisense	GGAA
		strand
NR1H3-1476-	Artificial	27 mer	UCACCUGUUUCAUUAGCAUCCGU	644
1542	Sequence	antisense	GGGA
		strand
NR1H3-1477-	Artificial	27 mer	CUCACUAGUUUCAUUAGCAUCCG	645
1543	Sequence	antisense	UGGG
		strand
NR1H3-1478-	Artificial	27 mer	GCUCAUCAGUUUCAUUAGCAUCC	646
1544	Sequence	antisense	GUGG
		strand
NR1H3-1479-	Artificial	27 mer	GGCUCUCCAGUUUCAUUAGCAUC	647
1545	Sequence	antisense	CGUG
		strand
NR1H3-1480-	Artificial	27 mer	AGGCUUACCAGUUUCAUUAGCAU	648
1546	Sequence	antisense	CCGU
		strand
NR1H3-1481-	Artificial	27 mer	GAGGCUCACCAGUUUCAUUAGCA	649
1547	Sequence	antisense	UCCG
		strand
NR1H3-1483-	Artificial	27 mer	CGGAGUCUCACCAGUUUCAUUAG	650
1549	Sequence	antisense	CAUC
		strand
NR1H3-1484-	Artificial	27 mer	CCGGAUGCUCACCAGUUUCAUUA	651
1550	Sequence	antisense	GCAU
		strand
NR1H3-1485-	Artificial	27 mer	UCCGGUGGCUCACCAGUUUCAUU	652
1551	Sequence	antisense	AGCA
		strand
NR1H3-1486-	Artificial	27 mer	GUCCGUAGGCUCACCAGUUUCAU	653
1552	Sequence	antisense	UAGC
		strand
NR1H3-1487-	Artificial	27 mer	GGUCCUGAGGCUCACCAGUUUCA	654
1553	Sequence	antisense	UUAG
		strand
NR1H3-1488-	Artificial	27 mer	GGGUCUGGAGGCUCACCAGUUUC	655
1554	Sequence	antisense	AUUA
		strand
NR1H3-1489-	Artificial	27 mer	AGGGUUCGGAGGCUCACCAGUUU	656
1555	Sequence	antisense	CAUU
		strand
NR1H3-1491-	Artificial	27 mer	UCAGGUUCCGGAGGCUCACCAGU	657
1557	Sequence	antisense	UUCA
		strand
NR1H3-1492-	Artificial	27 mer	CUCAGUGUCCGGAGGCUCACCAG	658
1558	Sequence	antisense	UUUC
		strand
NR1H3-1494-	Artificial	27 mer	UGCUCUGGGUCCGGAGGCUCACC	659
1560	Sequence	antisense	AGUU
		strand
NR1H3-1505-	Artificial	27 mer	UGAGUUGACGCUGCUCAGGGUCC	660
1571	Sequence	antisense	GGAG
		strand
NR1H3-1507-	Artificial	27 mer	UCUGAUUGGACGCUGCUCAGGGU	661
1573	Sequence	antisense	CCGG
		strand
NR1H3-1508-	Artificial	27 mer	CUCUGUGUGGACGCUGCUCAGGG	662
1574	Sequence	antisense	UCCG
		strand
NR1H3-1509-	Artificial	27 mer	GCUCUUAGUGGACGCUGCUCAGG	663
1575	Sequence	antisense	GUCC
		strand
NR1H3-1510-	Artificial	27 mer	UGCUCUGAGUGGACGCUGCUCAG	664
1576	Sequence	antisense	GGUC
		strand
NR1H3-1511-	Artificial	27 mer	UUGCUUUGAGUGGACGCUGCUCA	665
1577	Sequence	antisense	GGGU
		strand
NR1H3-1512-	Artificial	27 mer	CUUGCUCUGAGUGGACGCUGCUC	666
1578	Sequence	antisense	AGGG
		strand
NR1H3-1513-	Artificial	27 mer	ACUUGUUCUGAGUGGACGCUGCU	667
1579	Sequence	antisense	CAGG
		strand
NR1H3-1514-	Artificial	27 mer	CACUUUCUCUGAGUGGACGCUGC	668
1580	Sequence	antisense	UCAG
		strand
NR1H3-1515-	Artificial	27 mer	ACACUUGCUCUGAGUGGACGCUG	669
1581	Sequence	antisense	CUCA
		strand
NR1H3-1516-	Artificial	27 mer	AACACUUGCUCUGAGUGGACGCU	670
1582	Sequence	antisense	GCUC
		strand
NR1H3-1517-	Artificial	27 mer	AAACAUUUGCUCUGAGUGGACGC	671
1583	Sequence	antisense	UGCU
		strand
NR1H3-1518-	Artificial	27 mer	CAAACUCUUGCUCUGAGUGGACG	672
1584	Sequence	antisense	CUGC
		strand
NR1H3-1519-	Artificial	27 mer	GCAAAUACUUGCUCUGAGUGGAC	673
1585	Sequence	antisense	GCUG
		strand
NR1H3-1520-	Artificial	27 mer	UGCAAUCACUUGCUCUGAGUGGA	674
1586	Sequence	antisense	CGCU
		strand
NR1H3-1521-	Artificial	27 mer	GUGCAUACACUUGCUCUGAGUGG	675
1587	Sequence	antisense	ACGC
		strand
NR1H3-1522-	Artificial	27 mer	AGUGCUAACACUUGCUCUGAGUG	676
1588	Sequence	antisense	GACG
		strand
NR1H3-1523-	Artificial	27 mer	CAGUGUAAACACUUGCUCUGAGU	677
1589	Sequence	antisense	GGAC
		strand
NR1H3-1525-	Artificial	27 mer	CGCAGUGCAAACACUUGCUCUGA	678
1591	Sequence	antisense	GUGG
		strand
NR1H3-1526-	Artificial	27 mer	ACGCAUUGCAAACACUUGCUCUG	679
1592	Sequence	antisense	AGUG
		strand
NR1H3-1527-	Artificial	27 mer	GACGCUGUGCAAACACUUGCUCU	680
1593	Sequence	antisense	GAGU
		strand
NR1H3-1528-	Artificial	27 mer	AGACGUAGUGCAAACACUUGCUC	681
1594	Sequence	antisense	UGAG
		strand
NR1H3-1529-	Artificial	27 mer	CAGACUCAGUGCAAACACUUGCU	682
1595	Sequence	antisense	CUGA
		strand
NR1H3-1530-	Artificial	27 mer	GCAGAUGCAGUGCAAACACUUGC	683
1596	Sequence	antisense	UCUG
		strand
NR1H3-1531-	Artificial	27 mer	UGCAGUCGCAGUGCAAACACUUG	684
1597	Sequence	antisense	CUCU
		strand
NR1H3-1532-	Artificial	27 mer	CUGCAUACGCAGUGCAAACACUU	685
1598	Sequence	antisense	GCUC
		strand
NR1H3-1533-	Artificial	27 mer	CCUGCUGACGCAGUGCAAACACU	686
1599	Sequence	antisense	UGCU
		strand
NR1H3-1534-	Artificial	27 mer	UCCUGUAGACGCAGUGCAAACAC	687
1600	Sequence	antisense	UUGC
		strand
NR1H3-1535-	Artificial	27 mer	GUCCUUCAGACGCAGUGCAAACA	688
1601	Sequence	antisense	CUUG
		strand
NR1H3-1536-	Artificial	27 mer	UGUCCUGCAGACGCAGUGCAAAC	689
1602	Sequence	antisense	ACUU
		strand
NR1H3-1537-	Artificial	27 mer	UUGUCUUGCAGACGCAGUGCAAA	690
1603	Sequence	antisense	CACU
		strand
NR1H3-1538-	Artificial	27 mer	UUUGUUCUGCAGACGCAGUGCAA	691
1604	Sequence	antisense	ACAC
		strand
NR1H3-1539-	Artificial	27 mer	UUUUGUCCUGCAGACGCAGUGCA	692
1605	Sequence	antisense	AACA
		strand
NR1H3-1540-	Artificial	27 mer	UUUUUUUCCUGCAGACGCAGUGC	693
1606	Sequence	antisense	AAAC
		strand
NR1H3-1541-	Artificial	27 mer	CUUUUUGUCCUGCAGACGCAGUG	694
1607	Sequence	antisense	CAAA
		strand
NR1H3-1542-	Artificial	27 mer	GCUUUUUGUCCUGCAGACGCAGU	695
1608	Sequence	antisense	GCAA
		strand
NR1H3-1543-	Artificial	27 mer	AGCUUUUUGUCCUGCAGACGCAG	696
1609	Sequence	antisense	UGCA
		strand
NR1H3-1544-	Artificial	27 mer	GAGCUUUUUGUCCUGCAGACGCA	697
1610	Sequence	antisense	GUGC
		strand
NR1H3-1545-	Artificial	27 mer	GGAGCUUUUUGUCCUGCAGACGC	698
1611	Sequence	antisense	AGUG
		strand
NR1H3-1546-	Artificial	27 mer	GGGAGUUUUUUGUCCUGCAGAC	699
1612	Sequence	antisense	GCAGU
		strand
NR1H3-1547-	Artificial	27 mer	UGGGAUCUUUUUGUCCUGCAGAC	700
1613	Sequence	antisense	GCAG
		strand
NR1H3-1548-	Artificial	27 mer	GUGGGUGCUUUUUGUCCUGCAG	701
1614	Sequence	antisense	ACGCA
		strand
NR1H3-1549-	Artificial	27 mer	GGUGGUAGCUUUUUGUCCUGCA	702
1615	Sequence	antisense	GACGC
		strand
NR1H3-1550-	Artificial	27 mer	CGGUGUGAGCUUUUUGUCCUGCA	703
1616	Sequence	antisense	GACG
		strand
NR1H3-1551-	Artificial	27 mer	GCGGUUGGAGCUUUUUGUCCUGC	704
1617	Sequence	antisense	AGAC
		strand
NR1H3-1553-	Artificial	27 mer	CAGCGUUGGGAGCUUUUUGUCCU	705
1619	Sequence	antisense	GCAG
		strand
NR1H3-1554-	Artificial	27 mer	GCAGCUGUGGGAGCUUUUUGUCC	706
1620	Sequence	antisense	UGCA
		strand
NR1H3-1555-	Artificial	27 mer	AGCAGUGGUGGGAGCUUUUUGU	707
1621	Sequence	antisense	CCUGC
		strand
NR1H3-1556-	Artificial	27 mer	GAGCAUCGGUGGGAGCUUUUUG	708
1622	Sequence	antisense	UCCUG
		strand
NR1H3-1558-	Artificial	27 mer	GAGAGUAGCGGUGGGAGCUUUU	709
1624	Sequence	antisense	UGUCC
		strand
NR1H3-1559-	Artificial	27 mer	AGAGAUCAGCGGUGGGAGCUUU	710
1625	Sequence	antisense	UUGUC
		strand
NR1H3-1560-	Artificial	27 mer	CAGAGUGCAGCGGUGGGAGCUU	711
1626	Sequence	antisense	UUUGU
		strand
NR1H3-1561-	Artificial	27 mer	UCAGAUAGCAGCGGUGGGAGCU	712
1627	Sequence	antisense	UUUUG
		strand
NR1H3-1562-	Artificial	27 mer	CUCAGUGAGCAGCGGUGGGAGCU	713
1628	Sequence	antisense	UUUU
		strand
NR1H3-1563-	Artificial	27 mer	UCUCAUAGAGCAGCGGUGGGAGC	714
1629	Sequence	antisense	UUUU
		strand
NR1H3-1564-	Artificial	27 mer	AUCUCUGAGAGCAGCGGUGGGA	715
1630	Sequence	antisense	GCUUU
		strand
NR1H3-1565-	Artificial	27 mer	GAUCUUAGAGAGCAGCGGUGGG	716
1631	Sequence	antisense	AGCUU
		strand
NR1H3-1567-	Artificial	27 mer	CAGAUUUCAGAGAGCAGCGGUG	717
1633	Sequence	antisense	GGAGC
		strand
NR1H3-1569-	Artificial	27 mer	CCCAGUUCUCAGAGAGCAGCGGU	718
1635	Sequence	antisense	GGGA
		strand
NR1H3-1570-	Artificial	27 mer	UCCCAUAUCUCAGAGAGCAGCGG	719
1636	Sequence	antisense	UGGG
		strand
NR1H3-1572-	Artificial	27 mer	CAUCCUAGAUCUCAGAGAGCAGC	720
1638	Sequence	antisense	GGUG
		strand
NR1H3-1573-	Artificial	27 mer	ACAUCUCAGAUCUCAGAGAGCAG	721
1639	Sequence	antisense	CGGU
		strand
NR1H3-1574-	Artificial	27 mer	CACAUUCCAGAUCUCAGAGAGCA	722
1640	Sequence	antisense	GCGG
		strand
NR1H3-1577-	Artificial	27 mer	GUGCAUAUCCCAGAUCUCAGAGA	723
1643	Sequence	antisense	GCAG
		strand
NR1H3-1579-	Artificial	27 mer	UCGUGUACAUCCCAGAUCUCAGA	724
1645	Sequence	antisense	GAGC
		strand
NR1H3-1580-	Artificial	27 mer	UUCGUUCACAUCCCAGAUCUCAG	725
1646	Sequence	antisense	AGAG
		strand
NR1H3-1581-	Artificial	27 mer	AUUCGUGCACAUCCCAGAUCUCA	726
1647	Sequence	antisense	GAGA
		strand
NR1H3-1582-	Artificial	27 mer	CAUUCUUGCACAUCCCAGAUCUC	727
1648	Sequence	antisense	AGAG
		strand
NR1H3-1583-	Artificial	27 mer	UCAUUUGUGCACAUCCCAGAUCU	728
1649	Sequence	antisense	CAGA
		strand
NR1H3-1584-	Artificial	27 mer	GUCAUUCGUGCACAUCCCAGAUC	729
1650	Sequence	antisense	UCAG
		strand
NR1H3-1585-	Artificial	27 mer	AGUCAUUCGUGCACAUCCCAGAU	730
1651	Sequence	antisense	CUCA
		strand
NR1H3-1586-	Artificial	27 mer	CAGUCUUUCGUGCACAUCCCAGA	731
1652	Sequence	antisense	UCUC
		strand
NR1H3-1587-	Artificial	27 mer	ACAGUUAUUCGUGCACAUCCCAG	732
1653	Sequence	antisense	AUCU
		strand
NR1H3-1588-	Artificial	27 mer	AACAGUCAUUCGUGCACAUCCCA	733
1654	Sequence	antisense	GAUC
		strand
NR1H3-1589-	Artificial	27 mer	GAACAUUCAUUCGUGCACAUCCC	734
1655	Sequence	antisense	AGAU
		strand
NR1H3-1590-	Artificial	27 mer	AGAACUGUCAUUCGUGCACAUCC	735
1656	Sequence	antisense	CAGA
		strand
NR1H3-1591-	Artificial	27 mer	CAGAAUAGUCAUUCGUGCACAUC	736
1657	Sequence	antisense	CCAG
		strand
NR1H3-1592-	Artificial	27 mer	ACAGAUCAGUCAUUCGUGCACAU	737
1658	Sequence	antisense	CCCA
		strand
NR1H3-1593-	Artificial	27 mer	GACAGUACAGUCAUUCGUGCACA	738
1659	Sequence	antisense	UCCC
		strand
NR1H3-1656-	Artificial	27 mer	UUCCAUUUCUAGGAGGCAGCCAC	739
1720	Sequence	antisense	CAGG
		strand
NR1H3-1657-	Artificial	27 mer	GUUCCUCUUCUAGGAGGCAGCCA	740
1721	Sequence	antisense	CCAG
		strand
NR1H3-1658-	Artificial	27 mer	UGUUCUACUUCUAGGAGGCAGCC	741
1722	Sequence	antisense	ACCA
		strand
NR1H3-1659-	Artificial	27 mer	CUGUUUCACUUCUAGGAGGCAGC	742
1723	Sequence	antisense	CACC
		strand
NR1H3-1660-	Artificial	27 mer	UCUGUUCCACUUCUAGGAGGCAG	743
1724	Sequence	antisense	CCAC
		strand
NR1H3-1661-	Artificial	27 mer	GUCUGUUCCACUUCUAGGAGGCA	744
1725	Sequence	antisense	GCCA
		strand
NR1H3-1662-	Artificial	27 mer	AGUCUUUUCCACUUCUAGGAGGC	745
1726	Sequence	antisense	AGCC
		strand
NR1H3-1663-	Artificial	27 mer	CAGUCUGUUCCACUUCUAGGAGG	746
1727	Sequence	antisense	CAGC
		strand
NR1H3-1664-	Artificial	27 mer	UCAGUUUGUUCCACUUCUAGGAG	747
1728	Sequence	antisense	GCAG
		strand
NR1H3-1665-	Artificial	27 mer	CUCAGUCUGUUCCACUUCUAGGA	748
1729	Sequence	antisense	GGCA
		strand
NR1H3-1666-	Artificial	27 mer	UCUCAUUCUGUUCCACUUCUAGG	749
1730	Sequence	antisense	AGGC
		strand
NR1H3-1667-	Artificial	27 mer	UUCUCUGUCUGUUCCACUUCUAG	750
1731	Sequence	antisense	GAGG
		strand
NR1H3-1668-	Artificial	27 mer	CUUCUUAGUCUGUUCCACUUCUA	751
1732	Sequence	antisense	GGAG
		strand
NR1H3-1669-	Artificial	27 mer	CCUUCUCAGUCUGUUCCACUUCU	752
1733	Sequence	antisense	AGGA
		strand
NR1H3-1671-	Artificial	27 mer	GCCCUUCUCAGUCUGUUCCACUU	753
1735	Sequence	antisense	CUAG
		strand
NR1H3-1677-	Artificial	27 mer	AUGUUUGCCCUUCUCAGUCUGUU	754
1741	Sequence	antisense	CCAC
		strand
NR1H3-1679-	Artificial	27 mer	GAAUGUUUGCCCUUCUCAGUCUG	755
1743	Sequence	antisense	UUCC
		strand
NR1H3-1680-	Artificial	27 mer	GGAAUUUUUGCCCUUCUCAGUCU	756
1744	Sequence	antisense	GUUC
		strand
NR1H3-1681-	Artificial	27 mer	AGGAAUGUUUGCCCUUCUCAGUC	757
1745	Sequence	antisense	UGUU
		strand
NR1H3-1682-	Artificial	27 mer	CAGGAUUGUUUGCCCUUCUCAGU	758
1746	Sequence	antisense	CUGU
		strand
NR1H3-1683-	Artificial	27 mer	CCAGGUAUGUUUGCCCUUCUCAG	759
1747	Sequence	antisense	UCUG
		strand
NR1H3-1684-	Artificial	27 mer	CCCAGUAAUGUUUGCCCUUCUCA	760
1748	Sequence	antisense	GUCU
		strand
NR1H3-1685-	Artificial	27 mer	UCCCAUGAAUGUUUGCCCUUCUC	761
1749	Sequence	antisense	AGUC
		strand
NR1H3-1686-	Artificial	27 mer	CUCCCUGGAAUGUUUGCCCUUCU	762
1750	Sequence	antisense	CAGU
		strand
NR1H3-1687-	Artificial	27 mer	GCUCCUAGGAAUGUUUGCCCUUC	763
1751	Sequence	antisense	UCAG
		strand
NR1H3-1728-	Artificial	27 mer	UUUGAUUCUCUUUUAAUGCCACG	764
1792	Sequence	antisense	GGAG
		strand
NR1H3-1729-	Artificial	27 mer	CUUUGUCUCUCUUUUAAUGCCAC	765
1793	Sequence	antisense	GGGA
		strand
NR1H3-1730-	Artificial	27 mer	CCUUUUACUCUCUUUUAAUGCCA	766
1794	Sequence	antisense	CGGG
		strand
NR1H3-1731-	Artificial	27 mer	CCCUUUGACUCUCUUUUAAUGCC	767
1795	Sequence	antisense	ACGG
		strand
NR1H3-1732-	Artificial	27 mer	ACCCUUUGACUCUCUUUUAAUGC	768
1796	Sequence	antisense	CACG
		strand
NR1H3-763-	Artificial	36 mer sense	GUGUCCUGUCAGAAGAACAAGCA	769
783-860	Sequence	strand	GCCGAAAGGCUGC
NR1H3-765-	Artificial	36 mer sense	GUCCUGUCAGAAGAACAGAAGCA	770
785-862	Sequence	strand	GCCGAAAGGCUGC
NR1H3-767-	Artificial	36 mer sense	CCUGUCAGAAGAACAGAUCAGCA	771
787-864	Sequence	strand	GCCGAAAGGCUGC
NR1H3-768-	Artificial	36 mer sense	CUGUCAGAAGAACAGAUCCAGCA	772
788-865	Sequence	strand	GCCGAAAGGCUGC
NR1H3-769-	Artificial	36 mer sense	UGUCAGAAGAACAGAUCCGAGCA	773
789-866	Sequence	strand	GCCGAAAGGCUGC
NR1H3-794-	Artificial	36 mer sense	GAAACUGAAGCGGCAAGAGAGC	774
814-891	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1152-	Artificial	36 mer sense	GUGAUGCUUCUGGAGACAUAGC	775
1172-1249	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1189-	Artificial	36 mer sense	GGAGUGAGAGUAUCACCUUAGC	776
1209-1286	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1195-	Artificial	36 mer sense	AGAGUAUCACCUUCCUCAAAGCA	777
1215-1292	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1200-	Artificial	36 mer sense	AUCACCUUCCUCAAGGAUUAGCA	778
1220-1297	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1201-	Artificial	36 mer sense	UCACCUUCCUCAAGGAUUUAGCA	779
1221-1298	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1202-	Artificial	36 mer sense	CACCUUCCUCAAGGAUUUCAGCA	780
1222-1299	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1203-	Artificial	36 mer sense	ACCUUCCUCAAGGAUUUCAAGCA	781
1223-1300	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1204-	Artificial	36 mer sense	CCUUCCUCAAGGAUUUCAGAGCA	782
1224-1301	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1205-	Artificial	36 mer sense	CUUCCUCAAGGAUUUCAGUAGCA	783
1225-1302	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1206-	Artificial	36 mer sense	UUCCUCAAGGAUUUCAGUUAGCA	784
1226-1303	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1208-	Artificial	36 mer sense	CCUCAAGGAUUUCAGUUAUAGCA	785
1228-1305	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1209-	Artificial	36 mer sense	CUCAAGGAUUUCAGUUAUAAGC	786
1229-1306	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1210-	Artificial	36 mer sense	UCAAGGAUUUCAGUUAUAAAGC	787
1230-1307	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1211-	Artificial	36 mer sense	CAAGGAUUUCAGUUAUAACAGC	788
1231-1308	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1212-	Artificial	36 mer sense	AAGGAUUUCAGUUAUAACCAGC	789
1232-1309	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1213-	Artificial	36 mer sense	AGGAUUUCAGUUAUAACCGAGC	790
1233-1310	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1214-	Artificial	36 mer sense	GGAUUUCAGUUAUAACCGGAGC	791
1234-1311	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1221-	Artificial	36 mer sense	AGUUAUAACCGGGAAGACUAGC	792
1241-1318	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1249-	Artificial	36 mer sense	CAGGGCUGCAAGUGGAAUUAGC	793
