Compositions and methods for modulating
Oligonucleotides and compositions including the same are disclosed that modulate (e.g., inhibit, limit or reduce) sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) activity. Methods of making and using the oligonucleotides also are disclosed, particularly uses relating to treating diseases, disorders, and/or conditions associated with SCAP activity such as nonalcoholic fatty liver disease (NAFLD), (NASH), dyslipidemia, atherosclerotic cardiovascular disease (ASCVD), and/or other SCAP-associated conditions, diseases, and/or disorders.
1 . An RNAi oligonucleotide for modulating sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) activity, the RNAi oligonucleotide comprising a sense strand forming a duplex region with an antisense strand, wherein:
the sense strand comprises a nucleotide sequence as set forth in sequence: 5′-UCAACGGUUCCCUUGAUUUAGCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 333); and
the antisense strand comprises a nucleotide sequence as set forth in sequence: 5′-UAAAUCAAGGGAACCGUUGAGG-3′ (SEQ ID NO: 334).
2 . The RNAi oligonucleotide of claim 1 , wherein the RNAi oligonucleotide comprises at least one modified nucleotide.
3 . The RNAi oligonucleotide of claim 2 , wherein the modified nucleotide comprises a 2′-modification.
4 . The RNAi oligonucleotide of claim 1 , wherein all nucleotides of the RNAi oligonucleotide are modified.
5 . The RNAi oligonucleotide of claim 1 , wherein the RNAi oligonucleotide comprises at least one modified internucleotide linkage.
6 . The RNAi oligonucleotide of claim 1 , wherein the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog.
7 . The RNAi oligonucleotide of claim 1 , wherein at least one nucleotide of the RNAi oligonucleotide is conjugated to one or more targeting ligands.
8 . The RNAi oligonucleotide of claim 7 , wherein each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety.
9 . The RNAi oligonucleotide of claim 1 wherein up to 4 nucleotides of a stem-loop of the RNAi oligonucleotide are each conjugated to a monovalent GalNAc moiety.
10 . The RNAi oligonucleotide of claim 3 , wherein the 2′-modification is a modification selected from 2′-aminoethyl, 2′-fluoro (2′-F), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).
11 . The RNAi oligonucleotide of claim 3 , wherein the 2′-modification is a modification selected from the group consisting of 2′-F and 2′-OMe.
12 . The RNAi oligonucleotide of claim 5 , wherein the at least one modified internucleotide linkage is a phosphorothioate linkage.
13 . The RNAi oligonucleotide of claim 6 , wherein the phosphate analog is oxymethylphosphonate, vinyl phosphonate or malonylphosphonate.
14 . The RNAi oligonucleotide of claim 6 , wherein the phosphate analog is a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy.
15 . The RNAi oligonucleotide of claim 8 , wherein the GalNAc moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety, or a tetravalent GalNAc moiety.
16 . The RNAi oligonucleotide of claim 7 , wherein each targeting ligand comprises