1269-1346	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1254-	Artificial	36 mer sense	CUGCAAGUGGAAUUCAUCAAGCA	794
1274-1351	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1255-	Artificial	36 mer sense	UGCAAGUGGAAUUCAUCAAAGC	795
1275-1352	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1256-	Artificial	36 mer sense	GCAAGUGGAAUUCAUCAACAGCA	796
1276-1353	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1257-	Artificial	36 mer sense	CAAGUGGAAUUCAUCAACCAGCA	797
1277-1354	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1260-	Artificial	36 mer sense	GUGGAAUUCAUCAACCCCAAGCA	798
1280-1357	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1261-	Artificial	36 mer sense	UGGAAUUCAUCAACCCCAUAGCA	799
1281-1358	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1263-	Artificial	36 mer sense	GAAUUCAUCAACCCCAUCUAGCA	800
1283-1360	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1264-	Artificial	36 mer sense	AAUUCAUCAACCCCAUCUUAGCA	801
1284-1361	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1405-	Artificial	36 mer sense	UGCAGCACACAUAUGUGGAAGCA	802
1471-1502	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1409-	Artificial	36 mer sense	GCACACAUAUGUGGAAGCCAGCA	803
1475-1506	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1458-	Artificial	36 mer sense	CAUGACCGACUGAUGUUCCAGCA	804
1524-1555	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1464-	Artificial	36 mer sense	CGACUGAUGUUCCCACGGAAGCA	805
1530-1561	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1465-	Artificial	36 mer sense	GACUGAUGUUCCCACGGAUAGCA	806
1531-1562	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1467-	Artificial	36 mer sense	CUGAUGUUCCCACGGAUGCAGCA	807
1533-1564	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1469-	Artificial	36 mer sense	GAUGUUCCCACGGAUGCUAAGCA	808
1535-1566	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1470-	Artificial	36 mer sense	AUGUUCCCACGGAUGCUAAAGCA	809
1536-1567	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1480-	Artificial	36 mer sense	GGAUGCUAAUGAAACUGGUAGC	810
1546-1577	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1482-	Artificial	36 mer sense	AUGCUAAUGAAACUGGUGAAGC	811
1548-1579	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1524-	Artificial	36 mer sense	CACUCAGAGCAAGUGUUUGAGCA	812
1590-1621	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1594-	Artificial	36 mer sense	AUGUGCACGAAUGACUGUUAGC	813
1660-1691	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1595-	Artificial	36 mer sense	UGUGCACGAAUGACUGUUCAGCA	814
1661-1692	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1596-	Artificial	36 mer sense	GUGCACGAAUGACUGUUCUAGCA	815
1662	Sequence	strand	GCCGAAAGGCUGC
NR1H3-1670-	Artificial	36 mer sense	UAGAAGUGGAACAGACUGAAGC	816
1734	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1672-	Artificial	36 mer sense	GAAGUGGAACAGACUGAGAAGC	817
1736	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1673-	Artificial	36 mer sense	AAGUGGAACAGACUGAGAAAGC	818
1737	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1674-	Artificial	36 mer sense	AGUGGAACAGACUGAGAAGAGC	819
1738	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1675-	Artificial	36 mer sense	GUGGAACAGACUGAGAAGGAGC	820
1739-1766	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1676-	Artificial	36 mer sense	UGGAACAGACUGAGAAGGGAGC	821
1740-1767	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1678-	Artificial	36 mer sense	GAACAGACUGAGAAGGGCAAGC	822
1742-1769	Sequence	strand	AGCCGAAAGGCUGC
NR1H3-1207-	Artificial	36 mer sense	UCCUCAAGGAUUUCAGUUAAGCA	823
1227	Sequence	strand	GCCGGGCUGC
NR1H3-1220-	Artificial	36 mer sense	CAGUUAUAACCGGGAAGACAGCA	824
1240	Sequence	strand	GCCGGGCUGC
NR1H3-1224-	Artificial	36 mer sense	UAUAACCGGGAAGACUUUGAGC	825
1244	Sequence	strand	AGCCGGGCUGC
NR1H3-1244-	Artificial	36 mer sense	CAAAGCAGGGCUGCAAGUGAGCA	826
1264	Sequence	strand	GCCGGGCUGC
NR1H3-1252-	Artificial	36 mer sense	GGCUGCAAGUGGAAUUCAUAGC	827
1272	Sequence	strand	AGCCGGGCUGC
NR1H3-1259-	Artificial	36 mer sense	AGUGGAAUUCAUCAACCCCAGCA	828
1279	Sequence	strand	GCCGGGCUGC
NR1H3-1265-	Artificial	36 mer sense	AUUCAUCAACCCCAUCUUCAGCA	829
1285	Sequence	strand	GCCGGGCUGC
NR1H3-1266-	Artificial	36 mer sense	UUCAUCAACCCCAUCUUCGAGCA	830
1286	Sequence	strand	GCCGGGCUGC
NR1H3-1429-	Artificial	36 mer sense	UGCAUGCCUACGUCUCCAUAGCA	831
1495	Sequence	strand	GCCGGGCUGC
NR1H3-1433-	Artificial	36 mer sense	UGCCUACGUCUCCAUCCACAGCA	832
1499	Sequence	strand	GCCGGGCUGC
NR1H3-1437-	Artificial	36 mer sense	UACGUCUCCAUCCACCAUCAGCA	833
1503	Sequence	strand	GCCGGGCUGC
NR1H3-1439-	Artificial	36 mer sense	CGUCUCCAUCCACCAUCCCAGCA	834
1505	Sequence	strand	GCCGGGCUGC
NR1H3-1446-	Artificial	36 mer sense	AUCCACCAUCCCCAUGACCAGCA	835
1512	Sequence	strand	GCCGGGCUGC
NR1H3-1463-	Artificial	36 mer sense	CCGACUGAUGUUCCCACGGAGCA	836
1529	Sequence	strand	GCCGGGCUGC
NR1H3-1475-	Artificial	36 mer sense	CCCACGGAUGCUAAUGAAAAGCA	837
1541	Sequence	strand	GCCGGGCUGC
NR1H3-1479-	Artificial	36 mer sense	CGGAUGCUAAUGAAACUGGAGC	838
1545	Sequence	strand	AGCCGGGCUGC
NR1H3-1481-	Artificial	36 mer sense	GAUGCUAAUGAAACUGGUGAGC	839
1547	Sequence	strand	AGCCGGGCUGC
NR1H3-1485-	Artificial	36 mer sense	CUAAUGAAACUGGUGAGCCAGCA	840
1551	Sequence	strand	GCCGGGCUGC
NR1H3-1515-	Artificial	36 mer sense	AGCAGCGUCCACUCAGAGCAGCA	841
1581	Sequence	strand	GCCGGGCUGC
NR1H3-1517-	Artificial	36 mer sense	CAGCGUCCACUCAGAGCAAAGCA	842
1583	Sequence	strand	GCCGGGCUGC
NR1H3-1518-	Artificial	36 mer sense	AGCGUCCACUCAGAGCAAGAGCA	843
1584	Sequence	strand	GCCGGGCUGC
NR1H3-1533-	Artificial	36 mer sense	CAAGUGUUUGCACUGCGUCAGCA	844
1599	Sequence	strand	GCCGGGCUGC
NR1H3-1535-	Artificial	36 mer sense	AGUGUUUGCACUGCGUCUGAGCA	845
1601	Sequence	strand	GCCGGGCUGC
NR1H3-1545-	Artificial	36 mer sense	CUGCGUCUGCAGGACAAAAAGCA	846
1611	Sequence	strand	GCCGGGCUGC
NR1H3-1554-	Artificial	36 mer sense	CAGGACAAAAAGCUCCCACAGCA	847
1620	Sequence	strand	GCCGGGCUGC
NR1H3-1581-	Artificial	36 mer sense	UCUGAGAUCUGGGAUGUGCAGC	848
1647	Sequence	strand	AGCCGGGCUGC
NR1H3-1586-	Artificial	36 mer sense	GAUCUGGGAUGUGCACGAAAGC	849
1652	Sequence	strand	AGCCGGGCUGC
NR1H3-1587-	Artificial	36 mer sense	AUCUGGGAUGUGCACGAAUAGC	850
1653	Sequence	strand	AGCCGGGCUGC
NR1H3-1588-	Artificial	36 mer sense	UCUGGGAUGUGCACGAAUGAGC	851
1654	Sequence	strand	AGCCGGGCUGC
NR1H3-1663-	Artificial	36 mer sense	UGCCUCCUAGAAGUGGAACAGCA	852
1727	Sequence	strand	GCCGGGCUGC
NR1H3-1671-	Artificial	36 mer sense	AGAAGUGGAACAGACUGAGAGC	853
1735	Sequence	strand	AGCCGGGCUGC
NR1H3-1684-	Artificial	36 mer sense	ACUGAGAAGGGCAAACAUUAGC	854
1748	Sequence	strand	AGCCGGGCUGC
NR1H3-1731-	Artificial	36 mer sense	GUGGCAUUAAAAGAGAGUCAGC	855
1795	Sequence	strand	AGCCGGGCUGC
NR1H3-1732-	Artificial	36 mer sense	UGGCAUUAAAAGAGAGUCAAGC	856
1796	Sequence	strand	AGCCGGGCUGC
NR1H3-763-	Artificial	22 mer	UUGUUCUUCUGACAGGACACGG	857
783-860	Sequence	antisense
		strand
NR1H3-765-	Artificial	22 mer	UUCUGUUCUUCUGACAGGACGG	858
785-862	Sequence	antisense
		strand
NR1H3-767-	Artificial	22 mer	UGAUCUGUUCUUCUGACAGGGG	859
787-864	Sequence	antisense
		strand
NR1H3-768-	Artificial	22 mer	UGGAUCUGUUCUUCUGACAGGG	860
788-865	Sequence	antisense
		strand
NR1H3-769-	Artificial	22 mer	UCGGAUCUGUUCUUCUGACAGG	861
789-866	Sequence	antisense
		strand
NR1H3-794-	Artificial	22 mer	UCUCUUGCCGCUUCAGUUUCGG	862
814-891	Sequence	antisense
		strand
NR1H3-1152-	Artificial	22 mer	UAUGUCUCCAGAAGCAUCACGG	863
1172-1249	Sequence	antisense
		strand
NR1H3-1189-	Artificial	22 mer	UAAGGUGAUACUCUCACUCCGG	864
1209-1286	Sequence	antisense
		strand
NR1H3-1195-	Artificial	22 mer	UUUGAGGAAGGUGAUACUCUGG	865
1215-1292	Sequence	antisense
		strand
NR1H3-1200-	Artificial	22 mer	UAAUCCUUGAGGAAGGUGAUGG	866
1220-1297	Sequence	antisense
		strand
NR1H3-1201-	Artificial	22 mer	UAAAUCCUUGAGGAAGGUGAGG	867
1221-1298	Sequence	antisense
		strand
NR1H3-1202-	Artificial	22 mer	UGAAAUCCUUGAGGAAGGUGGG	868
1222-1299	Sequence	antisense
		strand
NR1H3-1203-	Artificial	22 mer	UUGAAAUCCUUGAGGAAGGUGG	869
1223-1300	Sequence	antisense
		strand
NR1H3-1204-	Artificial	22 mer	UCUGAAAUCCUUGAGGAAGGGG	870
1224-1301	Sequence	antisense
		strand
NR1H3-1205-	Artificial	22 mer	UACUGAAAUCCUUGAGGAAGGG	871
1225-1302	Sequence	antisense
		strand
NR1H3-1206-	Artificial	22 mer	UAACUGAAAUCCUUGAGGAAGG	872
1226-1303	Sequence	antisense
		strand
NR1H3-1208-	Artificial	22 mer	UAUAACUGAAAUCCUUGAGGGG	873
1228-1305	Sequence	antisense
		strand
NR1H3-1209-	Artificial	22 mer	UUAUAACUGAAAUCCUUGAGGG	874
1229-1306	Sequence	antisense
		strand
NR1H3-1210-	Artificial	22 mer	UUUAUAACUGAAAUCCUUGAGG	875
1230-1307	Sequence	antisense
		strand
NR1H3-1211-	Artificial	22 mer	UGUUAUAACUGAAAUCCUUGGG	876
1231-1308	Sequence	antisense
		strand
NR1H3-1212-	Artificial	22 mer	UGGUUAUAACUGAAAUCCUUGG	877
1232-1309	Sequence	antisense
		strand
NR1H3-1213-	Artificial	22 mer	UCGGUUAUAACUGAAAUCCUGG	878
1233-1310	Sequence	antisense
		strand
NR1H3-1214-	Artificial	22 mer	UCCGGUUAUAACUGAAAUCCGG	879
1234-1311	Sequence	antisense
		strand
NR1H3-1221-	Artificial	22 mer	UAGUCUUCCCGGUUAUAACUGG	880
1241-1318	Sequence	antisense
		strand
NR1H3-1249-	Artificial	22 mer	UAAUUCCACUUGCAGCCCUGGG	881
1269-1346	Sequence	antisense
		strand
NR1H3-1254-	Artificial	22 mer	UUGAUGAAUUCCACUUGCAGGG	882
1274-1351	Sequence	antisense
		strand
NR1H3-1255-	Artificial	22 mer	UUUGAUGAAUUCCACUUGCAGG	883
1275-1352	Sequence	antisense
		strand
NR1H3-1256-	Artificial	22 mer	UGUUGAUGAAUUCCACUUGCGG	884
1276-1353	Sequence	antisense
		strand
NR1H3-1257-	Artificial	22 mer	UGGUUGAUGAAUUCCACUUGGG	885
1277-1354	Sequence	antisense
		strand
NR1H3-1260-	Artificial	22 mer	UUGGGGUUGAUGAAUUCCACGG	886
1280-1357	Sequence	antisense
		strand
NR1H3-1261-	Artificial	22 mer	UAUGGGGUUGAUGAAUUCCAGG	887
1281-1358	Sequence	antisense
		strand
NR1H3-1263-	Artificial	22 mer	UAGAUGGGGUUGAUGAAUUCGG	888
1283-1360	Sequence	antisense
		strand
NR1H3-1264-	Artificial	22 mer	UAAGAUGGGGUUGAUGAAUUGG	889
1284-1361	Sequence	antisense
		strand
NR1H3-1405-	Artificial	22 mer	UUCCACAUAUGUGUGCUGCAGG	890
1471-1502	Sequence	antisense
		strand
NR1H3-1409-	Artificial	22 mer	UGGCUUCCACAUAUGUGUGCGG	891
1475-1506	Sequence	antisense
		strand
NR1H3-1458-	Artificial	22 mer	UGGAACAUCAGUCGGUCAUGGG	892
1524-1555	Sequence	antisense
		strand
NR1H3-1464-	Artificial	22 mer	UUCCGUGGGAACAUCAGUCGGG	893
1530-1561	Sequence	antisense
		strand
NR1H3-1465-	Artificial	22 mer	UAUCCGUGGGAACAUCAGUCGG	894
1531-1562	Sequence	antisense
		strand
NR1H3-1467-	Artificial	22 mer	UGCAUCCGUGGGAACAUCAGGG	895
1533-1564	Sequence	antisense
		strand
NR1H3-1469-	Artificial	22 mer	UUAGCAUCCGUGGGAACAUCGG	896
1535-1566	Sequence	antisense
		strand
NR1H3-1470-	Artificial	22 mer	UUUAGCAUCCGUGGGAACAUGG	897
1536-1567	Sequence	antisense
		strand
NR1H3-1480-	Artificial	22 mer	UACCAGUUUCAUUAGCAUCCGG	898
1546-1577	Sequence	antisense
		strand
NR1H3-1482-	Artificial	22 mer	UUCACCAGUUUCAUUAGCAUGG	899
1548-1579	Sequence	antisense
		strand
NR1H3-1524-	Artificial	22 mer	UCAAACACUUGCUCUGAGUGGG	900
1590-1621	Sequence	antisense
		strand
NR1H3-1594-	Artificial	22 mer	UAACAGUCAUUCGUGCACAUGG	901
1660-1691	Sequence	antisense
		strand
NR1H3-1595-	Artificial	22 mer	UGAACAGUCAUUCGUGCACAGG	902
1661-1692	Sequence	antisense
		strand
NR1H3-1596-	Artificial	22 mer	UAGAACAGUCAUUCGUGCACGG	903
1662	Sequence	antisense
		strand
NR1H3-1670-	Artificial	22 mer	UUCAGUCUGUUCCACUUCUAGG	904
1734	Sequence	antisense
		strand
NR1H3-1672-	Artificial	22 mer	UUCUCAGUCUGUUCCACUUCGG	905
1736	Sequence	antisense
		strand
NR1H3-1673-	Artificial	22 mer	UUUCUCAGUCUGUUCCACUUGG	906
1737	Sequence	antisense
		strand
NR1H3-1674-	Artificial	22 mer	UCUUCUCAGUCUGUUCCACUGG	907
1738	Sequence	antisense
		strand
NR1H3-1675-	Artificial	22 mer	UCCUUCUCAGUCUGUUCCACGG	908
1739-1766	Sequence	antisense
		strand
NR1H3-1676-	Artificial	22 mer	UCCCUUCUCAGUCUGUUCCAGG	909
1740-1767	Sequence	antisense
		strand
NR1H3-1678-	Artificial	22 mer	UUGCCCUUCUCAGUCUGUUCGG	910
1742-1769	Sequence	antisense
		strand
NR1H3-1207-	Artificial	22 mer	UUAACUGAAAUCCUUGAGGAGG	911
1227	Sequence	antisense
		strand
NR1H3-1220-	Artificial	22 mer	UGUCUUCCCGGUUAUAACUGGG	912
1240	Sequence	antisense
		strand
NR1H3-1224-	Artificial	22 mer	UCAAAGUCUUCCCGGUUAUAGG	913
1244	Sequence	antisense
		strand
NR1H3-1244-	Artificial	22 mer	UCACUUGCAGCCCUGCUUUGGG	914
1264	Sequence	antisense
		strand
NR1H3-1252-	Artificial	22 mer	UAUGAAUUCCACUUGCAGCCGG	915
1272	Sequence	antisense
		strand
NR1H3-1259-	Artificial	22 mer	UGGGGUUGAUGAAUUCCACUGG	916
1279	Sequence	antisense
		strand
	Artificial	22 mer	UGAAGAUGGGGUUGAUGAAUGG	917
NR1H3-1265-	Sequence	antisense
1285		strand
	Artificial	22 mer	UCGAAGAUGGGGUUGAUGAAGG	918
NR1H3-1266-	Sequence	antisense
1286		strand
NR1H3-1429-	Artificial	22 mer	UAUGGAGACGUAGGCAUGCAGG	919
1495	Sequence	antisense
		strand
NR1H3-1433-	Artificial	22 mer	UGUGGAUGGAGACGUAGGCAGG	920
1499	Sequence	antisense
		strand
NR1H3-1437-	Artificial	22 mer	UGAUGGUGGAUGGAGACGUAGG	921
1503	Sequence	antisense
		strand
NR1H3-1439-	Artificial	22 mer	UGGGAUGGUGGAUGGAGACGGG	922
1505	Sequence	antisense
		strand
NR1H3-1446-	Artificial	22 mer	UGGUCAUGGGGAUGGUGGAUGG	923
1512	Sequence	antisense
		strand
NR1H3-1463-	Artificial	22 mer	UCCGUGGGAACAUCAGUCGGGG	924
1529	Sequence	antisense
		strand
NR1H3-1475-	Artificial	22 mer	UUUUCAUUAGCAUCCGUGGGGG	925
1541	Sequence	antisense
		strand
NR1H3-1479-	Artificial	22 mer	UCCAGUUUCAUUAGCAUCCGGG	926
1545	Sequence	antisense
		strand
NR1H3-1481-	Artificial	22 mer	UCACCAGUUUCAUUAGCAUCGG	927
1547	Sequence	antisense
		strand
NR1H3-1485-	Artificial	22 mer	UGGCUCACCAGUUUCAUUAGGG	928
1551	Sequence	antisense
		strand
NR1H3-1515-	Artificial	22 mer	UGCUCUGAGUGGACGCUGCUGG	929
1581	Sequence	antisense
		strand
NR1H3-1517-	Artificial	22 mer	UUUGCUCUGAGUGGACGCUGGG	930
1583	Sequence	antisense
		strand
NR1H3-1518-	Artificial	22 mer	UCUUGCUCUGAGUGGACGCUGG	931
1584	Sequence	antisense
		strand
NR1H3-1533-	Artificial	22 mer	UGACGCAGUGCAAACACUUGGG	932
1599	Sequence	antisense
		strand
NR1H3-1535-	Artificial	22 mer	UCAGACGCAGUGCAAACACUGG	933
1601	Sequence	antisense
		strand
NR1H3-1545-	Artificial	22 mer	UUUUUGUCCUGCAGACGCAGGG	934
1611	Sequence	antisense
		strand
NR1H3-1554-	Artificial	22 mer	UGUGGGAGCUUUUUGUCCUGGG	935
1620	Sequence	antisense
		strand
NR1H3-1581-	Artificial	22 mer	UGCACAUCCCAGAUCUCAGAGG	936
1647	Sequence	antisense
		strand
NR1H3-1586-	Artificial	22 mer	UUUCGUGCACAUCCCAGAUCGG	937
1652	Sequence	antisense
		strand
NR1H3-1587-	Artificial	22 mer	UAUUCGUGCACAUCCCAGAUGG	938
1653	Sequence	antisense
		strand
NR1H3-1588-	Artificial	22 mer	UCAUUCGUGCACAUCCCAGAGG	939
1654	Sequence	antisense
		strand
NR1H3-1663-	Artificial	22 mer	UGUUCCACUUCUAGGAGGCAGG	940
1727	Sequence	antisense
		strand
NR1H3-1671-	Artificial	22 mer	UCUCAGUCUGUUCCACUUCUGG	941
1735	Sequence	antisense
		strand
NR1H3-1684-	Artificial	22 mer	UAAUGUUUGCCCUUCUCAGUGG	942
1748	Sequence	antisense
		strand
NR1H3-1731-	Artificial	22 mer	UGACUCUCUUUUAAUGCCACGG	943
1795	Sequence	antisense
		strand
NR1H3-1732-	Artificial	22 mer	UUGACUCUCUUUUAAUGCCAGG	944
1796	Sequence	antisense
		strand
NR1H3-763-	Artificial	Modified	[mGs][mU][mG][mU][mC][mC][mU]	945
783-860	Sequence	sense strand	[fG][fU][fC][fA][mG][mA][mA][mG]
			[mA][mA][mC][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-765-	Artificial	Modified	[mGs][mU][mC][mC][mU][mG][mU]	946
785-862	Sequence	sense strand	[fC][fA][fG][fA][mA][mG][mA][mA]
			[mC][mA][mG][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-767-	Artificial	Modified	[mCs][mC][mU][mG][mU][mC][mA]	947
787-864	Sequence	sense strand	[fG][fA][fA][fG][mA][mA][mC][mA]
			[mG][mA][mU][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-768-	Artificial	Modified	[mCs][mU][mG][mU][mC][mA][mG]	948
788-865	Sequence	sense strand	[fA][fA][fG][fA][mA][mC][mA][mG]
			[mA][mU][mC][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-769-	Artificial	Modified	[mUs][mG][mU][mC][mA][mG][mA]	949
789-866	Sequence	sense strand	[fA][fG][fA][fA][mC][mA][mG][mA]
			[mU][mC][mC][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-794-	Artificial	Modified	[mGs][mA][mA][mA][mC][mU][mG]	950
814-891	Sequence	sense strand	[fA][fA][fG][fC][mG][mG][mC][mA]
			[mA][mG][mA][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1152-	Artificial	Modified	[mGs][mU][mG][mA][mU][mG][mC]	951
1172-1249	Sequence	sense strand	[fU][fU][fC][fU][mG][mG][mA][mG]
			[mA][mC][mA][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1189-	Artificial	Modified	[mGs][mG][mA][mG][mU][mG][mA]	952
1209-1286	Sequence	sense strand	[fG][fA][fG][fU][mA][mU][mC][mA]
			[mC][mC][mU][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1195-	Artificial	Modified	[mAs][mG][mA][mG][mU][mA][mU]	953
1215-1292	Sequence	sense strand	[fC][fA][fC][fC][mU][mU][mC][mC]
			[mU][mC][mA][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1200-	Artificial	Modified	[mAs][mU][mC][mA][mC][mC][mU]	954
1220-1297	Sequence	sense strand	[fU][fC][fC][fU][mC][mA][mA][mG]
			[mG][mA][mU][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1201-	Artificial	Modified	[mUs][mC][mA][mC][mC][mU][mU]	955
1221-1298	Sequence	sense strand	[fC][fC][fU][fC][mA][mA][mG][mG]
			[mA][mU][mU][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1202-	Artificial	Modified	[mCs][mA][mC][mC][mU][mU][mC]	956
1222-1299	Sequence	sense strand	[fC][fU][fC][fA][mA][mG][mG][mA]
			[mU][mU][mU][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1203-	Artificial	Modified	[mAs][mC][mC][mU][mU][mC][mC]	957
1223-1300	Sequence	sense strand	[fU][fC][fA][fA][mG][mG][mA][mU]
			[mU][mU][mC][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1204-	Artificial	Modified	[mCs][mC][mU][mU][mC][mC][mU]	958
1224-1301	Sequence	sense strand	[fC][fA][fA][fG][mG][mA][mU][mU]
			[mU][mC][mA][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1205-	Artificial	Modified	[mCs][mU][mU][mC][mC][mU][mC]	959
1225-1302	Sequence	sense strand	[fA][fA][fG][fG][mA][mU][mU][mU]
			[mC][mA][mG][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1206-	Artificial	Modified	[mUs][mU][mC][mC][mU][mC][mA]	960
1226-1303	Sequence	sense strand	[fA][fG][fG][fA][mU][mU][mU][mC]
			[mA][mG][mU][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1207-	Artificial	Modified	[mUs][mC][mC][mU][mC][mA][mAf	961
1227	Sequence	sense strand	[fG][fG][fA][fU][mU][mU][mC][mA]
			[mG][mU][mU][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1208-	Artificial	Modified	[mCs][mC][mU][mC][mA][mA][mG]	962
1228-1305	Sequence	sense strand	[fG][fA][fU][fU][mU][mC][mA][mG]
			[mU][mU][mA][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1209-	Artificial	Modified	[mCs][mU][mC][mA][mA][mG][mG]	963
1229-1306	Sequence	sense strand	[fA][fU][fU][fU][mC][mA][mG][mU]
			[mU][mA][mU][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1210-	Artificial	Modified	[mUs][mC][mA][mA][mG][mG][mA]	964
1230-1307	Sequence	sense strand	[fU][fU][fU][fC][mA][mG][mU][mU]
			[mA][mU][mA][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1211-	Artificial	Modified	[mCs][mA][mA][mG][mG][mA][mU]	965
1231-1308	Sequence	sense strand	[fU][fU][fC][fA][mG][mU][mU][mA]
			[mU][mA][mA][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC
NR1H3-1212-	Artificial	Modified	[mAs][mA][mG][mG][mA][mU][mU]	966
1232-1309	Sequence	sense strand	[fU][fC][fA][fG][mU][mU][mA][mU]
			[mA][mA][mC][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1213-	Artificial	Modified	[mAs][mG][mG][mA][mU][mU][mU]	967
1233-1310	Sequence	sense strand	[fC][fA][fG][fU][mU][mA][mU][mA]
			[mA][mC][mC][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1214-	Artificial	Modified	[mGs][mG][mA][mU][mU][mU][mC]	968
1234-1311	Sequence	sense strand	[fA][fG][fU][fU][mA][mU][mA][mA]
			[mC][mC][mG][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1220	Artificial	Modified	[mCs][mA][mG][mU][mU][mA][mU]	969
	Sequence	sense strand	[fA][fA][fC][fC][mG][mG][mG][mA]
			[mA][mG][mA][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1221-	Artificial	Modified	[mAs][mG][mU][mU][mA][mU][mA]	970
1241-1318	Sequence	sense strand	[fA][fC][fC][fG][mG][mG][mA][mA]
			[mG][mA][mC][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1224-	Artificial	Modified	[mUs][mA][mU][mA][mA][mC][mC]	971
1244	Sequence	sense strand	[mU][mU][mU][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1244-	Artificial	Modified	[mCs][mA][mA][mA][mG][mC][mA]	972
1264	Sequence	sense strand	[fG][fG][fG][fC][mU][mG][mC][mA]
			[mA][mG][mU][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1249-	Artificial	Modified	[mCs][mA][mG][mG][mG][mC][mU]	973
1269-1346	Sequence	sense strand	[fG][fC][fA][fA][mG][mU][mG][mG]
			[mA][mA][mU][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1252-	Artificial	Modified	[mGs][mG][mC][mU][mG][mC][mA]	974
1272	Sequence	sense strand	[fA][fG][fU][fG][mG][mA][mA][mU]
			[mU][mC][mA][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1254-	Artificial	Modified	[mCs][mU][mG][mC][mA][mA][mG]	975
1274-1351	Sequence	sense strand	[fU][fG][fG][fA][mA][mU][mU][mC]
			[mA][mU][mC][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1255-	Artificial	Modified	[mUs][mG][mC][mA][mA][mG][mU]	976
1275-1352	Sequence	sense strand	[fG][fG][fA][fA][mU][mU][mC][mA]
			[mU][mC][mA][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1256-	Artificial	Modified	[mGs][mC][mA][mA][mG][mU][mG]	977
1276-1353	Sequence	sense strand	[fG][fA][fA][fU][mU][mC][mA][mU]
			[mC][mA][mA][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1257-	Artificial	Modified	[mCs][mA][mA][mG][mU][mG][mG]	978
1277-1354	Sequence	sense strand	[fA][fA][fU][fU][mC][mA][mU][mC]
			[mA][mA][mC][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1259	Artificial	Modified	[mAs][mG][mU][mG][mG][mA][mA]	979
	Sequence	sense strand	[fU][fU][fC][fA][mU][mC][mA][mA]
			[mC][mC][mC][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1260-	Artificial	Modified	[mGs][mU][mG][mG][mA][mA][mU][f	980
1280-1357	Sequence	sense strand	[fU][fC][fA][fU][mC][mA][mA][mC]
			[mC][mC][mC][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1261-	Artificial	Modified	[mUs][mG][mG][mA][mA][mU][mU]	981
1281-1358	Sequence	sense strand	[fC][fA][fU][fC][mA][mA][mC][mC]
			[mC][mC][mA][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAclrademA-GalNAclrademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1263-	Artificial	Modified	[mGs][mA][mA][mU][mU][mC][mA]	982
1283-1360	Sequence	sense strand	[fU][fC][fA][fA][mC][mC][mC][mC]
			[mA][mU][mC][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1264-	Artificial	Modified	[mAs][mA][mU][mU][mC][mA][mU]	983
1284-1361	Sequence	sense strand	[fC][fA][fA][fC][mC][mC][mC][mA]
			[mU][mC][mU][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1265-	Artificial	Modified	[mAs][mU][mU][mC][mA][mU][mC]	984
1285	Sequence	sense strand	[fA][fA][fC][fC][mC][mC][mA][mU]
			[mC][mU][mU][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1266-	Artificial	Modified	[mUs][mU][mC][mA][mU][mC][mA]	985
1286	Sequence	sense strand	[fA][fC][fC][fC][mC][mA][mU][mC]
			[mU][mU][mC][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1405-	Artificial	Modified	[mUs][mG][mC][mA][mG][mC][mA]	986
1471-1502	Sequence	sense strand	[fC][fA][fC][fA][mU][mA][mU][mG]
			[mU][mG][mG][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1409-	Artificial	Modified	[mGs][mC][mA][mC][mA][mC][mA]	987
1475-1506	Sequence	sense strand	[fU][fA][fU][fG][mU][mG][mG][mA]
			[mA][mG][mC][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1429-	Artificial	Modified	[mUs][mG][mC][mA][mU][mG][mC]	988
1495	Sequence	sense strand	[fC][fU][fA][fC][mG][mU][mC][mU]
			[mC][mC][mA][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1433-	Artificial	Modified	[mUs][mG][mC][mC][mU][mA][mC]	989
1499	Sequence	sense strand	[fG][fU][fC][fU][mC][mC][mA][mU]
			[mC][mC][mA][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1437-	Artificial	Modified	[mUs][mA][mC][mG][mU][mC][mU]	990
1503	Sequence	sense strand	[fC][fC][fA][fU][mC][mC][mA][mC]
			[mC][mA][mU][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1439-	Artificial	Modified	[mCs][mG][mU][mC][mU][mC][mC]	991
1505	Sequence	sense strand	[fA][fU][fC][fC][mA][mC][mC][mA]
			[mU][mC][mC][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1446-	Artificial	Modified	[mAs][mU][mC][mC][mA][mC][mC]	992
1512	Sequence	sense strand	[fA][fU][fC][fC][mC][mC][mA][mU]
			[mG][mA][mC][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1458-	Artificial	Modified	[mCs][mA][mU][mG][mA][mC][mC]	993
1524-1555	Sequence	sense strand	[fG][fA][fC][fU][mG][mA][mU][mG]
			[mU][mU][mC][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1463-	Artificial	Modified	[mCs][mC][mG][mA][mC][mU][mG]	994
1529	Sequence	sense strand	[fA][fU][fG][fU][mU][mC][mC][mC]
			[mA][mC][mG][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1464-	Artificial	Modified	[mCs][mG][mA][mC][mU][mG][mA]	995
1530-1561	Sequence	sense strand	[fU][fG][fU][fU][mC][mC][mC][mA]
			[mC][mG][mG][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1465-	Artificial	Modified	[mGs][mA][mC][mU][mG][mA][mU]	996
1531-1562	Sequence	sense strand	[fG][fU][fU][fC][mC][mC][mA][mC]
			[mG][mG][mA][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1467-	Artificial	Modified	[mCs][mU][mG][mA][mU][mG][mU]	997
1533-1564	Sequence	sense strand	[fU][fC][fC][fC][mA][mC][mG][mG]
			[mA][mU][mG][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1469-	Artificial	Modified	[mGs][mA][mU][mG][mU][mU][mC]	998
1535-1566	Sequence	sense strand	[fC][fC][fA][fC][mG][mG][mA][mU]
			[mG][mC][mU][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1470-	Artificial	Modified	[mAs][mU][mG][mU][mU][mC][mC]	999
1536-1567	Sequence	sense strand	[fC][fA][fC][fG][mG][mA][mU][mG]
			[mC][mU][mA][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1475-	Artificial	Modified	[mCs][mC][mC][mA][mC][mG][mG]	1000
1541	Sequence	sense strand	[fA][fU][fG][fC][mU][mA][mA][mU]
			[mG][mA][mA][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1479-	Artificial	Modified	[mCs][mG][mG][mA][mU][mG][mC]	1001
1545	Sequence	sense strand	[fU][fA][fA][fU][mG][mA][mA][mA]
			[mC][mU][mG][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1480-	Artificial	Modified	[mGs][mG][mA][mU][mG][mC][mU]	1002
1546-1577	Sequence	sense strand	[fA][fA][fU][fG][mA][mA][mA][mC]
			[mU][mG][mG][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1481-	Artificial	Modified	[mGs][mA][mU][mG][mC][mU][mA]	1003
1547	Sequence	sense strand	[fA][fU][fG][fA][mA][mA][mC][mU]
			[mG][mG][mU][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1482-	Artificial	Modified	[mAs][mU][mG][mC][mU][mA][mA]	1004
1548-1579	Sequence	sense strand	[fU][fG][fA][fA][mA][mC][mU][mG]
			[mG][mU][mG][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1485-	Artificial	Modified	[mCs][mU][mA][mA][mU][mG][mA]	1005
1551	Sequence	sense strand	[fA][fA][fC][fU][mG][mG][mU][mG]
			[mA][mG][mC][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1515-	Artificial	Modified	[mAs][mG][mC][mA][mG][mC][mG]	1006
1581	Sequence	sense strand	[fU][fC][fC][fA][mC][mU][mC][mA]
			[mG][mA][mG][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1517-	Artificial	Modified	[mCs][mA][mG][mC][mG][mU][mC]	1007
1583	Sequence	sense strand	[fC][fA][fC][fU][mC][mA][mG][mA]
			[mG][mC][mA][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1518-	Artificial	Modified	[mAs][mG][mC][mG][mU][mC][mC]	1008
1584	Sequence	sense strand	[fA][fC][fU][fC][mA][mG][mA][mG]
			[mC][mA][mA][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1524-	Artificial	Modified	[mCs][mA][mC][mU][mC][mA][mG]	1009
1590-1621	Sequence	sense strand	[fA][fG][fC][fA][mA][mG][mU][mG]
			[mU][mU][mU][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1533-	Artificial	Modified	[mCs][mA][mA][mG][mU][mG][mU]	1010
1599	Sequence	sense strand	[fU][fU][fG][fC][mA][mC][mU][mG]
			[mC][mG][mU][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1535-	Artificial	Modified	[mAs][mG][mU][mG][mU][mU][mU]	1011
1601	Sequence	sense strand	[fG][fC][fA][fC][mU][mG][mC][mG]
			[mU][mC][mU][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1545-	Artificial	Modified	[mCs][mU][mG][mC][mG][mU][mC]	1012
1611	Sequence	sense strand	[fU][fG][fC][fA][mG][mG][mA][mC]
			[mA][mA][mA][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1554-	Artificial	Modified	[mCs][mA][mG][mG][mA][mC][mA]	1013
1620	Sequence	sense strand	[fA][fA][fA][fA][mG][mC][mU][mC]
			[mC][mC][mA][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1581-	Artificial	Modified	[mUs][mC][mU][mG][mA][mG][mA]	1014
1647	Sequence	sense strand	[fU][fC][fU][fG][mG][mG][mA][mU]
			[mG][mU][mG][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1586-	Artificial	Modified	[mGs][mA][mU][mC][mU][mG][mG]	1015
1652	Sequence	sense strand	[fG][fA][fU][fG][mU][mG][mC][mA]
			[mC][mG][mA][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1587-	Artificial	Modified	[mAs][mU][mC][mU][mG][mG][mG]	1016
1653	Sequence	sense strand	[fA][fU][fG][fU][mG][mC][mA][mC]
			[mG][mA][mA][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1588-	Artificial	Modified	[mUs][mC][mU][mG][mG][mG][mA]	1017
1654	Sequence	sense strand	[fU][fG][fU][fG][mC][mA][mC][mG]
			[mA][mA][mU][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1594-	Artificial	Modified	[mAs][mU][mG][mU][mG][mC][mA]	1018
1660-1691	Sequence	sense strand	[fC][fG][fA][fA][mU][mG][mA][mC]
			[mU][mG][mU][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1595-	Artificial	Modified	[mUs][mG][mU][mG][mC][mA][mC]	1019
1661-1692	Sequence	sense strand	[fG][fA][fA][fU][mG][mA][mC][mU]
			[mG][mU][mU][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1596-	Artificial	Modified	[mGs][mU][mG][mC][mA][mC][mG]	1020
1662	Sequence	sense strand	[fA][fA][fU][fG][mA][mC][mU][mG]
			[mU][mU][mC][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1663-	Artificial	Modified	[mUs][mG][mC][mC][mU][mC][mC]	1021
1727	Sequence	sense strand	[fU][fA][fG][fA][mA][mG][mU][mG]
			[mG][mA][mA][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1670-	Artificial	Modified	[mUs][mA][mG][mA][mA][mG][mU]	1022
1734	Sequence	sense strand	[fG][fG][fA][fA][mC][mA][mG][mA]
			[mC][mU][mG][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1671-	Artificial	Modified	[mAs][mG][mA][mA][mG][mU][mG]	1023
1735	Sequence	sense strand	[fG][fA][fA][fC][mA][mG][mA][mC]
			[mU][mG][mA][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1672-	Artificial	Modified	[mGs][mA][mA][mG][mU][mG][mG]	1024
1736	Sequence	sense strand	[fA][fA][fC][fA][mG][mA][mC][mU]
			[mG][mA][mG][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1673-	Artificial	Modified	[mAs][mA][mG][mU][mG][mG][mA]	1025
1737	Sequence	sense strand	[fA][fC][fA][fG][mA][mC][mU][mG]
			[mA][mG][mA][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1674-	Artificial	Modified	[mAs][mG][mU][mG][mG][mA][mA]	1026
1738	Sequence	sense strand	[fC][fA][fG][fA][mC][mU][mG][mA]
			[mG][mA][mA][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1675-	Artificial	Modified	[mGs][mU][mG][mG][mA][mA][mC]	1027
1739-1766	Sequence	sense strand	[fA][fG][fA][fC][mU][mG][mA][mG]
			[mA][mA][mG][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1676-	Artificial	Modified	[mUs][mG][mG][mA][mA][mC][mA]	1028
1740-1767	Sequence	sense strand	[fG][fA][fC][fU][mG][mA][mG][mA]
			[mA][mG][mG][mG][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1678-	Artificial	Modified	[mGs][mA][mA][mC][mA][mG][mA]	1029
1742-1769	Sequence	sense strand	[fC][fU][fG][fA][mG][mA][mA][mG]
			[mG][mG][mC][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1684-	Artificial	Modified	[mAs][mC][mU][mG][mA][mG][mA]	1030
1748	Sequence	sense strand	[fA][fG][fG][fG][mC][mA][mA][mA]
			[mC][mA][mU][mU][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1731-	Artificial	Modified	[mGs][mU][mG][mG][mC][mA][mU]	1031
1795	Sequence	sense strand	[fU][fA][fA][fA][mA][mG][mA][mG]
			[mA][mG][mU][mC][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-1732-	Artificial	Modified	[mUs][mG][mG][mC][mA][mU][mU]	1032
1796	Sequence	sense strand	[fA][fA][fA][fA][mG][mA][mG][mA]
			[mG][mU][mC][mA][mA][mG][mC][mA]
			[mG][mC][mC][mG][ademA-
			GalNAc][ademA-GalNAc][ademA-
			GalNAc][mG][mG][mC][mU][mG][mC]
NR1H3-763-	Artificial	Modified	[MePhosphonate-4O-	1033
783-860	Sequence	antisense	mUs][fUs][fGs][fU][fU][mC][fU][mU]
		strand	[mC][fU][mG][mA][mC][fA][mG][mG]
			[mA][mC][mA][mCs][mGs][mG]
NR1H3-765-	Artificial	Modified	[MePhosphonate-4O-	1034
785-862	Sequence	antisense	mUs][fUs][fCs][fU][fG][mU][fU][mC]
		strand	[mU][fU][mC][mU][mG][fA][mC][mA]
			[mG][mG][mA][mCs][mGs][mG]
NR1H3-767-	Artificial	Modified	[MePhosphonate-4O-	1035
787-864	Sequence	antisense	mUs][fGs][fAs][fU][fC][mU][fG][mU]
		strand	[mU][fC][mU][mU][mC][fU][mG][mA]
			[mC][mA][mG][mGs][mGs][mG]
NR1H3-768-	Artificial	Modified	[MePhosphonate-4O-	1036
788-865	Sequence	antisense	mUs][fGs][fGs][fA][fU][mC][fU][mG]
		strand	[mU][fU][mC][mU][mU][fC][mU][mG]
			[mA][mC][mA][mGs][mGs][mG]
NR1H3-769-	Artificial	Modified	[MePhosphonate-4O-	1037
789-866	Sequence	antisense	mUs][fCs][fG][mG][fA][mU][fC][mU]
		strand	[mG][fU][mU][mC][mU][fU][mC][mU]
			[mG][mA][mC][mAs][mGs][mG]
NR1H3-794-	Artificial	Modified	[MePhosphonate-4O-	1038
814-891	Sequence	antisense	mUs][fCs][fUs][fC][fU][mU][fG][mC]
		strand	[mC][fG][mC][mU][mU][fC][mA][mG]
			[mU][mU][mU][mCs][mGs][mG]
NR1H3-1152-	Artificial	Modified	[MePhosphonate-4O-	1039
1172-1249	Sequence	antisense	[mUs][fAs][fUs][fG][fU][mC][fU][mC]
		strand	[mC][fA][mG][mA][mA][fG][mC][mA]
			[mU][mC][mA][mCs][mGs][mG]
NR1H3-1189-	Artificial	Modified	[MePhosphonate-4O-	1040
1209-1286	Sequence	antisense	mUs][fAs][fAs][fG][fG][mU][fG][mA]
		strand	[mU][fA][mC][mU][mC][fU][mC][mA]
			[mC][mU][mC][mCs][mGs][mG]
NR1H3-1195-	Artificial	Modified	[MePhosphonate-4O-	1041
1215-1292	Sequence	antisense	mUs][fUs][fUs][fG][fA][mG][fG][mA]
		strand	[mA][fG][mG][mU][mG][fA][mU][mA]
			[mC][mU][mC][mUs][mGs][mG]
NR1H3-1200-	Artificial	Modified	[MePhosphonate-4O-	1042
1220-1297	Sequence	antisense	mUs][fAs][fAs][fU][fC][mC][fU][mU]
		strand	[mG][fA][mG][mG][mA][fA][mG][mG]
			[mU][mG][mA][mUs][mGs][mG]
NR1H3-1201-	Artificial	Modified	[MePhosphonate-4O-	1043
1221-1298	Sequence	antisense	mUs][fAs][fAs][fA][fU][mC][fC][mU]
		strand	[mU][fG][mA][mG][mG][fA][mA][mG]
			[mG][mU][mG][mAs][mGs][mG]
NR1H3-1202-	Artificial	Modified	[MePhosphonate-4O-	1044
1222-1299	Sequence	antisense	mUs][fGs][fAs][fA][fA][mU][fC][mC]
		strand	[mU][fU][mG][mA][mG][fG][mA][mA]
			[mG][mG][mU][mGs][mGs][mG]
NR1H3-1203-	Artificial	Modified	[MePhosphonate-4O-	1045
1223-1300	Sequence	antisense	mUs][fUs][fGs][fA][fA][mA][fU][mC]
		strand	[mC][fU][mU][mG][mA][fG][mG][mA]
			[mA][mG][mG][mUs][mGs][mG]
NR1H3-1204-	Artificial	Modified	[MePhosphonate-4O-	1046
1224-1301	Sequence	antisense	mUs][fCs][fUs][fG][fA][mA][fA][mU]
		strand	[mC][fC][mU][mU][mG][fA][mG][mG]
			[mA][mA][mG][mGs][mGs][mG]
NR1H3-1205-	Artificial	Modified	[MePhosphonate-4O-	1047
1225-1302	Sequence	antisense	mUs][fAs][fCs][fU][fG][mA][fA][mA]
		strand	[mU][fC][mC][mU][mU][fG][mA][mG]
			[mG][mA][mA][mGs][mGs][mG]
NR1H3-1206-	Artificial	Modified	[MePhosphonate-4O-	1048
1226-1303	Sequence	antisense	mUs][fAs][fAs][fC][fU][mG][fA][mA]
		strand	[mA][fU][mC][mC][mU][fU][mG][mA]
			[mG][mG][mA][mAs][mGs][mG]
NR1H3-1207-	Artificial	Modified	[MePhosphonate-4O-	1049
1227	Sequence	antisense	mUs][fUs][fAs][fA][fC][mU][fG][mA]
		strand	[mA][fA][mU][mC][mC][fU][mU][mG]
			[mA][mG][mG][mAs][mGs][mG]
NR1H3-1208-	Artificial	Modified	[MePhosphonate-4O-	1050
1228-1305	Sequence	antisense	mUs][fAs][fUs][fA][fA][mC][fU][mG]
		strand	[mA][fA][mA][mU][mC][fC][mU][mU]
			[mG][mA][mG][mGs][mGs][mG]
NR1H3-1209-	Artificial	Modified	[MePhosphonate-4O-	1051
1229-1306	Sequence	antisense	mUs][fUs][fAs][fU][fA][mA][fC][mU]
		strand	[mG][fA][mA][mA][mU][fC][mC][mU]
			[mU][mG][mA][mGs][mGs][mG]
NR1H3-1210-	Artificial	Modified	[MePhosphonate-4O-	1052
1230-1307	Sequence	antisense	mUs][fUs][fUs][fA][fU][mA][fA][mC]
		strand	[mU][fG][mA][mA][mA][fU][mC][mC]
			[mU][mU][mG][mAs][mGs][mG]
NR1H3-1211-	Artificial	Modified	[MePhosphonate-4O-	1053
1231-1308	Sequence	antisense	mUs][fGs][fUs][fU][fA][mU][fA][mA]
		strand	[mC][fU][mG][mA][mA][fA][mU][mC]
			[mC][mU][mU][mGs][mGs][mG]
NR1H3-1212-	Artificial	Modified	[MePhosphonate-4O-	1054
1232-1309	Sequence	antisense	mUs][fGs][fGs][fU][fU][mA][fU][mA]
		strand	[mA][fC][mU][mG][mA][fA][mA][mU]
			[mC][mC][mU][mUs][mGs][mG]
NR1H3-1213-	Artificial	Modified	[MePhosphonate-4O-	1055
1233-1310	Sequence	antisense	mUs][fCs][fGs][fG][fU][mU][fA][mU]
		strand	[mA][fA][mC][mU][mG][fA][mA][mA]
			[mU][mC][mC][mUs][mGs][mG]
NR1H3-1214-	Artificial	Modified	[MePhosphonate-4O-	1056
1234-1311	Sequence	antisense	mUs][fCs][fCs][fG][fG][mU][fU][mA]
		strand	[mU][fA][mA][mC][mU][fG][mA][mA]
			[mA][mU][mC][mCs][mGs][mG]
NR1H3-1220	Artificial	Modified	[MePhosphonate-4O-	1057
	Sequence	antisense	mUs][fGs][fUs][fC][fU][mU][fC][mC]
		strand	[mC][fG][mG][mU][mU][fA][mU][mA]
			[mA][mC][mU][mGs][mGs][mG]
NR1H3-1221-	Artificial	Modified	[MePhosphonate-4O-	1058
1241-1318	Sequence	antisense	mUs][fAs][fGs][fU][fC][mU][fU][mC]
		strand	[mC][fC][mG][mG][mU][fU][mA][mU]
			[mA][mA][mC][mUs][mGs][mG]
NR1H3-1224-	Artificial	Modified	[MePhosphonate-4O-	1059
1244	Sequence	antisense	mUs][fCs][fAs][fA][fA][mG][fU][mC]
		strand	[mU][fU][mC][mC][mC][fG][mG][mU]
			[mU][mA][mU][mAs][mGs][mG]
NR1H3-1244-	Artificial	Modified	[MePhosphonate-4O-	1060
1264	Sequence	antisense	mUs][fCs][fAs][fC][fU][mU][fG][mC]
		strand	[mA][fG][mC][mC][mC][fU][mG][mC]
			[mU][mU][mU][mGs][mGs][mG]
NR1H3-1249-	Artificial	Modified	[MePhosphonate-4O-	1061
1269-1346	Sequence	antisense	mUs][fAs][fAs][fU][fU][mC][fC][mA]
		strand	[mC][fU][mU][mG][mC][fA][mG][mC]
			[mC][mC][mU][mGs][mGs][mG]
NR1H3-1252-	Artificial	Modified	[MePhosphonate-4O-	1062
1272	Sequence	antisense	mUs][fAs][fUs][fG][fA][mA][fU][mU]
		strand	[mC][fC][mA][mC][mU][fU][mG][mC]
			[mA][mG][mC][mCs][mGs][mG]
NR1H3-1254-	Artificial	Modified	[MePhosphonate-4O-	1063
1274-1351	Sequence	antisense	mUs][fUs][fGs][fA][fU][mG][fA][mA]
		strand	[mU][fU][mC][mC][mA][fC][mU][mU]
			[mG][mC][mA][mGs][mGs][mG]
NR1H3-1255-	Artificial	Modified	[MePhosphonate-4O-	1064
1275-1352	Sequence	antisense	mUs][fUs][fUs][fG][fA][mU][fG][mA]
		strand	[mA][fU][mU][mC][mC][fA][mC][mU]
			[mU][mG][mC][mAs][mGs][mG]
NR1H3-1256-	Artificial	Modified	[MePhosphonate-4O-	1065
1276-1353	Sequence	antisense	mUs][fGs][fUs][fU][fG][mA][fU][mG]
		strand	[mA][fA][mU][mU][mC][fC][mA][mC]
			[mU][mU][mG][mCs][mGs][mG]
NR1H3-1257-	Artificial	Modified	[MePhosphonate-4O-	1066
1277-1354	Sequence	antisense	mUs][fGs][fGs][fU][fU][mG][fA][mU]
		strand	[mG][fA][mA][mU][mU][fC][mC][mA]
			[mC][mU][mU][mGs][mGs][mG]
NR1H3-1259	Artificial	Modified	[MePhosphonate-4O-	1067
	Sequence	antisense	mUs][fGs][fGs][fG][fG][mU][fU][mG]
		strand	[mA][fU][mG][mA][mA][fU][mU][mC]
			[mC][mA][mC][mUs][mGs][mG]
NR1H3-1260-	Artificial	Modified	[MePhosphonate-4O-	1068
1280-1357	Sequence	antisense	mUs][fUs][fGs][fG][fG][mG][fU][mU]
		strand	[mG][fA][mU][mG][mA][fA][mU][mU]
			[mC][mC][mA][mCs][mGs][mG]
NR1H3-1261-	Artificial	Modified	[MePhosphonate-4O-	1069
1281-1358	Sequence	antisense	mUs][fAs][fUs][fG][fG][mG][fG][mU]
		strand	[mU][fG][mA][mU][mG][fA][mA][mU]
			[mU][mC][mC][mAs][mGs][mG]
NR1H3-1263-	Artificial	Modified	[MePhosphonate-4O-	1070
1283-1360	Sequence	antisense	mUs][fAs][fGs][fA][fU][mG][fG][mG]
		strand	[mG][fU][mU][mG][mA][fU][mG][mA]
			[mA][mU][mU][mCs][mGs][mG]
NR1H3-1264-	Artificial	Modified	[MePhosphonate-4O-	1071
1284-1361	Sequence	antisense	mUs][fAs][fAs][fG][fA][mU][fG][mG]
		strand	[mG][fG][mU][mU][mG][fA][mU][mG]
			[mA][mA][mU][mUs][mGs][mG]
NR1H3-1265-	Artificial	Modified	[MePhosphonate-4O-	1072
1285	Sequence	antisense	mUs][fGs][fAs][fA][fG][mA][fU][mG]
		strand	[mG][fG][mG][mU][mU][fG][mA][mU]
			[mG][mA][mA][mUs][mGs][mG]
NR1H3-1266-	Artificial	Modified	[MePhosphonate-4O-	1073
1286	Sequence	antisense	mUs][fCs][fGs][fA][fA][mG][fA][mU]
		strand	[mG][fG][mG][mG][mU][fU][mG][mA]
			[mU][mG][mA][mAs][mGs][mG]
NR1H3-1405-	Artificial	Modified	[MePhosphonate-4O-	1074
1471-1502	Sequence	antisense	mUs][fUs][fCs][fC][fA][mC][fA][mU]
		strand	[mA][fU][mG][mU][mG][fU][mG][mC]
			[mU][mG][mC][mAs][mGs][mG]
NR1H3-1409-	Artificial	Modified	[MePhosphonate-4O-	1075
1475-1506	Sequence	antisense	mUs][fGs][fGs][fC][fU][mU][fC][mC]
		strand	[mA][fC][mA][mU][mA][fU][mG][mU]
			[mG][mU][mG][mCs][mGs][mG]
NR1H3-1429-	Artificial	Modified	[MePhosphonate-4O-	1076
1495	Sequence	antisense	mUs][fAs][fUs][fG][fG][mA][fG][mA]
		strand	[mC][fG][mU][mA][mG][fG][mC][mA]
			[mU][mG][mC][mAs][mGs][mG]
NR1H3-1433-	Artificial	Modified	[MePhosphonate-4O-	1077
1499	Sequence	antisense	mUs][fGs][fUs][fG][fG][mA][fU][mG]
		strand	[mG][fA][mG][mA][mC][fG][mU][mA]
			[mG][mG][mC][mAs][mGs][mG]
NR1H3-1437-	Artificial	Modified	[MePhosphonate-4O-	1078
1503	Sequence	antisense	mUs][fGs][fAs][fU][fG][mG][fU][mG]
		strand	[mG][fA][mU][mG][mG][fA][mG][mA]
			[mC][mG][mU][mAs][mGs][mG]
NR1H3-1439-	Artificial	Modified	[MePhosphonate-4O-	1079
1505	Sequence	antisense	mUs][fGs][fGs][fG][fA][mU][fG][mG]
		strand	[mU][fG][mG][mA][mU][fG][mG][mA]
			[mG][mA][mC][mGs][mGs][mG]
NR1H3-1446-	Artificial	Modified	[MePhosphonate-4O-	1080
1512	Sequence	antisense	mUs][fGs][fGs][fU][fC][mA][fU][mG]
		strand	[mG][fG][mG][mA][mU][fG][mG][mU]
			[mG][mG][mA][mUs][mGs][mG]
NR1H3-1458-	Artificial	Modified	[MePhosphonate-4O-	1081
1524-1555	Sequence	antisense	mUs][fGs][fGs][fA][fA][mC][fA][mU]
		strand	[mC][fA][mG][mU][mC][fG][mG][mU]
			[mC][mA][mU][mGs][mGs][mG]
NR1H3-1463-	Artificial	Modified	[MePhosphonate-4O-	1082
1529	Sequence	antisense	mUs][fCs][fCs][fG][fU][mG][fG][mG]
		strand	[mA][fA][mC][mA][mU][fC][mA][mG]
			[mU][mC][mG][mGs][mGs][mG]
NR1H3-1464-	Artificial	Modified	[MePhosphonate-4O-	1083
1530-1561	Sequence	antisense	mUs][fUs][fCs][fC][fG][mU][fG][mG]
		strand	[mG][fA][mA][mC][mA][fU][mC][mA]
			[mG][mU][mC][mGs][mGs][mG]
NR1H3-1465-	Artificial	Modified	[MePhosphonate-4O-	1084
1531-1562	Sequence	antisense	mUs][fAs][fUs][fC][fC][mG][fU][mG]
		strand	[mG][fG][mA][mA][mC][fA][mU][mC]
			[mA][mG][mU][mCs][mGs][mG]
NR1H3-1467-	Artificial	Modified	[MePhosphonate-4O-	1085
1533-1564	Sequence	antisense	mUs][fGs][fCs][fA][fU][mC][fC][mG]
		strand	[mU][fG][mG][mG][mA][fA][mC][mA]
			[mU][mC][mA][mGs][mGs][mG]
NR1H3-1469-	Artificial	Modified	[MePhosphonate-4O-	1086
1535-1566	Sequence	antisense	mUs][fUs][fA][mG][fC][mA][fU][mC]
		strand	[mC][fG][mU][mG][mG][fG][mA][mA]
			[mC][mA][mU][mCs][mGs][mG]
NR1H3-1470-	Artificial	Modified	[MePhosphonate-4O-	1087
1536-1567	Sequence	antisense	mUs][fUs][fUs][fA][fG][mC][fA][mU]
		strand	[mC][fC][mG][mU][mG][fG][mG][mA]
			[mA][mC][mA][mUs][mGs][mG]
NR1H3-1475-	Artificial	Modified	[MePhosphonate-4O-	1088
1541	Sequence	antisense	mUs][fUs][fUs][fU][fC][mA][fU][mU]
		strand	[mA][fG][mC][mA][mU][fC][mC][mG]
			[mU][mG][mG][mGs][mGs][mG]
NR1H3-1479-	Artificial	Modified	[MePhosphonate-4O-	1089
1545	Sequence	antisense	mUs][fCs][fCs][fA][fG][mU][fU][mU]
		strand	[mC][fA][mU][mU][mA][fG][mC][mA]
			[mU][mC][mC][mGs][mGs][mG]
NR1H3-1480-	Artificial	Modified	[MePhosphonate-4O-	1090
1546-1577	Sequence	antisense	mUs][fAs][fCs][fC][fA][mG][fU][mU]
		strand	[mU][fC][mA][mU][mU][fA][mG][mC]
			[mA][mU][mC][mCs][mGs][mG]
NR1H3-1481-	Artificial	Modified	[MePhosphonate-4O-	1091
1547	Sequence	antisense	mUs][fCs][fAs][fC][fC][mA][fG][mU]
		strand	[mU][fU][mC][mA][mU][fU][mA][mG]
			[mC][mA][mU][mCs][mGs][mG]
NR1H3-1482-	Artificial	Modified	[MePhosphonate-4O-	1092
1548-1579	Sequence	antisense	mUs][fUs][fCs][fA][fC][mC][fA][mG]
		strand	[mU][fU][mU][mC][mA][fU][mU][mA]
			[mG][mC][mA][mUs][mGs][mG]
NR1H3-1485-	Artificial	Modified	[MePhosphonate-4O-	1093
1551	Sequence	antisense	mUs][fGs][fGs][fC][fU][mC][fA][mC]
		strand	[mC][fA][mG][mU][mU][fU][mC][mA]
			[mU][mU][mA][mGs][mGs][mG]
NR1H3-1515-	Artificial	Modified	[MePhosphonate-4O-	1094
1581	Sequence	antisense	mUs][fGs][fCs][fU][fC][mU][fG][mA]
		strand	[mG][fU][mG][mG][mA][fC][mG][mC]
			[mU][mG][mC][mUs][mGs][mG]
NR1H3-1517-	Artificial	Modified	[MePhosphonate-4O-	1095
1583	Sequence	antisense	mUs][fUs][fUs][fG][fC][mU][fC][mU]
		strand	[mG][fA][mG][mU][mG][fG][mA][mC]
			[mG][mC][mU][mGs][mGs][mG]
NR1H3-1518-	Artificial	Modified	[MePhosphonate-4O-	1096
1584	Sequence	antisense	mUs][fCs][fUs][fU][fG][mC][fU][mC]
		strand	[mU][fG][mA][mG][mU][fG][mG][mA]
			[mC][mG][mC][mUs][mGs][mG]
NR1H3-1524-	Artificial	Modified	[MePhosphonate-4O-	1097
1590-1621	Sequence	antisense	mUs][fCs][fAs][fA][fA][mC][fA][mC]
		strand	[mU][fU][mG][mC][mU][fC][mU][mG]
			[mA][mG][mU][mGs][mGs][mG]
NR1H3-1533-	Artificial	Modified	[MePhosphonate-4O-	1098
1599	Sequence	antisense	mUs][fGs][fAs][fC][fG][mC][fA][mG]
		strand	[mU][fG][mC][mA][mA][fA][mC][mA]
			[mC][mU][mU][mGs][mGs][mG]
NR1H3-1535-	Artificial	Modified	[MePhosphonate-4O-	1099
1601	Sequence	antisense	mUs][fCs][fAs][fG][fA][mC][fG][mC]
		strand	[mA][fG][mU][mG][mC][fA][mA][mA]
			[mC][mA][mC][mUs][mGs][mG]
NR1H3-1545-	Artificial	Modified	[MePhosphonate-4O-	1100
1611	Sequence	antisense	mUs][fUs][fUs][fU][fU][mG][fU][mC]
		strand	[mC][fU][mG][mC][mA][fG][mA][mC]
			[mG][mC][mA][mGs][mGs][mG]
NR1H3-1554-	Artificial	Modified	[MePhosphonate-4O-	1101
1620	Sequence	antisense	mUs][fGs][fUs][fG][fG][mG][fA][mG]
		strand	[mC][fU][mU][mU][mU][fU][mG][mU]
			[mC][mC][mU][mGs][mGs][mG]
NR1H3-1581-	Artificial	Modified	[MePhosphonate-4O-	1102
1647	Sequence	antisense	mUs][fGs][fCs][fA][fC][mA][fU][mC]
		strand	[mC][fC][mA][mG][mA][fU][mC][mU]
			[mC][mA][mG][mAs][mGs][mG]
NR1H3-1586-	Artificial	Modified	[MePhosphonate-4O-	1103
1652	Sequence	antisense	mUs][fUs][fUs][fC][fG][mU][fG][mC]
		strand	[mA][fC][mA][mU][mC][fC][mC][mA]
			[mG][mA][mU][mCs][mGs][mG]
NR1H3-1587-	Artificial	Modified	[MePhosphonate-4O-	1104
1653	Sequence	antisense	mUs][fAs][fUs][fU][fC][mG][fU][mG]
		strand	[mC][fA][mC][mA][mU][fC][mC][mC]
			[mA][mG][mA][mUs][mGs][mG]
NR1H3-1588-	Artificial	Modified	[MePhosphonate-4O-	1105
1654	Sequence	antisense	mUs][fCs][fAs][fU][fU][mC][fG][mU]
		strand	[mG][fC][mA][mC][mA][fU][mC][mC]
			[mC][mA][mG][mAs][mGs][mG]
NR1H3-1594-	Artificial	Modified	[MePhosphonate-4O-	1106
1660-1691	Sequence	antisense	mUs][fAs][fAs][fC][fA][mG][fU][mC]
		strand	[mA][fU][mU][mC][mG][fU][mG][mC]
			[mA][mC][mA][mUs][mGs][mG]
NR1H3-1595-	Artificial	Modified	[MePhosphonate-4O-	1107
1661-1692	Sequence	antisense	mUs][fGs][fAs][fA][fC][mA][fG][mU]
		strand	[mC][fA][mU][mU][mC][fG][mU][mG]
			[mC][mA][mC][mAs][mGs][mG]
NR1H3-1596-	Artificial	Modified	[MePhosphonate-4O-	1108
1662	Sequence	antisense	mUs][fAs][fGs][fA][fA][mC][fA][mG]
		strand	[mU][fC][mA][mU][mU][fC][mG][mU]
			[mG][mC][mA][mCs][mGs][mG]
NR1H3-1663-	Artificial	Modified	[MePhosphonate-4O-	1109
1727	Sequence	antisense	mUs][fGs][fUs][fU][fC][mC][fA][mC]
		strand	[mU][fU][mC][mU][mA][fG][mG][mA]
			[mG][mG][mC][mAs][mGs][mG]
NR1H3-1670-	Artificial	Modified	[MePhosphonate-4O-	1110
1734	Sequence	antisense	mUs][fUs][fCs][fA][fG][mU][fC][mU]
		strand	[mG][fU][mU][mC][mC][fA][mC][mU]
			[mU][mC][mU][mAs][mGs][mG]
NR1H3-1671-	Artificial	Modified	[MePhosphonate-4O-	1111
1735	Sequence	antisense	mUs][fCs][fUs][fC][fA][mG][fU][mC]
		strand	[mU][fG][mU][mU][mC][fC][mA][mC]
			[mU][mU][mC][mUs][mGs][mG]
NR1H3-1672-	Artificial	Modified	[MePhosphonate-4O-	1112
1736	Sequence	antisense	mUs][fUs][fCs][fU][fC][mA][fG][mU]
		strand	[mC][fU][mG][mU][mU][fC][mC][mA]
			[mC][mU][mU][mCs][mGs][mG]
NR1H3-1673-	Artificial	Modified	[MePhosphonate-4O-	1113
1737	Sequence	antisense	mUs][fUs][fUs][fC][fU][mC][fA][mG]
		strand	[mU][fC][mU][mG][mU][fU][mC][mC]
			[mA][mC][mU][mUs][mGs][mG]
NR1H3-1674-	Artificial	Modified	[MePhosphonate-4O-	1114
1738	Sequence	antisense	mUs][fCs][fUs][fU][fC][mU][fC][mA]
		strand	[mG][fU][mC][mU][mG][fU][mU][mC]
			[mC][mA][mC][mUs][mGs][mG]
NR1H3-1675-	Artificial	Modified	[MePhosphonate-4O-	1115
1739-1766	Sequence	antisense	mUs][fCs][fCs][fU][fU][mC][fU][mC]
		strand	[mA][fG][mU][mC][mU][fG][mU][mU]
			[mC][mC][mA][mCs][mGs][mG]
NR1H3-1676-	Artificial	Modified	[MePhosphonate-4O-	1116
1740-1767	Sequence	antisense	mUs][fCs][fCs][fC][fU][mU][fC][mU]
		strand	[mC][fA][mG][mU][mC][fU][mG][mU]
			[mU][mC][mC][mAs][mGs][mG]
NR1H3-1678-	Artificial	Modified	[MePhosphonate-4O-	1117
1742-1769	Sequence	antisense	mUs][fUs][fGs][fC][fC][mC][fU][mU]
		strand	[mC][fU][mC][mA][mG][fU][mC][mU]
			[mG][mU][mU][mCs][mGs][mG]
NR1H3-1684-	Artificial	Modified	[MePhosphonate-4O-	1118
1748	Sequence	antisense	mUs][fAs][fAs][fU][fG][mU][fU][mU]
		strand	[mG][fC][mC][mC][mU][fU][mC][mU]
			[mC][mA][mG][mUs][mGs][mG]
NR1H3-1731-	Artificial	Modified	[MePhosphonate-4O-	1119
1795	Sequence	antisense	mUs][fGs][fAs][fC][fU][mC][fU][mC]
		strand	[mU][fU][mU][mU][mA][fA][mU][mG]
			[mC][mC][mA][mCs][mGs][mG]
NR1H3-1732-	Artificial	Modified	[MePhosphonate-4O-	1120
1796	Sequence	antisense	mUs][fUs][fGs][fA][fC][mU][fC][mU]
		strand	[mC][fU][mU][mU][mU][fA][mA][mU]
			[mG][mC][mC][mAs][mGs][mG]
Stem-loop	Artificial		GCAGCCGAAAGGCUGC	1121
	Sequence
Forward-1198	Artificial		GTTATAACCGGGAAGACTTTGC	1122
	Sequence
Reverse-1326	Artificial		TGATAGCAATGAGCAAGGCA	1123
	Sequence
Probe-1253	Artificial		ATGGCCCTGGAGAACTCGAAGAT	1124
	Sequence		G
NR1H3-764-	Hs-Mf-	19 mer sense	UGUCCUGUCAGAAGAACAG	1125
784-861	Mm	strand
NR1H3-766-	Hs-Mf-	19 mer sense	UCCUGUCAGAAGAACAGAU	1126
786-863	Mm	strand
NR1H3-789-	Hs-Mf-	19 mer sense	CUGAAGAAACUGAAGCGGC	1127
809-886	Mm	strand
NR1H3-790-	Hs-Mf-	19 mer sense	UGAAGAAACUGAAGCGGCA	1128
810-887	Mm	strand
NR1H3-791-	Hs-Mf-	19 mer sense	GAAGAAACUGAAGCGGCAA	1129
811-888	Mm	strand
NR1H3-792-	Hs-Mf-	19 mer sense	AAGAAACUGAAGCGGCAAG	1130
812-889	Mm	strand
NR1H3-793-	Hs-Mf-	19 mer sense	AGAAACUGAAGCGGCAAGA	1131
813-890	Mm	strand
NR1H3-795-	Hs-Mf-	19 mer sense	AAACUGAAGCGGCAAGAGG	1132
815-892	Mm	strand
NR1H3-796-	Hs-Mf-	19 mer sense	AACUGAAGCGGCAAGAGGA	1133
816-893	Mm	strand
NR1H3-797-	Hs-Mf-	19 mer sense	ACUGAAGCGGCAAGAGGAG	1134
817-894	Mm	strand
NR1H3-798-	Hs-Mf-	19 mer sense	CUGAAGCGGCAAGAGGAGG	1135
818-895	Mm	strand
NR1H3-799-	Hs-Mf-	19 mer sense	UGAAGCGGCAAGAGGAGGA	1136
819-896	Mm	strand
NR1H3-802-	Hs-Mf-	19 mer sense	AGCGGCAAGAGGAGGAACA	1137
822-899	Mm	strand
NR1H3-803-	Hs-Mf-	19 mer sense	GCGGCAAGAGGAGGAACAG	1138
823-900	Mm	strand
NR1H3-804-	Hs-Mf-	19 mer sense	CGGCAAGAGGAGGAACAGG	1139
824-901	Mm	strand
NR1H3-806-	Hs-Mf-	19 mer sense	GCAAGAGGAGGAACAGGCU	1140
826-903	Mm	strand
NR1H3-808-	Hs-Mf-	19 mer sense	AAGAGGAGGAACAGGCUCA	1141
828-905	Mm	strand
NR1H3-809-	Hs-Mf-	19 mer sense	AGAGGAGGAACAGGCUCAU	1142
829-906	Mm	strand
NR1H3-810-	Hs-Mf-	19 mer sense	GAGGAGGAACAGGCUCAUG	1143
830-907	Mm	strand
NR1H3-811-	Hs-Mf-	19 mer sense	AGGAGGAACAGGCUCAUGC	1144
831-908	Mm	strand
NR1H3-813-	Hs-Mf-	19 mer sense	GAGGAACAGGCUCAUGCCA	1145
833-910	Mm	strand
NR1H3-844-	Hs-Mf	19 mer sense	CCAGGGCUUCCUCACCCCC	1146
864		strand
NR1H3-895-	Hs-Mf-	19 mer sense	UGGGCAUGAUCGAGAAGCU	1147
915-992	Mm	strand
NR1H3-898-	Hs-Mf-	19 mer sense	GCAUGAUCGAGAAGCUCGU	1148
918-995	Mm	strand
NR1H3-915-	Hs-Mf-	19 mer sense	GUCGCUGCCCAGCAACAGU	1149
935-1012	Mm	strand
NR1H3-917-	Hs-Mf-	19 mer sense	CGCUGCCCAGCAACAGUGU	1150
937-1014	Mm	strand
NR1H3-922-	Hs-Mf-	19 mer sense	CCCAGCAACAGUGUAACCG	1151
942-1019	Mm	strand
NR1H3-924-	Hs-Mf-	19 mer sense	CAGCAACAGUGUAACCGGC	1152
944-1021	Mm	strand
NR1H3-925-	Hs-Mf-	19 mer sense	AGCAACAGUGUAACCGGCG	1153
945-1022	Mm	strand
NR1H3-927-	Hs-Mf-	19 mer sense	CAACAGUGUAACCGGCGCU	1154
947-1024	Mm	strand
NR1H3-928-	Hs-Mf-	19 mer sense	AACAGUGUAACCGGCGCUC	1155
948-1025	Mm	strand
NR1H3-929-	Hs-Mf-	19 mer sense	ACAGUGUAACCGGCGCUCC	1156
949-1026	Mm	strand
NR1H3-930-	Hs-Mf-	19 mer sense	CAGUGUAACCGGCGCUCCU	1157
950-1027	Mm	strand
NR1H3-931-	Hs-Mf-	19 mer sense	AGUGUAACCGGCGCUCCUU	1158
951-1028	Mm	strand
NR1H3-932-	Hs-Mf-	19 mer sense	GUGUAACCGGCGCUCCUUU	1159
952-1029	Mm	strand
NR1H3-933-	Hs-Mf-	19 mer sense	UGUAACCGGCGCUCCUUUU	1160
953-1030	Mm	strand
NR1H3-941-	Hs-Mf	19 mer sense	GCGCUCCUUUUCUGACCGG	1161
961		strand
NR1H3-944-	Hs-Mf	19 mer sense	CUCCUUUUCUGACCGGCUU	1162
964		strand
NR1H3-945-	Hs-Mf	19 mer sense	UCCUUUUCUGACCGGCUUC	1163
965		strand
NR1H3-946-	Hs-Mf	19 mer sense	CCUUUUCUGACCGGCUUCG	1164
966		strand
NR1H3-947-	Hs-Mf	19 mer sense	CUUUUCUGACCGGCUUCGA	1165
967		strand
NR1H3-949-	Hs-Mf	19 mer sense	UUUCUGACCGGCUUCGAGU	1166
969		strand
NR1H3-951-	Hs-Mf	19 mer sense	UCUGACCGGCUUCGAGUCA	1167
971		strand
NR1H3-952-	Hs-Mf	19 mer sense	CUGACCGGCUUCGAGUCAC	1168
972		strand
NR1H3-953-	Hs-Mf	19 mer sense	UGACCGGCUUCGAGUCACG	1169
973		strand
NR1H3-1151-	Hs-Mf-	19 mer sense	GGUGAUGCUUCUGGAGACA	1170
1171-1248	Mm	strand
NR1H3-1153-	Hs-Mf-	19 mer sense	UGAUGCUUCUGGAGACAUC	1171
1173-1250	Mm	strand
NR1H3-1154-	Hs-Mf-	19 mer sense	GAUGCUUCUGGAGACAUCU	1172
1174-1251	Mm	strand
NR1H3-1155-	Hs-Mf-	19 mer sense	AUGCUUCUGGAGACAUCUC	1173
1175-1252	Mm	strand
NR1H3-1156-	Hs-Mf-	19 mer sense	UGCUUCUGGAGACAUCUCG	1174
1176-1253	Mm	strand
NR1H3-1157-	Hs-Mf-	19 mer sense	GCUUCUGGAGACAUCUCGG	1175
1177-1254	Mm	strand
NR1H3-1158-	Hs-Mf-	19 mer sense	CUUCUGGAGACAUCUCGGA	1176
1178-1255	Mm	strand
NR1H3-1159-	Hs-Mf-	19 mer sense	UUCUGGAGACAUCUCGGAG	1177
1179-1256	Mm	strand
NR1H3-1160-	Hs-Mf-	19 mer sense	UCUGGAGACAUCUCGGAGG	1178
1180-1257	Mm	strand
NR1H3-1161-	Hs-Mf-	19 mer sense	CUGGAGACAUCUCGGAGGU	1179
1181-1258	Mm	strand
NR1H3-1162-	Hs-Mf-	19 mer sense	UGGAGACAUCUCGGAGGUA	1180
1182-1259	Mm	strand
NR1H3-1163-	Hs-Mf-	19 mer sense	GGAGACAUCUCGGAGGUAC	1181
1183-1260	Mm	strand
NR1H3-1164-	Hs-Mf-	19 mer sense	GAGACAUCUCGGAGGUACA	1182
1184-1261	Mm	strand
NR1H3-1165-	Hs-Mf-	19 mer sense	AGACAUCUCGGAGGUACAA	1183
1185-1262	Mm	strand
NR1H3-1166-	Hs-Mf-	19 mer sense	GACAUCUCGGAGGUACAAC	1184
1186-1263	Mm	strand
NR1H3-1167-	Hs-Mf-	19 mer sense	ACAUCUCGGAGGUACAACC	1185
1187-1264	Mm	strand
NR1H3-1169-	Hs-Mf-	19 mer sense	AUCUCGGAGGUACAACCCU	1186
1189-1266	Mm	strand
NR1H3-1170-	Hs-Mf-	19 mer sense	UCUCGGAGGUACAACCCUG	1187
1190-1267	Mm	strand
NR1H3-1171-	Hs-Mf-	19 mer sense	CUCGGAGGUACAACCCUGG	1188
1191-1268	Mm	strand
NR1H3-1173-	Hs-Mf-	19 mer sense	CGGAGGUACAACCCUGGGA	1189
1193-1270	Mm	strand
NR1H3-1175-	Hs-Mf-	19 mer sense	GAGGUACAACCCUGGGAGU	1190
1195-1272	Mm	strand
NR1H3-1176-	Hs-Mf-	19 mer sense	AGGUACAACCCUGGGAGUG	1191
1196-1273	Mm	strand
NR1H3-1177-	Hs-Mf-	19 mer sense	GGUACAACCCUGGGAGUGA	1192
1197-1274	Mm	strand
NR1H3-1178-	Hs-Mf-	19 mer sense	GUACAACCCUGGGAGUGAG	1193
1198-1275	Mm	strand
NR1H3-1179-	Hs-Mf-	19 mer sense	UACAACCCUGGGAGUGAGA	1194
1199-1276	Mm	strand
NR1H3-1180-	Hs-Mf-	19 mer sense	ACAACCCUGGGAGUGAGAG	1195
1200-1277	Mm	strand
NR1H3-1181-	Hs-Mf-	19 mer sense	CAACCCUGGGAGUGAGAGU	1196
1201-1278	Mm	strand
NR1H3-1182-	Hs-Mf-	19 mer sense	AACCCUGGGAGUGAGAGUA	1197
1202-1279	Mm	strand
NR1H3-1183-	Hs-Mf-	19 mer sense	ACCCUGGGAGUGAGAGUAU	1198
1203-1280	Mm	strand
NR1H3-1184-	Hs-Mf-	19 mer sense	CCCUGGGAGUGAGAGUAUC	1199
1204-1281	Mm	strand
NR1H3-1185-	Hs-Mf-	19 mer sense	CCUGGGAGUGAGAGUAUCA	1200
1205-1282	Mm	strand
NR1H3-1186-	Hs-Mf-	19 mer sense	CUGGGAGUGAGAGUAUCAC	1201
1206-1283	Mm	strand
NR1H3-1187-	Hs-Mf-	19 mer sense	UGGGAGUGAGAGUAUCACC	1202
1207-1284	Mm	strand
NR1H3-1188-	Hs-Mf-	19 mer sense	GGGAGUGAGAGUAUCACCU	1203
1208-1285	Mm	strand
NR1H3-1190-	Hs-Mf-	19 mer sense	GAGUGAGAGUAUCACCUUC	1204
1210-1287	Mm	strand
NR1H3-1191-	Hs-Mf-	19 mer sense	AGUGAGAGUAUCACCUUCC	1205
1211-1288	Mm	strand
NR1H3-1192-	Hs-Mf-	19 mer sense	GUGAGAGUAUCACCUUCCU	1206
1212-1289	Mm	strand
NR1H3-1193-	Hs-Mf-	19 mer sense	UGAGAGUAUCACCUUCCUC	1207
1213-1290	Mm	strand
NR1H3-1194-	Hs-Mf-	19 mer sense	GAGAGUAUCACCUUCCUCA	1208
1214-1291	Mm	strand
NR1H3-1196-	Hs-Mf-	19 mer sense	GAGUAUCACCUUCCUCAAG	1209
1216-1293	Mm	strand
NR1H3-1197-	Hs-Mf-	19 mer sense	AGUAUCACCUUCCUCAAGG	1210
1217-1294	Mm	strand
NR1H3-1198-	Hs-Mf-	19 mer sense	GUAUCACCUUCCUCAAGGA	1211
1218-1295	Mm	strand
NR1H3-1199-	Hs-Mf-	19 mer sense	UAUCACCUUCCUCAAGGAU	1212
1219-1296	Mm	strand
NR1H3-1200-	Hs-Mf-	19 mer sense	AUCACCUUCCUCAAGGAUU	1213
1220-1297	Mm	strand
NR1H3-1203-	Hs-Mf-	19 mer sense	ACCUUCCUCAAGGAUUUCA	1214
1223-1300	Mm	strand
NR1H3-1204-	Hs-Mf-	19 mer sense	CCUUCCUCAAGGAUUUCAG	1215
1224-1301	Mm	strand
NR1H3-1207-	Hs-Mf-	19 mer sense	UCCUCAAGGAUUUCAGUUA	1216
1227-1304	Mm	strand
NR1H3-1211-	Hs-Mf-	19 mer sense	CAAGGAUUUCAGUUAUAAC	1217
1231-1308	Mm	strand
NR1H3-1212-	Hs-Mf-	19 mer sense	AAGGAUUUCAGUUAUAACC	1218
1232-1309	Mm	strand
NR1H3-1213-	Hs-Mf-	19 mer sense	AGGAUUUCAGUUAUAACCG	1219
1233-1310	Mm	strand
NR1H3-1214-	Hs-Mf-	19 mer sense	GGAUUUCAGUUAUAACCGG	1220
1234-1311	Mm	strand
NR1H3-1215-	Hs-Mf-	19 mer sense	GAUUUCAGUUAUAACCGGG	1221
1235-1312	Mm	strand
NR1H3-1216-	Hs-Mf-	19 mer sense	AUUUCAGUUAUAACCGGGA	1222
1236-1313	Mm	strand
NR1H3-1217-	Hs-Mf-	19 mer sense	UUUCAGUUAUAACCGGGAA	1223
1237-1314	Mm	strand
NR1H3-1218-	Hs-Mf-	19 mer sense	UUCAGUUAUAACCGGGAAG	1224
1238-1315	Mm	strand
NR1H3-1219-	Hs-Mf-	19 mer sense	UCAGUUAUAACCGGGAAGA	1225
1239-1316	Mm	strand
NR1H3-1220-	Hs-Mf-	19 mer sense	CAGUUAUAACCGGGAAGAC	1226
1240-1317	Mm	strand
NR1H3-1222-	Hs-Mf-	19 mer sense	GUUAUAACCGGGAAGACUU	1227
1242-1319	Mm	strand
NR1H3-1223-	Hs-Mf-	19 mer sense	UUAUAACCGGGAAGACUUU	1228
1243-1320	Mm	strand
NR1H3-1224-	Hs-Mf-	19 mer sense	UAUAACCGGGAAGACUUUG	1229
1244-1321	Mm	strand
NR1H3-1225-	Hs-Mf-	19 mer sense	AUAACCGGGAAGACUUUGC	1230
1245-1322	Mm	strand
NR1H3-1226-	Hs-Mf-	19 mer sense	UAACCGGGAAGACUUUGCC	1231
1246-1323	Mm	strand
NR1H3-1227-	Hs-Mf-	19 mer sense	AACCGGGAAGACUUUGCCA	1232
1247-1324	Mm	strand
NR1H3-1228-	Hs-Mf-	19 mer sense	ACCGGGAAGACUUUGCCAA	1233
1248-1325	Mm	strand
NR1H3-1229-	Hs-Mf-	19 mer sense	CCGGGAAGACUUUGCCAAA	1234
1249-1326	Mm	strand
NR1H3-1232-	Hs-Mf-	19 mer sense	GGAAGACUUUGCCAAAGCA	1235
1252-1329	Mm	strand
NR1H3-1233-	Hs-Mf-	19 mer sense	GAAGACUUUGCCAAAGCAG	1236
1253-1330	Mm	strand
NR1H3-1234-	Hs-Mf-	19 mer sense	AAGACUUUGCCAAAGCAGG	1237
1254-1331	Mm	strand
NR1H3-1235-	Hs-Mf-	19 mer sense	AGACUUUGCCAAAGCAGGG	1238
1255-1332	Mm	strand
NR1H3-1236-	Hs-Mf-	19 mer sense	GACUUUGCCAAAGCAGGGC	1239
1256-1333	Mm	strand
NR1H3-1237-	Hs-Mf-	19 mer sense	ACUUUGCCAAAGCAGGGCU	1240
1257-1334	Mm	strand
NR1H3-1238-	Hs-Mf-	19 mer sense	CUUUGCCAAAGCAGGGCUG	1241
1258-1335	Mm	strand
NR1H3-1241-	Hs-Mf-	19 mer sense	UGCCAAAGCAGGGCUGCAA	1242
1261-1338	Mm	strand
NR1H3-1242-	Hs-Mf-	19 mer sense	GCCAAAGCAGGGCUGCAAG	1243
1262-1339	Mm	strand
NR1H3-1243-	Hs-Mf-	19 mer sense	CCAAAGCAGGGCUGCAAGU	1244
1263-1340	Mm	strand
NR1H3-1244-	Hs-Mf-	19 mer sense	CAAAGCAGGGCUGCAAGUG	1245
1264-1341	Mm	strand
NR1H3-1245-	Hs-Mf-	19 mer sense	AAAGCAGGGCUGCAAGUGG	1246
1265-1342	Mm	strand
NR1H3-1246-	Hs-Mf-	19 mer sense	AAGCAGGGCUGCAAGUGGA	1247
1266-1343	Mm	strand
NR1H3-1247-	Hs-Mf-	19 mer sense	AGCAGGGCUGCAAGUGGAA	1248
1267-1344	Mm	strand
NR1H3-1248-	Hs-Mf-	19 mer sense	GCAGGGCUGCAAGUGGAAU	1249
1268-1345	Mm	strand
NR1H3-1250-	Hs-Mf-	19 mer sense	AGGGCUGCAAGUGGAAUUC	1250
1270-1347	Mm	strand
NR1H3-1251-	Hs-Mf-	19 mer sense	GGGCUGCAAGUGGAAUUCA	1251
1271-1348	Mm	strand
NR1H3-1252-	Hs-Mf-	19 mer sense	GGCUGCAAGUGGAAUUCAU	1252
1272-1349	Mm	strand
NR1H3-1253-	Hs-Mf-	19 mer sense	GCUGCAAGUGGAAUUCAUC	1253
1273-1350	Mm	strand
NR1H3-1256-	Hs-Mf-	19 mer sense	GCAAGUGGAAUUCAUCAAC	1254
1276-1353	Mm	strand
NR1H3-1258-	Hs-Mf-	19 mer sense	AAGUGGAAUUCAUCAACCC	1255
1278-1355	Mm	strand
NR1H3-1259-	Hs-Mf-	19 mer sense	AGUGGAAUUCAUCAACCCC	1256
1279-1356	Mm	strand
NR1H3-1261-	Hs-Mf-	19 mer sense	UGGAAUUCAUCAACCCCAU	1257
1281-1358	Mm	strand
NR1H3-1262-	Hs-Mf-	19 mer sense	GGAAUUCAUCAACCCCAUC	1258
1282-1359	Mm	strand
NR1H3-1265-	Hs-Mf-	19 mer sense	AUUCAUCAACCCCAUCUUC	1259
1285-1362	Mm	strand
NR1H3-1266-	Hs-Mf-	19 mer sense	UUCAUCAACCCCAUCUUCG	1260
1286-1363	Mm	strand
NR1H3-1267-	Hs-Mf-	19 mer sense	UCAUCAACCCCAUCUUCGA	1261
1287-1364	Mm	strand
NR1H3-1268-	Hs-Mf-	19 mer sense	CAUCAACCCCAUCUUCGAG	1262
1288-1365	Mm	strand
NR1H3-1269-	Hs-Mf-	19 mer sense	AUCAACCCCAUCUUCGAGU	1263
1289-1366	Mm	strand
NR1H3-1270-	Hs-Mf-	19 mer sense	UCAACCCCAUCUUCGAGUU	1264
1290-1367	Mm	strand
NR1H3-1271-	Hs-Mf-	19 mer sense	CAACCCCAUCUUCGAGUUC	1265
1291-1368	Mm	strand
NR1H3-1272-	Hs-Mf-	19 mer sense	AACCCCAUCUUCGAGUUCU	1266
1292-1369	Mm	strand
NR1H3-1273-	Hs-Mf-	19 mer sense	ACCCCAUCUUCGAGUUCUC	1267
1293-1370	Mm	strand
NR1H3-1275-	Hs-Mf-	19 mer sense	CCCAUCUUCGAGUUCUCCA	1268
1295-1372	Mm	strand
NR1H3-1276-	Hs-Mf-	19 mer sense	CCAUCUUCGAGUUCUCCAG	1269
1296-1373	Mm	strand
NR1H3-1277-	Hs-Mf-	19 mer sense	CAUCUUCGAGUUCUCCAGG	1270
1297-1374	Mm	strand
NR1H3-1278-	Hs-Mf-	19 mer sense	AUCUUCGAGUUCUCCAGGG	1271
1298-1375	Mm	strand
NR1H3-1279-	Hs-Mf-	19 mer sense	UCUUCGAGUUCUCCAGGGC	1272
1299-1376	Mm	strand
NR1H3-1280-	Hs-Mf-	19 mer sense	CUUCGAGUUCUCCAGGGCC	1273
1300-1377	Mm	strand
NR1H3-1281-	Hs-Mf-	19 mer sense	UUCGAGUUCUCCAGGGCCA	1274
1301-1378	Mm	strand
NR1H3-1282-	Hs-Mf-	19 mer sense	UCGAGUUCUCCAGGGCCAU	1275
1302-1379	Mm	strand
NR1H3-1283-	Hs-Mf-	19 mer sense	CGAGUUCUCCAGGGCCAUG	1276
1303-1380	Mm	strand
NR1H3-1284-	Hs-Mf-	19 mer sense	GAGUUCUCCAGGGCCAUGA	1277
1304-1381	Mm	strand
NR1H3-1285-	Hs-Mf-	19 mer sense	AGUUCUCCAGGGCCAUGAA	1278
1305-1382	Mm	strand
NR1H3-1286-	Hs-Mf-	19 mer sense	GUUCUCCAGGGCCAUGAAU	1279
1306-1383	Mm	strand
NR1H3-1288-	Hs-Mf-	19 mer sense	UCUCCAGGGCCAUGAAUGA	1280
1308-1385	Mm	strand
NR1H3-1289-	Hs-Mf-	19 mer sense	CUCCAGGGCCAUGAAUGAG	1281
1309-1386	Mm	strand
NR1H3-1290-	Hs-Mf-	19 mer sense	UCCAGGGCCAUGAAUGAGC	1282
1310-1387	Mm	strand
NR1H3-1291-	Hs-Mf-	19 mer sense	CCAGGGCCAUGAAUGAGCU	1283
1311-1388	Mm	strand
NR1H3-1292-	Hs-Mf-	19 mer sense	CAGGGCCAUGAAUGAGCUG	1284
1312-1389	Mm	strand
NR1H3-1293-	Hs-Mf-	19 mer sense	AGGGCCAUGAAUGAGCUGC	1285
1313-1390	Mm	strand
NR1H3-1294-	Hs-Mf-	19 mer sense	GGGCCAUGAAUGAGCUGCA	1286
1314-1391	Mm	strand
NR1H3-1295-	Hs-Mf-	19 mer sense	GGCCAUGAAUGAGCUGCAA	1287
1315-1392	Mm	strand
NR1H3-1296-	Hs-Mf-	19 mer sense	GCCAUGAAUGAGCUGCAAC	1288
1316-1393	Mm	strand
NR1H3-1297-	Hs-Mf-	19 mer sense	CCAUGAAUGAGCUGCAACU	1289
1317-1394	Mm	strand
NR1H3-1338-	Hs-Mf-	19 mer sense	CUCAUUGCUAUCAGCAUCU	1290
1358-1435	Mm	strand
NR1H3-1339-	Hs-Mf-	19 mer sense	UCAUUGCUAUCAGCAUCUU	1291
1359-1436	Mm	strand
NR1H3-1340-	Hs-Mf-	19 mer sense	CAUUGCUAUCAGCAUCUUC	1292
1360-1437	Mm	strand
NR1H3-1341-	Hs-Mf-	19 mer sense	AUUGCUAUCAGCAUCUUCU	1293
1361-1438	Mm	strand
NR1H3-1342-	Hs-Mf-	19 mer sense	UUGCUAUCAGCAUCUUCUC	1294
1362-1439	Mm	strand
NR1H3-1343-	Hs-Mf-	19 mer sense	UGCUAUCAGCAUCUUCUCU	1295
1363-1440	Mm	strand
NR1H3-1344-	Hs-Mf-	19 mer sense	GCUAUCAGCAUCUUCUCUG	1296
1364-1441	Mm	strand
NR1H3-1345-	Hs-Mf-	19 mer sense	CUAUCAGCAUCUUCUCUGC	1297
1365-1442	Mm	strand
NR1H3-1346-	Hs-Mf-	19 mer sense	UAUCAGCAUCUUCUCUGCA	1298
1366-1443	Mm	strand
NR1H3-1347-	Hs-Mf-	19 mer sense	AUCAGCAUCUUCUCUGCAG	1299
1367-1444	Mm	strand
NR1H3-1377-	Hs-Mf-	19 mer sense	GUGCAGGACCAGCUCCAGG	1300
1443-1474	Mm	strand
NR1H3-1379-	Hs-Mf-	19 mer sense	GCAGGACCAGCUCCAGGUA	1301
1445-1476	Mm	strand
NR1H3-1383-	Hs-Mf-	19 mer sense	GACCAGCUCCAGGUAGAGA	1302
1449-1480	Mm	strand
NR1H3-1384-	Hs-Mf-	19 mer sense	ACCAGCUCCAGGUAGAGAG	1303
1450-1481	Mm	strand
NR1H3-1385-	Hs-Mf-	19 mer sense	CCAGCUCCAGGUAGAGAGG	1304
1451-1482	Mm	strand
NR1H3-1387-	Hs-Mf-	19 mer sense	AGCUCCAGGUAGAGAGGCU	1305
1453-1484	Mm	strand
NR1H3-1388-	Hs-Mf-	19 mer sense	GCUCCAGGUAGAGAGGCUG	1306
1454-1485	Mm	strand
NR1H3-1391-	Hs-Mf-	19 mer sense	CCAGGUAGAGAGGCUGCAG	1307
1457-1488	Mm	strand
NR1H3-1393-	Hs-Mf-	19 mer sense	AGGUAGAGAGGCUGCAGCA	1308
1459-1490	Mm	strand
NR1H3-1394-	Hs-Mf-	19 mer sense	GGUAGAGAGGCUGCAGCAC	1309
1460-1491	Mm	strand
NR1H3-1395-	Hs-Mf-	19 mer sense	GUAGAGAGGCUGCAGCACA	1310
1461-1492	Mm	strand
NR1H3-1396-	Hs-Mf-	19 mer sense	UAGAGAGGCUGCAGCACAC	1311
1462-1493	Mm	strand
NR1H3-1397-	Hs-Mf-	19 mer sense	AGAGAGGCUGCAGCACACA	1312
1463-1494	Mm	strand
NR1H3-1398-	Hs-Mf-	19 mer sense	GAGAGGCUGCAGCACACAU	1313
1464-1495	Mm	strand
NR1H3-1399-	Hs-Mf-	19 mer sense	AGAGGCUGCAGCACACAUA	1314
1465-1496	Mm	strand
NR1H3-1400-	Hs-Mf-	19 mer sense	GAGGCUGCAGCACACAUAU	1315
1466-1497	Mm	strand
NR1H3-1401-	Hs-Mf-	19 mer sense	AGGCUGCAGCACACAUAUG	1316
1467-1498	Mm	strand
NR1H3-1402-	Hs-Mf-	19 mer sense	GGCUGCAGCACACAUAUGU	1317
1468-1499	Mm	strand
NR1H3-1403-	Hs-Mf-	19 mer sense	GCUGCAGCACACAUAUGUG	1318
1469-1500	Mm	strand
NR1H3-1404-	Hs-Mf-	19 mer sense	CUGCAGCACACAUAUGUGG	1319
1470-1501	Mm	strand
NR1H3-1406-	Hs-Mf-	19 mer sense	GCAGCACACAUAUGUGGAA	1320
1472-1503	Mm	strand
NR1H3-1407-	Hs-Mf-	19 mer sense	CAGCACACAUAUGUGGAAG	1321
1473-1504	Mm	strand
NR1H3-1408-	Hs-Mf-	19 mer sense	AGCACACAUAUGUGGAAGC	1322
1474-1505	Mm	strand
NR1H3-1410-	Hs-Mf-	19 mer sense	CACACAUAUGUGGAAGCCC	1323
1476-1507	Mm	strand
NR1H3-1411-	Hs-Mf-	19 mer sense	ACACAUAUGUGGAAGCCCU	1324
1477-1508	Mm	strand
NR1H3-1412-	Hs-Mf-	19 mer sense	CACAUAUGUGGAAGCCCUG	1325
1478-1509	Mm	strand
NR1H3-1413-	Hs-Mf-	19 mer sense	ACAUAUGUGGAAGCCCUGC	1326
1479-1510	Mm	strand
NR1H3-1414-	Hs-Mf-	19 mer sense	CAUAUGUGGAAGCCCUGCA	1327
1480-1511	Mm	strand
NR1H3-1415-	Hs-Mf-	19 mer sense	AUAUGUGGAAGCCCUGCAU	1328
1481-1512	Mm	strand
NR1H3-1416-	Hs-Mf-	19 mer sense	UAUGUGGAAGCCCUGCAUG	1329
1482-1513	Mm	strand
NR1H3-1417-	Hs-Mf-	19 mer sense	AUGUGGAAGCCCUGCAUGC	1330
1483-1514	Mm	strand
NR1H3-1418-	Hs-Mf-	19 mer sense	UGUGGAAGCCCUGCAUGCC	1331
1484-1515	Mm	strand
NR1H3-1419-	Hs-Mf-	19 mer sense	GUGGAAGCCCUGCAUGCCU	1332
1485-1516	Mm	strand
NR1H3-1420-	Hs-Mf-	19 mer sense	UGGAAGCCCUGCAUGCCUA	1333
1486-1517	Mm	strand
NR1H3-1421-	Hs-Mf-	19 mer sense	GGAAGCCCUGCAUGCCUAC	1334
1487-1518	Mm	strand
NR1H3-1422-	Hs-Mf-	19 mer sense	GAAGCCCUGCAUGCCUACG	1335
1488-1519	Mm	strand
NR1H3-1423-	Hs-Mf-	19 mer sense	AAGCCCUGCAUGCCUACGU	1336
1489-1520	Mm	strand
NR1H3-1424-	Hs-Mf-	19 mer sense	AGCCCUGCAUGCCUACGUC	1337
1490-1521	Mm	strand
NR1H3-1425-	Hs-Mf-	19 mer sense	GCCCUGCAUGCCUACGUCU	1338
1491-1522	Mm	strand
NR1H3-1426-	Hs-Mf-	19 mer sense	CCCUGCAUGCCUACGUCUC	1339
1492-1523	Mm	strand
NR1H3-1427-	Hs-Mf-	19 mer sense	CCUGCAUGCCUACGUCUCC	1340
1493-1524	Mm	strand
NR1H3-1428-	Hs-Mf-	19 mer sense	CUGCAUGCCUACGUCUCCA	1341
1494-1525	Mm	strand
NR1H3-1429-	Hs-Mf-	19 mer sense	UGCAUGCCUACGUCUCCAU	1342
1495-1526	Mm	strand
NR1H3-1430-	Hs-Mf-	19 mer sense	GCAUGCCUACGUCUCCAUC	1343
1496-1527	Mm	strand
NR1H3-1431-	Hs-Mf-	19 mer sense	CAUGCCUACGUCUCCAUCC	1344
1497-1528	Mm	strand
NR1H3-1432-	Hs-Mf-	19 mer sense	AUGCCUACGUCUCCAUCCA	1345
1498-1529	Mm	strand
NR1H3-1433-	Hs-Mf-	19 mer sense	UGCCUACGUCUCCAUCCAC	1346
1499-1530	Mm	strand
NR1H3-1434-	Hs-Mf-	19 mer sense	GCCUACGUCUCCAUCCACC	1347
1500-1531	Mm	strand
NR1H3-1435-	Hs-Mf-	19 mer sense	CCUACGUCUCCAUCCACCA	1348
1501-1532	Mm	strand
NR1H3-1436-	Hs-Mf-	19 mer sense	CUACGUCUCCAUCCACCAU	1349
1502-1533	Mm	strand
NR1H3-1437-	Hs-Mf-	19 mer sense	UACGUCUCCAUCCACCAUC	1350
1503-1534	Mm	strand
NR1H3-1438-	Hs-Mf-	19 mer sense	ACGUCUCCAUCCACCAUCC	1351
1504-1535	Mm	strand
NR1H3-1439-	Hs-Mf-	19 mer sense	CGUCUCCAUCCACCAUCCC	1352
1505-1536	Mm	strand
NR1H3-1440-	Hs-Mf-	19 mer sense	GUCUCCAUCCACCAUCCCC	1353
1506-1537	Mm	strand
NR1H3-1442-	Hs-Mf-	19 mer sense	CUCCAUCCACCAUCCCCAU	1354
1508-1539	Mm	strand
NR1H3-1443-	Hs-Mf-	19 mer sense	UCCAUCCACCAUCCCCAUG	1355
1509-1540	Mm	strand
NR1H3-1444-	Hs-Mf-	19 mer sense	CCAUCCACCAUCCCCAUGA	1356
1510-1541	Mm	strand
NR1H3-1445-	Hs-Mf-	19 mer sense	CAUCCACCAUCCCCAUGAC	1357
1511-1542	Mm	strand
NR1H3-1446-	Hs-Mf-	19 mer sense	AUCCACCAUCCCCAUGACC	1358
1512-1543	Mm	strand
NR1H3-1447-	Hs-Mf	19 mer sense	UCCACCAUCCCCAUGACCG	1359
1513		strand
NR1H3-1448-	Hs-Mf	19 mer sense	CCACCAUCCCCAUGACCGA	1360
1514		strand
NR1H3-1449-	Hs-Mf	19 mer sense	CACCAUCCCCAUGACCGAC	1361
1515		strand
NR1H3-1450-	Hs-Mf	19 mer sense	ACCAUCCCCAUGACCGACU	1362
1516		strand
NR1H3-1451-	Hs-Mf	19 mer sense	CCAUCCCCAUGACCGACUG	1363
1517		strand
NR1H3-1452-	Hs-Mf-	19 mer sense	CAUCCCCAUGACCGACUGA	1364
1518-1549	Mm	strand
NR1H3-1453-	Hs-Mf-	19 mer sense	AUCCCCAUGACCGACUGAU	1365
1519-1550	Mm	strand
NR1H3-1454-	Hs-Mf-	19 mer sense	UCCCCAUGACCGACUGAUG	1366
1520-1551	Mm	strand
NR1H3-1455-	Hs-Mf-	19 mer sense	CCCCAUGACCGACUGAUGU	1367
1521-1552	Mm	strand
NR1H3-1456-	Hs-Mf-	19 mer sense	CCCAUGACCGACUGAUGUU	1368
1522-1553	Mm	strand
NR1H3-1457-	Hs-Mf-	19 mer sense	CCAUGACCGACUGAUGUUC	1369
1523-1554	Mm	strand
NR1H3-1459-	Hs-Mf-	19 mer sense	AUGACCGACUGAUGUUCCC	1370
1525-1556	Mm	strand
NR1H3-1460-	Hs-Mf-	19 mer sense	UGACCGACUGAUGUUCCCA	1371
1526-1557	Mm	strand
NR1H3-1461-	Hs-Mf-	19 mer sense	GACCGACUGAUGUUCCCAC	1372
1527-1558	Mm	strand
NR1H3-1462-	Hs-Mf-	19 mer sense	ACCGACUGAUGUUCCCACG	1373
1528-1559	Mm	strand
NR1H3-1463-	Hs-Mf-	19 mer sense	CCGACUGAUGUUCCCACGG	1374
1529-1560	Mm	strand
NR1H3-1465-	Hs-Mf-	19 mer sense	GACUGAUGUUCCCACGGAU	1375
1531-1562	Mm	strand
NR1H3-1466-	Hs-Mf-	19 mer sense	ACUGAUGUUCCCACGGAUG	1376
1532-1563	Mm	strand
NR1H3-1468-	Hs-Mf-	19 mer sense	UGAUGUUCCCACGGAUGCU	1377
1534-1565	Mm	strand
NR1H3-1469-	Hs-Mf-	19 mer sense	GAUGUUCCCACGGAUGCUA	1378
1535-1566	Mm	strand
NR1H3-1471-	Hs-Mf-	19 mer sense	UGUUCCCACGGAUGCUAAU	1379
1537-1568	Mm	strand
NR1H3-1472-	Hs-Mf-	19 mer sense	GUUCCCACGGAUGCUAAUG	1380
1538-1569	Mm	strand
NR1H3-1473-	Hs-Mf-	19 mer sense	UUCCCACGGAUGCUAAUGA	1381
1539-1570	Mm	strand
NR1H3-1474-	Hs-Mf-	19 mer sense	UCCCACGGAUGCUAAUGAA	1382
1540-1571	Mm	strand
NR1H3-1475-	Hs-Mf-	19 mer sense	CCCACGGAUGCUAAUGAAA	1383
1541-1572	Mm	strand
NR1H3-1476-	Hs-Mf-	19 mer sense	CCACGGAUGCUAAUGAAAC	1384
1542-1573	Mm	strand
NR1H3-1477-	Hs-Mf-	19 mer sense	CACGGAUGCUAAUGAAACU	1385
1543-1574	Mm	strand
NR1H3-1478-	Hs-Mf-	19 mer sense	ACGGAUGCUAAUGAAACUG	1386
1544-1575	Mm	strand
NR1H3-1479-	Hs-Mf-	19 mer sense	CGGAUGCUAAUGAAACUGG	1387
1545-1576	Mm	strand
NR1H3-1480-	Hs-Mf-	19 mer sense	GGAUGCUAAUGAAACUGGU	1388
1546-1577	Mm	strand
NR1H3-1481-	Hs-Mf-	19 mer sense	GAUGCUAAUGAAACUGGUG	1389
1547-1578	Mm	strand
NR1H3-1483-	Hs-Mf-	19 mer sense	UGCUAAUGAAACUGGUGAG	1390
1549-1580	Mm	strand
NR1H3-1484-	Hs-Mf-	19 mer sense	GCUAAUGAAACUGGUGAGC	1391
1550-1581	Mm	strand
NR1H3-1485-	Hs-Mf-	19 mer sense	CUAAUGAAACUGGUGAGCC	1392
1551-1582	Mm	strand
NR1H3-1486-	Hs-Mf-	19 mer sense	UAAUGAAACUGGUGAGCCU	1393
1552-1583	Mm	strand
NR1H3-1487-	Hs-Mf-	19 mer sense	AAUGAAACUGGUGAGCCUC	1394
1553-1584	Mm	strand
NR1H3-1488-	Hs-Mf-	19 mer sense	AUGAAACUGGUGAGCCUCC	1395
1554-1585	Mm	strand
NR1H3-1489-	Hs-Mf-	19 mer sense	UGAAACUGGUGAGCCUCCG	1396
1555-1586	Mm	strand
NR1H3-1491-	Hs-Mf-	19 mer sense	AAACUGGUGAGCCUCCGGA	1397
1557-1588	Mm	strand
NR1H3-1492-	Hs-Mf-	19 mer sense	AACUGGUGAGCCUCCGGAC	1398
1558-1589	Mm	strand
NR1H3-1494-	Hs-Mf	19 mer sense	CUGGUGAGCCUCCGGACCC	1399
1560		strand
NR1H3-1505-	Hs-Mf-	19 mer sense	CCGGACCCUGAGCAGCGUC	1400
1571-1602	Mm	strand
NR1H3-1507-	Hs-Mf-	19 mer sense	GGACCCUGAGCAGCGUCCA	1401
1573-1604	Mm	strand
NR1H3-1508-	Hs-Mf	19 mer sense	GACCCUGAGCAGCGUCCAC	1402
1574		strand
NR1H3-1509-	Hs-Mf	19 mer sense	ACCCUGAGCAGCGUCCACU	1403
1575		strand
NR1H3-1510-	Hs-Mf	19 mer sense	CCCUGAGCAGCGUCCACUC	1404
1576		strand
NR1H3-1511-	Hs-Mf-	19 mer sense	CCUGAGCAGCGUCCACUCA	1405
1577-1608	Mm	strand
NR1H3-1512-	Hs-Mf-	19 mer sense	CUGAGCAGCGUCCACUCAG	1406
1578-1609	Mm	strand
NR1H3-1513-	Hs-Mf-	19 mer sense	UGAGCAGCGUCCACUCAGA	1407
1579-1610	Mm	strand
NR1H3-1514-	Hs-Mf-	19 mer sense	GAGCAGCGUCCACUCAGAG	1408
1580-1611	Mm	strand
NR1H3-1515-	Hs-Mf-	19 mer sense	AGCAGCGUCCACUCAGAGC	1409
1581-1612	Mm	strand
NR1H3-1516-	Hs-Mf-	19 mer sense	GCAGCGUCCACUCAGAGCA	1410
1582-1613	Mm	strand
NR1H3-1517-	Hs-Mf-	19 mer sense	CAGCGUCCACUCAGAGCAA	1411
1583-1614	Mm	strand
NR1H3-1518-	Hs-Mf-	19 mer sense	AGCGUCCACUCAGAGCAAG	1412
1584-1615	Mm	strand
NR1H3-1519-	Hs-Mf-	19 mer sense	GCGUCCACUCAGAGCAAGU	1413
1585-1616	Mm	strand
NR1H3-1520-	Hs-Mf-	19 mer sense	CGUCCACUCAGAGCAAGUG	1414
1586-1617	Mm	strand
NR1H3-1521-	Hs-Mf-	19 mer sense	GUCCACUCAGAGCAAGUGU	1415
1587-1618	Mm	strand
NR1H3-1522-	Hs-Mf-	19 mer sense	UCCACUCAGAGCAAGUGUU	1416
1588-1619	Mm	strand
NR1H3-1523-	Hs-Mf-	19 mer sense	CCACUCAGAGCAAGUGUUU	1417
1589-1620	Mm	strand
NR1H3-1525-	Hs-Mf-	19 mer sense	ACUCAGAGCAAGUGUUUGC	1418
1591-1622	Mm	strand
NR1H3-1526-	Hs-Mf-	19 mer sense	CUCAGAGCAAGUGUUUGCA	1419
1592-1623	Mm	strand
NR1H3-1527-	Hs-Mf-	19 mer sense	UCAGAGCAAGUGUUUGCAC	1420
1593-1624	Mm	strand
NR1H3-1528-	Hs-Mf-	19 mer sense	CAGAGCAAGUGUUUGCACU	1421
1594-1625	Mm	strand
NR1H3-1529-	Hs-Mf-	19 mer sense	AGAGCAAGUGUUUGCACUG	1422
1595-1626	Mm	strand
NR1H3-1530-	Hs-Mf-	19 mer sense	GAGCAAGUGUUUGCACUGC	1423
1596-1627	Mm	strand
NR1H3-1531-	Hs-Mf-	19 mer sense	AGCAAGUGUUUGCACUGCG	1424
1597-1628	Mm	strand
NR1H3-1532-	Hs-Mf-	19 mer sense	GCAAGUGUUUGCACUGCGU	1425
1598-1629	Mm	strand
NR1H3-1533-	Hs-Mf-	19 mer sense	CAAGUGUUUGCACUGCGUC	1426
1599-1630	Mm	strand
NR1H3-1534-	Hs-Mf-	19 mer sense	AAGUGUUUGCACUGCGUCU	1427
1600-1631	Mm	strand
NR1H3-1535-	Hs-Mf-	19 mer sense	AGUGUUUGCACUGCGUCUG	1428
1601-1632	Mm	strand
NR1H3-1536-	Hs-Mf-	19 mer sense	GUGUUUGCACUGCGUCUGC	1429
1602-1633	Mm	strand
NR1H3-1537-	Hs-Mf-	19 mer sense	UGUUUGCACUGCGUCUGCA	1430
1603-1634	Mm	strand
NR1H3-1538-	Hs-Mf-	19 mer sense	GUUUGCACUGCGUCUGCAG	1431
1604-1635	Mm	strand
NR1H3-1539-	Hs-Mf-	19 mer sense	UUUGCACUGCGUCUGCAGG	1432
1605-1636	Mm	strand
NR1H3-1540-	Hs-Mf-	19 mer sense	UUGCACUGCGUCUGCAGGA	1433
1606-1637	Mm	strand
NR1H3-1541-	Hs-Mf-	19 mer sense	UGCACUGCGUCUGCAGGAC	1434
1607-1638	Mm	strand
NR1H3-1542-	Hs-Mf-	19 mer sense	GCACUGCGUCUGCAGGACA	1435
1608-1639	Mm	strand
NR1H3-1543-	Hs-Mf-	19 mer sense	CACUGCGUCUGCAGGACAA	1436
1609-1640	Mm	strand
NR1H3-1544-	Hs-Mf-	19 mer sense	ACUGCGUCUGCAGGACAAA	1437
1610-1641	Mm	strand
NR1H3-1545-	Hs-Mf-	19 mer sense	CUGCGUCUGCAGGACAAAA	1438
1611-1642	Mm	strand
NR1H3-1546-	Hs-Mf-	19 mer sense	UGCGUCUGCAGGACAAAAA	1439
1612-1643	Mm	strand
NR1H3-1547-	Hs-Mf-	19 mer sense	GCGUCUGCAGGACAAAAAG	1440
1613-1644	Mm	strand
NR1H3-1548-	Hs-Mf-	19 mer sense	CGUCUGCAGGACAAAAAGC	1441
1614-1645	Mm	strand
NR1H3-1549-	Hs-Mf-	19 mer sense	GUCUGCAGGACAAAAAGCU	1442
1615-1646	Mm	strand
NR1H3-1550-	Hs-Mf-	19 mer sense	UCUGCAGGACAAAAAGCUC	1443
1616-1647	Mm	strand
NR1H3-1551-	Hs-Mf-	19 mer sense	CUGCAGGACAAAAAGCUCC	1444
1617-1648	Mm	strand
NR1H3-1553-	Hs-Mf-	19 mer sense	GCAGGACAAAAAGCUCCCA	1445
1619-1650	Mm	strand
NR1H3-1554-	Hs-Mf-	19 mer sense	CAGGACAAAAAGCUCCCAC	1446
1620-1651	Mm	strand
NR1H3-1555-	Hs-Mf-	19 mer sense	AGGACAAAAAGCUCCCACC	1447
1621-1652	Mm	strand
NR1H3-1556-	Hs-Mf-	19 mer sense	GGACAAAAAGCUCCCACCG	1448
1622-1653	Mm	strand
NR1H3-1558-	Hs-Mf-	19 mer sense	ACAAAAAGCUCCCACCGCU	1449
1624-1655	Mm	strand
NR1H3-1559-	Hs-Mf-	19 mer sense	CAAAAAGCUCCCACCGCUG	1450
1625-1656	Mm	strand
NR1H3-1560-	Hs-Mf-	19 mer sense	AAAAAGCUCCCACCGCUGC	1451
1626-1657	Mm	strand
NR1H3-1561-	Hs-Mf-	19 mer sense	AAAAGCUCCCACCGCUGCU	1452
1627-1658	Mm	strand
NR1H3-1562-	Hs-Mf	19 mer sense	AAAGCUCCCACCGCUGCUC	1453
1628		strand
NR1H3-1563-	Hs-Mf	19 mer sense	AAGCUCCCACCGCUGCUCU	1454
1629		strand
NR1H3-1564-	Hs-Mf	19 mer sense	AGCUCCCACCGCUGCUCUC	1455
1630		strand
NR1H3-1565-	Hs-Mf	19 mer sense	GCUCCCACCGCUGCUCUCU	1456
1631		strand
NR1H3-1567-	Hs-Mf	19 mer sense	UCCCACCGCUGCUCUCUGA	1457
1633		strand
NR1H3-1569-	Hs-Mf	19 mer sense	CCACCGCUGCUCUCUGAGA	1458
1635		strand
NR1H3-1570-	Hs-Mf	19 mer sense	CACCGCUGCUCUCUGAGAU	1459
1636		strand
NR1H3-1572-	Hs-Mf-	19 mer sense	CCGCUGCUCUCUGAGAUCU	1460
1638-1669	Mm	strand
NR1H3-1573-	Hs-Mf-	19 mer sense	CGCUGCUCUCUGAGAUCUG	1461
1639-1670	Mm	strand
NR1H3-1574-	Hs-Mf-	19 mer sense	GCUGCUCUCUGAGAUCUGG	1462
1640-1671	Mm	strand
NR1H3-1577-	Hs-Mf-	19 mer sense	GCUCUCUGAGAUCUGGGAU	1463
1643-1674	Mm	strand
NR1H3-1579-	Hs-Mf-	19 mer sense	UCUCUGAGAUCUGGGAUGU	1464
1645-1676	Mm	strand
NR1H3-1580-	Hs-Mf-	19 mer sense	CUCUGAGAUCUGGGAUGUG	1465
1646-1677	Mm	strand
NR1H3-1581-	Hs-Mf-	19 mer sense	UCUGAGAUCUGGGAUGUGC	1466
1647-1678	Mm	strand
NR1H3-1582-	Hs-Mf-	19 mer sense	CUGAGAUCUGGGAUGUGCA	1467
1648-1679	Mm	strand
NR1H3-1583-	Hs-Mf-	19 mer sense	UGAGAUCUGGGAUGUGCAC	1468
1649-1680	Mm	strand
NR1H3-1584-	Hs-Mf-	19 mer sense	GAGAUCUGGGAUGUGCACG	1469
1650-1681	Mm	strand
NR1H3-1585-	Hs-Mf-	19 mer sense	AGAUCUGGGAUGUGCACGA	1470
1651-1682	Mm	strand
NR1H3-1586-	Hs-Mf-	19 mer sense	GAUCUGGGAUGUGCACGAA	1471
1652-1683	Mm	strand
NR1H3-1587-	Hs-Mf-	19 mer sense	AUCUGGGAUGUGCACGAAU	1472
1653-1684	Mm	strand
NR1H3-1588-	Hs-Mf-	19 mer sense	UCUGGGAUGUGCACGAAUG	1473
1654-1685	Mm	strand
NR1H3-1589-	Hs-Mf-	19 mer sense	CUGGGAUGUGCACGAAUGA	1474
1655-1686	Mm	strand
NR1H3-1590-	Hs-Mf-	19 mer sense	UGGGAUGUGCACGAAUGAC	1475
1656-1687	Mm	strand
NR1H3-1591-	Hs-Mf-	19 mer sense	GGGAUGUGCACGAAUGACU	1476
1657-1688	Mm	strand
NR1H3-1592-	Hs-Mf-	19 mer sense	GGAUGUGCACGAAUGACUG	1477
1658-1689	Mm	strand
NR1H3-1593-	Hs-Mf-	19 mer sense	GAUGUGCACGAAUGACUGU	1478
1659-1690	Mm	strand
NR1H3-1656-	Hs-Mf	19 mer sense	UGGUGGCUGCCUCCUAGAA	1479
1720		strand
NR1H3-1657-	Hs-Mf	19 mer sense	GGUGGCUGCCUCCUAGAAG	1480
1721		strand
NR1H3-1658-	Hs-Mf	19 mer sense	GUGGCUGCCUCCUAGAAGU	1481
1722		strand
NR1H3-1659-	Hs-Mf	19 mer sense	UGGCUGCCUCCUAGAAGUG	1482
1723		strand
NR1H3-1660-	Hs-Mf	19 mer sense	GGCUGCCUCCUAGAAGUGG	1483
1724		strand
NR1H3-1661-	Hs-Mf	19 mer sense	GCUGCCUCCUAGAAGUGGA	1484
1725		strand
NR1H3-1662-	Hs-Mf	19 mer sense	CUGCCUCCUAGAAGUGGAA	1485
1726		strand
NR1H3-1663-	Hs-Mf	19 mer sense	UGCCUCCUAGAAGUGGAAC	1486
1727		strand
NR1H3-1664-	Hs-Mf	19 mer sense	GCCUCCUAGAAGUGGAACA	1487
1728		strand
NR1H3-1665-	Hs-Mf	19 mer sense	CCUCCUAGAAGUGGAACAG	1488
1729		strand
NR1H3-1666-	Hs-Mf	19 mer sense	CUCCUAGAAGUGGAACAGA	1489
1730		strand
NR1H3-1667-	Hs-Mf	19 mer sense	UCCUAGAAGUGGAACAGAC	1490
1731		strand
NR1H3-1668-	Hs-Mf	19 mer sense	CCUAGAAGUGGAACAGACU	1491
1732		strand
NR1H3-1669-	Hs-Mf	19 mer sense	CUAGAAGUGGAACAGACUG	1492
1733		strand
NR1H3-1671-	Hs-Mf	19 mer sense	AGAAGUGGAACAGACUGAG	1493
1735		strand
NR1H3-1677-	Hs-Mf-	19 mer sense	GGAACAGACUGAGAAGGGC	1494
1741-1768	Mm	strand
NR1H3-1679-	Hs-Mf-	19 mer sense	AACAGACUGAGAAGGGCAA	1495
1743-1770	Mm	strand
NR1H3-1680-	Hs-Mf-	19 mer sense	ACAGACUGAGAAGGGCAAA	1496
1744-1771	Mm	strand
NR1H3-1681-	Hs-Mf-	19 mer sense	CAGACUGAGAAGGGCAAAC	1497
1745-1772	Mm	strand
NR1H3-1682-	Hs-Mf-	19 mer sense	AGACUGAGAAGGGCAAACA	1498
1746-1773	Mm	strand
NR1H3-1683-	Hs-Mf-	19 mer sense	GACUGAGAAGGGCAAACAU	1499
1747-1774	Mm	strand
NR1H3-1684-	Hs-Mf-	19 mer sense	ACUGAGAAGGGCAAACAUU	1500
1748-1775	Mm	strand
NR1H3-1685-	Hs-Mf-	19 mer sense	CUGAGAAGGGCAAACAUUC	1501
1749-1776	Mm	strand
NR1H3-1686-	Hs-Mf-	19 mer sense	UGAGAAGGGCAAACAUUCC	1502
1750-1777	Mm	strand
NR1H3-1687-	Hs-Mf-	19 mer sense	GAGAAGGGCAAACAUUCCU	1503
1751-1778	Mm	strand
NR1H3-1728-	Hs-Mf	19 mer sense	CCCGUGGCAUUAAAAGAGA	1504
1792		strand
NR1H3-1729-	Hs-Mf	19 mer sense	CCGUGGCAUUAAAAGAGAG	1505
1793		strand
NR1H3-1730-	Hs-Mf	19 mer sense	CGUGGCAUUAAAAGAGAGU	1506
1794		strand
NR1H3-1731-	Hs-Mf	19 mer sense	GUGGCAUUAAAAGAGAGUC	1507
1795		strand
NR1H3-1732-	Hs-Mf-	19 mer sense	UGGCAUUAAAAGAGAGUCA	1508
1796-1826	Mm	strand
NR1H3-1209-	Hs-Mf-	19 mer sense	CUCAAGGAUUUCAGUUAUA	1509
1229-1306	Mm	strand
NR1H3-1210-	Hs-Mf-	19 mer sense	UCAAGGAUUUCAGUUAUAA	1510
1230-1307	Mm	strand
NR1H3-1594-	Hs-Mf-	19 mer sense	AUGUGCACGAAUGACUGUU	1511
1660-1691	Mm	strand
NR1H3-1209-	Hs-Mf-	19 mer	UAUAACUGAAAUCCUUGAG	1512
1229-1306	Mm	antisense
		strand
NR1H3-1210-	Hs-Mf-	19 mer	UUAUAACUGAAAUCCUUGA	1513
1230-1307	Mm	antisense
		strand
NR1H3-1515-	Hs-Mf-	19 mer	GCUCUGAGUGGACGCUGCU	1514
1581-1612	Mm	antisense
		strand
NR1H3-1594-	Hs-Mf-	19 mer	AACAGUCAUUCGUGCACAU	1515
1660-1691	Mm	antisense
		strand
DNA	Homo		ATGGAATTCC CCATTGGATC	1516
	sapiens		CCTCGAAACT AACAACTTCC
			GTCGCTTTAC TCCGGAGTCA
			CTGGTGGAGA TAGAGAAGCA
			AATTGCTGCC AAGCAGGGAA
			CAAAGAAAGC CAGAGAGAAG
			CATAGGGAGC AGAAGGACCA
			AGAAGAGAAG CCTCGGCCCC
			AGCTGGACTT GAAAGCCTGC
			AACCAGCTGC CCAAGTTCTA
			TGGTGAGCTC CCAGCAGAAC
			TGATCGGGGA GCCCCTGGAG
			GATCTAGATC CGTTCTACAG
			CACACACCGG ACATTTATGG
			TGCTGAACAA AGGGAGGACC
			ATTTCCCGGT TTAGTGCCAC
			TCGGGCCCTG TGGCTATTCA
			GTCCTTTCAA CCTGATCAGA
			AGAACGGCCA TCAAAGTGTC
			TGTCCACTCG TGGTTCAGTT
			TATTTATTAC GGTCACTATT
			TTGGTTAATT GTGTGTGCAT
			GACCCGAACT GACCTTCCAG
			AGAAAATTGA ATATGTCTTC
			ACTGTCATTT ACACCTTTGA
			AGCCTTGATA AAGATACTGG
			CAAGAGGATT TTGTCTAAAT
			GAGTTCACGT ACCTGAGAGA
			TCCTTGGAAC TGGCTGGATT
			TTAGCGTCAT TACCCTGGCA
			TATGTTGGCA CAGCAATAGA
			TCTCCGTGGG ATCTCAGGCC
			TGCGGACATT CAGAGTTCTT
			AGAGCATTAA AAACAGTTTC
			TGTGATCCCA GGCCTGAAGG
			TCATTGTGGG GGCCCTGATT
			CACTCAGTGA AGAAACTGGC
			TGATGTGACC ATCCTCACCA
			TCTTCTGCCT AAGTGTTTTT
			GCCTTGGTGG GGCTGCAACT
			CTTCAAGGGC AACCTCAAAA
			ATAAATGTGT CAAGAATGAC
			ATGGCTGTCA ATGAGACAAC
			CAACTACTCA TCTCACAGAA
			AACCAGATAT CTACATAAAT
			AAGCGAGGCA CTTCTGACCC
			CTTACTGTGT GGCAATGGAT
			CTGACTCAGG CCACTGCCCT
			GATGGTTATA TCTGCCTTAA
			AACTTCTGAC AACCCGGATT
			TTAACTACAC CAGCTTTGAT
			TCCTTTGCTT GGGCTTTCCT
			CTCACTGTTC
			CGCCTCATGA CACAGGATTC
			CTGGGAACGCCTCTACCAGC
			AGACCCTGAG GACTTCTGGG
			AAAATCTATA TGATCTTTTT
			TGTGCTCGTA ATCTTCCTGG
			GATCTTTCTA CCTGGTCAAC
			TTGATCTTGG CTGTAGTCAC
			CATGGCGTAT GAGGAGCAGA
			ACCAGGCAAC CACTGATGAA
			ATTGAAGCAA AGGAGAAGAA
			GTTCCAGGAG GCCCTCGAGA
			TGCTCCGGAA GGAGCAGGAG
			GTGCTAGCAG CACTAGGGAT
			TGACACAACC TCTCTCCACT
			CCCACAATGG ATCACCTTTA
			ACCTCCAAAA ATGCCAGTGA
			GAGAAGGCAT AGAATAAAGC
			CAAGAGTGTC AGAGGGCTCC
			ACAGAAGACA ACAAATCACC
			CCGCTCTGAT CCTTACAACC
			AGCGCAGGAT GTCTTTTCTA
			GGCCTCGCCT CTGGAAAACG
			CCGGGCTAGT CATGGCAGTG
			TGTTCCATTT CCGGTCCCCT
			GGCCGAGATA TCTCACTCCC
			TGAGGGAGTC ACAGATGATG
			GAGTCTTTCC TGGAGACCAC
			GAAAGCCATC GGGGCTCTCT
			GCTGCTGGGT GGGGGTGCTG
			GCCAGCAAGG CCCCCTCCCT
			AGAAGCCCTC TTCCTCAACC
			CAGCAACCCT GACTCCAGGC
			ATGGAGAAGA TGAACACCAA
			CCGCCGCCCA CTAGTGAGCT
			TGCCCCTGGA GCTGTCGATG
			TCTCGGCATT CGATGCAGGA
			CAAAAGAAGA CTTTCTTGTC
			AGCAGAATAC TTAGATGAAC
			CTTTCCGGGC CCAAAGGGCA
			ATGAGTGTTG TCAGTATCAT
			AACCTCCGTC CTTGAGGAAC
			TCGAGGAGTC TGAACAGAAG
			TGCCCACCCT GCTTGACCAG
			CTTGTCTCAG AAGTATCTGA
			TCTGGGATTG CTGCCCCATG
			TGGGTGAAGC TCAAGACAAT
			TCTCTTTGGG CTTGTGACGG
			ATCCCTTTGC AGAGCTCACC
			ATCACCTTGT GCATCGTGGT
			GAACACCATC TTCATGGCCA
			TGGAGCACCA TGGCATGAGC
			CCTACCTTCG AAGCCATGCT
			CCAGATAGGC AACATCGTCT
			TTACCATATT
			TTTTACTGCT GAAATGGTCT
			TCAAAATCAT TGCCTTCGAC
			CCATACTATT ATTTCCAGAA
			GAAGTGGAAT ATCTTTGACT
			GCATCATCGT CACTGTGAGT
			CTGCTAGAGC TGGGCGTGGC
			CAAGAAGGGA AGCCTGTCTG
			TGCTGCGGAG CTTCCGCTTG
			CTGCGCGTAT TCAAGCTGGC
			CAAATCCTGG CCCACCTTAA
			ACACACTCAT CAAGATCATC
			GGAAACTCAG TGGGGGCACT
			GGGGAACCTC ACCATCATCC
			TGGCCATCAT TGTCTTTGTC
			TTTGCTCTGG TTGGCAAGCA
			GCTCCTAGGG GAAAACTACC
			GTAACAACCG AAAAAATATC
			TCCGCGCCCC ATGAAGACTG
			GCCCCGCTGG CACATGCACG
			ACTTCTTCCA CTCTTTCCTC
			ATTGTCTTCC GTATCCTCTG
			TGGAGAGTGG ATTGAGAACA
			TGTGGGCCTG CATGGAAGTT
			GGCCAAAAAT CCATATGCCT
			CATCCTTTTC TTGACGGTGA
			TGGTGCTAGG GAACCTGGTG
			GTGCTTAACC TGTTCATCGC
			CCTGCTATTG AACTCTTTCA
			GTGCTGACAA CCTCACAGCC
			CCGGAGGACG ATGGGGAGGT
			GAACAACCTG CAGGTGGCCC
			TGGCACGGAT CCAGGTCTTT
			GGCCATCGTA CCAAACAGGC
			TCTTTGCAGC TTCTTCAGCA
			GGTCCTGCCC ATTCCCCCAG
			CCCAAGGCAG AGCCTGAGCT
			GGTGGTGAAA CTCCCACTCT
			CCAGCTCCAA GGCTGAGAAC
			CACATTGCTG CCAACACTGC
			CAGGGGGAGC TCTGGAGGGC
			TCCAAGCTCC CAGAGGCCCC
			AGGGATGAGC ACAGTGACTT
			CATCGCTAAT CCGACTGTGT
			GGGTCTCTGT GCCCATTGCT
			GAGGGTGAAT CTGATCTTGA
			TGACTTGGAG GATGATGGTG
			GGGAAGATGC TCAGAGCTTC
			CAGCAGGAAG TGATCCCCAA
			AGGACAGCAG GAGCAGCTGC
			AGCAAGTCGA GAGGTGTGGG
			GACCACCTGA CACCCAGGAG
			CCCAGGCACT GGAACATCTT
			CTGAGGACCT GGCTCCATCC
			CTGGGTGAGA CGTGGAAAGA
			TGAGTCTGTT CCTCAGGTCC
			CTGCTGAGGG AGTGGACGAC
			ACAAGCTCCT CTGAGGGCAG
			CACGGTGGAC TGCCTAGATC
			CTGAGGAAAT CCTGAGGAAG
			ATCCCTGAGC TGGCAGATGA
			CCTGGAAGAA CCAGATGACT
			GCTTCACAGA AGGATGCATT
			CGCCACTGTC CCTGCTGCAA
			ACTGGATACC ACCAAGAGTC
			CATGGGATGT GGGCTGGCAG
			GTGCGCAAGA CTTGCTACCG
			TATCGTGGAG CACAGCTGGT
			TTGAGAGCTT CATCATCTTC
			ATGATCCTGC TCAGCAGTGG
			ATCTCTGGCC TTTGAAGACT
			ATTACCTGGA CCAGAAGCCC
			ACGGTGAAAG CTTTGCTGGA
			GTACACTGAC AGGGTCTTCA
			CCTTTATCTT TGTGTTCGAG
			ATGCTGCTTA AGTGGGTGGC
			CTATGGCTTC AAAAAGTACT
			TCACCAATGC CTGGTGCTGG
			CTGGACTTCC TCATTGTGAA
			TATCTCACTG ATAAGTCTCA
			CAGCGAAGAT TCTGGAATAT
			TCTGAAGTGG CTCCCATCAA
			AGCCCTTCGA ACCCTTCGCG
			CTCTGCGGCC ACTGCGGGCT
			CTTTCTCGAT TTGAAGGCAT
			GCGGGTGGTG GTGGATGCCC
			TGGTGGGCGC CATCCCATCC
			ATCATGAATG TCCTCCTCGT
			CTGCCTCATC TTCTGGCTCA
			TCTTCAGCAT CATGGGTGTG
			AACCTCTTCG CAGGGAAGTT
			TTGGAGGTGC ATCAACTATA
			CCGATGGAGA GTTTTCCCTT
			GTACCTTTGT CGATTGTGAA
			TAACAAGTCT GACTGCAAGA
			TTCAAAACTC CACTGGCAGC
			TTCTTCTGGG TCAATGTGAA
			AGTCAACTTT GATAATGTTG
			CAATGGGTTA CCTTGCACTT
			CTGCAGGTGG CAACCTTTAA
			AGGCTGGATG GACATTATGT
			ATGCAGCTGT TGATTCCCGG
			GAGGTCAACA TGCAACCCAA
			GTGGGAGGAC AACGTGTACA
			TGTATTTGTA CTTTGTCATC
			TTCATCATTT TTGGAGGCTT
			CTTCACACTG AATCTCTTTG
			TTGGGGTCAT AATTGACAAC
			TTCAATCAAC AGAAAAAAAA
			GTTAGGGGGC CAGGACATCT
			TCATGACAGA GGAGCAGAAG
			AAATACTACA ATGCCATGAA
			GAAGTTGGGC TCCAAGAAGC
			CCCAGAAGCC CATCCCACGG
			CCCCTGAACA AGTTCCAGGG
			TTTTGTCTTT GACATCGTGA
			CCAGACAAGC TTTTGACATC
			ACCATCATGG TCCTCATCTG
			CCTCAACATG ATCACCATGA
			TGGTGGAGAC TGATGACCAA
			AGTGAAGAAA AGACGAAAAT
			TCTGGGCAAA ATCAACCAGT
			TCTTTGTGGC CGTCTTCACA
			GGCGAATGTG TCATGAAGAT
			GTTCGCTTTG AGGCAGTACT
			ACTTCACAAA TGGCTGGAAT
			GTGTTTGACT TCATTGTGGT
			GGTTCTCTCC ATTGCGAGCC
			TGATTTTTTC TGCAATTCTT
			AAGTCACTTC AAAGTTACTT
			CTCCCCAACG CTCTTCAGAG
			TCATCCGCCT GGCCCGAATT
			GGCCGCATCC TCAGACTGAT
			CCGAGCGGCC AAGGGGATCC
			GCACACTGCT CTTTGCCCTC
			ATGATGTCCC TGCCTGCCCT
			CTTCAACATC GGGCTGTTGC
			TATTCCTTGT CATGTTCATC
			TACTCTATCT TCGGTATGTC
			CAGCTTTCCC CATGTGAGGT
			GGGAGGCTGG CATCGACGAC
			ATGTTCAACT TCCAGACCTT
			CGCCAACAGC ATGCTGTGCC
			TCTTCCAGAT TACCACGTCG
			GCCGGCTGGG ATGGCCTCCT
			CAGCCCCATC CTCAACACAG
			GGCCCCCCTA CTGTGACCCC
			AATCTGCCCA ACAGCAATGG
			CACCAGAGGG GACTGTGGGA
			GCCCAGCCGT AGGCATCATC
			TTCTTCACCA CCTACATCAT
			CATCTCCTTC CTCATCGTGG
			TCAACATGTA CATTGCAGTG
			ATTCTGGAGA ACTTCAATGT
			GGCCACGGAG GAGAGCACTG
			AGCCCCTGAG TGAGGACGAC
			TTTGACATGT TCTATGAGAC
			CTGGGAGAAG TTTGACCCAG
			AGGCCACTCA GTTTATTACC
			TTTTCTGCTC TCTCGGACTT
			TGCAGACACT CTCTCTGGTC
			CCCTGAGAAT CCCAAAACCC
			AATCGAAATA TACTGATCCA
			GATGGACCTG CCTTTGGTCC
			CTGGAGATAA GATCCACTGC
			TTGGACATCC TTTTTGCTTT
			CACCAAGAAT GTCCTAGGAG
			AATCCGGGGA GTTGGATTCT
			CTGAAGGCAA ATATGGAGGA
			GAAGTTTATG GCAACTAATC
			TTTCAAAATC ATCCTATGAA
			CCAATAGCAA CCACTCTCCG
			ATGGAAGCAA GAAGACATTT
			CAGCCACTGT CATTCAAAAG
			GCCTATCGGA GCTATGTGCT
			GCACCGCTCC ATGGCACTCT
			CTAACACCCC ATGTGTGCCC
			AGAGCTGAGG AGGAGGCTGC
			ATCACTCCCA GATGAAGGTT
			TTGTTGCATT CACAGCAAAT
			GAAAATTGTG TACTCCCAGA
			CAAATCTGAA ACTGCTTCTG
			CCACATCATT CCCACCGTCC
			TATGAGAGTG TCACTAGAGG
			CCTTAGTGAT AGAGTCAACA
			TGAGGACATC TAGCTCAATA
			CAAAATGAAG ATGAAGCCAC
			CAGTATGGAG CTGATTGCCC
			CTGGGCCCTA GTGA
Forward-942	Artificial		GTCTCTGTGCAGGAGATAGTTG	1517
	Sequence
Reverse-1399	Artificial		GGAGGCTCACCAGTTTCATTA	1518
	Sequence
NR1H3-1207-	Hs-Mf-	36 mer sense	UCCUCAAGGAUUUCAGUUAAGCA	1519
1227-1304	Mm	strand	GCCGAAAGGCUGC
NR1H3-1220-	Hs-Mf-	36 mer sense	CAGUUAUAACCGGGAAGACAGCA	1520
1240-1317	Mm	strand	GCCGAAAGGCUGC
NR1H3-1224-	Hs-Mf-	36 mer sense	UAUAACCGGGAAGACUUUGAGC	1521
1244-1321	Mm	strand	AGCCGAAAGGCUGC
NR1H3-1244-	Hs-Mf-	36 mer sense	CAAAGCAGGGCUGCAAGUGAGCA	1522
1264-1341	Mm	strand	GCCGAAAGGCUGC
NR1H3-1252-	Hs-Mf-	36 mer sense	GGCUGCAAGUGGAAUUCAUAGC	1523
1272-1349	Mm	strand	AGCCGAAAGGCUGC
NR1H3-1259-	Hs-Mf-	36 mer sense	AGUGGAAUUCAUCAACCCCAGCA	1524
1279-1356	Mm	strand	GCCGAAAGGCUGC
NR1H3-1265-	Hs-Mf-	36 mer sense	AUUCAUCAACCCCAUCUUCAGCA	1525
1285-1362	Mm	strand	GCCGAAAGGCUGC
NR1H3-1266-	Hs-Mf-	36 mer sense	UUCAUCAACCCCAUCUUCGAGCA	1526
1286-1363	Mm	strand	GCCGAAAGGCUGC
NR1H3-1429-	Hs-Mf-	36 mer sense	UGCAUGCCUACGUCUCCAUAGCA	1527
1495-1526	Mm	strand	GCCGAAAGGCUGC
NR1H3-1433-	Hs-Mf-	36 mer sense	UGCCUACGUCUCCAUCCACAGCA	1528
1499-1530	Mm	strand	GCCGAAAGGCUGC
NR1H3-1437-	Hs-Mf-	36 mer sense	UACGUCUCCAUCCACCAUCAGCA	1529
1503-1534	Mm	strand	GCCGAAAGGCUGC
NR1H3-1439-	Hs-Mf-	36 mer sense	CGUCUCCAUCCACCAUCCCAGCA	1530
1505-1536	Mm	strand	GCCGAAAGGCUGC
NR1H3-1446-	Hs-Mf-	36 mer sense	AUCCACCAUCCCCAUGACCAGCA	1531
1512-1543	Mm	strand	GCCGAAAGGCUGC
NR1H3-1463-	Hs-Mf-	36 mer sense	CCGACUGAUGUUCCCACGGAGCA	1532
1529-1560	Mm	strand	GCCGAAAGGCUGC
NR1H3-1475-	Hs-Mf-	36 mer sense	CCCACGGAUGCUAAUGAAAAGCA	1533
1541-1572	Mm	strand	GCCGAAAGGCUGC
NR1H3-1479-	Hs-Mf-	36 mer sense	CGGAUGCUAAUGAAACUGGAGC	1534
1545-1576	Mm	strand	AGCCGAAAGGCUGC
NR1H3-1481-	Hs-Mf-	36 mer sense	GAUGCUAAUGAAACUGGUGAGC	1535
1547-1578	Mm	strand	AGCCGAAAGGCUGC
NR1H3-1485-	Hs-Mf-	36 mer sense	CUAAUGAAACUGGUGAGCCAGCA	1536
1551-1582	Mm	strand	GCCGAAAGGCUGC
NR1H3-1515-	Hs-Mf-	36 mer sense	AGCAGCGUCCACUCAGAGCAGCA	1537
1581-1612	Mm	strand	GCCGAAAGGCUGC
NR1H3-1517-	Hs-Mf-	36 mer sense	CAGCGUCCACUCAGAGCAAAGCA	1538
1583-1614	Mm	strand	GCCGAAAGGCUGC
NR1H3-1518-	Hs-Mf-	36 mer sense	AGCGUCCACUCAGAGCAAGAGCA	1539
1584-1615	Mm	strand	GCCGAAAGGCUGC
NR1H3-1533-	Hs-Mf-	36 mer sense	CAAGUGUUUGCACUGCGUCAGCA	1540
1599-1630	Mm	strand	GCCGAAAGGCUGC
NR1H3-1535-	Hs-Mf-	36 mer sense	AGUGUUUGCACUGCGUCUGAGCA	1541
1601-1632	Mm	strand	GCCGAAAGGCUGC
NR1H3-1545-	Hs-Mf-	36 mer sense	CUGCGUCUGCAGGACAAAAAGCA	1542
1611-1642	Mm	strand	GCCGAAAGGCUGC
NR1H3-1554-	Hs-Mf-	36 mer sense	CAGGACAAAAAGCUCCCACAGCA	1543
1620-1651	Mm	strand	GCCGAAAGGCUGC
NR1H3-1581-	Hs-Mf-	36 mer sense	UCUGAGAUCUGGGAUGUGCAGC	1544
1647-1678	Mm	strand	AGCCGAAAGGCUGC
NR1H3-1586-	Hs-Mf-	36 mer sense	GAUCUGGGAUGUGCACGAAAGC	1545
1652-1683	Mm	strand	AGCCGAAAGGCUGC
NR1H3-1587-	Hs-Mf-	36 mer sense	AUCUGGGAUGUGCACGAAUAGC	1546
1653-1684	Mm	strand	AGCCGAAAGGCUGC
NR1H3-1588-	Hs-Mf-	36 mer sense	UCUGGGAUGUGCACGAAUGAGC	1547
1654-1685	Mm	strand	AGCCGAAAGGCUGC
NR1H3-1663-	Hs-Mf	36 mer sense	UGCCUCCUAGAAGUGGAACAGCA	1548
1727		strand	GCCGAAAGGCUGC
NR1H3-1671-	Hs-Mf	36 mer sense	AGAAGUGGAACAGACUGAGAGC	1549
1735		strand	AGCCGAAAGGCUGC
NR1H3-1684-	Hs-Mf-	36 mer sense	ACUGAGAAGGGCAAACAUUAGC	1550
1748-1775	Mm	strand	AGCCGAAAGGCUGC
NR1H3-1731-	Hs-Mf	36 mer sense	GUGGCAUUAAAAGAGAGUCAGC	1551
1795		strand	AGCCGAAAGGCUGC
NR1H3-1732-	Hs-Mf-	36 mer sense	UGGCAUUAAAAGAGAGUCAAGC	1552
1796-1826	Mm	strand	AGCCGAAAGGCUGC

Claims

1. A double stranded RNAi oligonucleotide (dsRNAi) for reducing NR1H3 expression, comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, and wherein (i) the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 786 and 874, respectively;(ii) the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 787 and 875, respectively;(iii) the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 1537 and 929, respectively; or(iv) the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 813 and 901, 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: 786 and 874, 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: 787 and 875, 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: 1537 and 929, 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: 813 and 901, respectively.

6. The double stranded RNAi oligonucleotide (dsRNAi) of claim 1, 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.

7. The double stranded RNAi oligonucleotide (dsRNAi) of claim 6, wherein (i) S1 and S2 are 6 nucleotides in length; and(ii) L is a triloop or a tetraloop.

8. The double stranded RNAi oligonucleotide (dsRNAi) of claim 7, wherein L is a tetraloop comprising the sequence 5′-GAAA-3′.

9. The double stranded RNAi oligonucleotide (dsRNAi) of claim 6, wherein the stem-loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1121).

10. The double stranded RNAi oligonucleotide (dsRNAi) of claim 6, wherein at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands.

11. The double stranded RNAi oligonucleotide (dsRNAi) of claim 10, wherein each targeting ligand comprises a carbohydrate, amino sugar, cholesterol, polypeptide or lipid.

12. The double stranded RNAi oligonucleotide (dsRNAi) of claim 10, wherein the targeting ligand is a hepatocyte targeting ligand and each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety.

13. The double stranded RNAi oligonucleotide (dsRNAi) of claim 12, wherein the N-acetylgalactosamine (GalNAc) moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety.

14. The double stranded RNAi oligonucleotide (dsRNAi) of claim 10, 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.

15. The double stranded RNAi oligonucleotide (dsRNAi) of claim 14, 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.

16. The double stranded RNAi oligonucleotide (dsRNAi) of claim 14, wherein the targeting ligand is a hepatocyte targeting ligand and each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety.

17. The double stranded RNAi oligonucleotide (dsRNAi) of claim 16, wherein the N-acetylgalactosamine (GalNAc) moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety.

18. The double stranded RNAi oligonucleotide (dsRNAi) of claim 14, 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.

19. The double stranded RNAi oligonucleotide (dsRNAi) of claim 6, 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.

20. The double stranded RNAi oligonucleotide (dsRNAi) of claim 19, wherein all nucleotides of the oligonucleotide are modified, and the modification is 2′-fluoro and 2′-O-methyl.

21. The double stranded RNAi oligonucleotide (dsRNAi) of claim 19, 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.

22. The double stranded RNAi oligonucleotide (dsRNAi) of claim 21, wherein (i) the oligonucleotide comprises at least one phosphorothioate linkage, wherein (a) the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) 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′; 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′, or (ii) the antisense strand comprises a phosphorylated nucleotide at the 5′ terminus, selected from uridine and adenosine, 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, 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.

23. A double stranded RNAi oligonucleotide (dsRNAi) for reducing NR1H3 expression, 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 the sequence and all of the modifications of 5′-mCs-mU-mC-mA-mA-mG-mG-fA-fU-fU-fU-mC-mA-mG-mU-mU-mA-mU-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 963), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fUs-fAs-fU-fA-mA-fC-mU-mG-fA-mA-mA-mU-fC-mC-mU-mU-mG-mA-mGs-mGs-mG-3′ (SEQ ID NO: 1051), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

24. The double stranded RNAi oligonucleotide (dsRNAi) of claim 23, wherein the sense strand comprises the sequence and all of the modifications of 5′-mCs-mU-mC-mA-mA-mG-mG-fA-fU-fU-fU-mC-mA-mG-mU-mU-mA-mU-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 963), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fUs-fAs-fU-fA-mA-fC-mU-mG-fA-mA-mA-mU-fC-mC-mU-mU-mG-mA-mGs-mGs-mG-3′ (SEQ ID NO: 1051), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

25. The double stranded RNAi oligonucleotide (dsRNAi) of claim 23, wherein the sense strand comprises the sequence and all of the modifications of 5′-mUs-mC-mA-mA-mG-mG-mA-fU-fU-fU-fC-mA-mG-mU-mU-mA-mU-mA-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 964), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fUs-fUs-fA-fU-mA-fA-mC-mU-fG-mA-mA-mA-fU-mC-mC-mU-mU-mG-mAs-mGs-mG-3′ (SEQ ID NO: 1052), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

26. The double stranded RNAi oligonucleotide (dsRNAi) of claim 23, wherein the sense strand comprises the sequence and all of the modifications of 5′-mAs-mG-mC-mA-mG-mC-mG-fU-fC-fC-fA-mC-mU-mC-mA-mG-mA-mG-mC-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1006), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fGs-fCs-fU-fC-mU-fG-mA-mG-fU-mG-mG-mA-fC-mG-mC-mU-mG-mC-mUs-mGs-mG-3′ (SEQ ID NO: 1094), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

27. The double stranded RNAi oligonucleotide (dsRNAi) of claim 23, wherein the sense strand comprises the sequence and all of the modifications of 5′-mAs-mU-mG-mU-mG-mC-mA-fC-fG-fA-fA-mU-mG-mA-mC-mU-mG-mU-mU-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1018), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fAs-fAs-fC-fA-mG-fU-mC-mA-fU-mU-mC-mG-fU-mG-mC-mA-mC-mA-mUs-mGs-mG-3′ (SEQ ID NO: 1106), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

28. A pharmaceutical composition comprising a double stranded RNAi oligonucleotide of claim 23, and a pharmaceutically acceptable carrier, delivery agent or excipient.

29. 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 23.

30. 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 28.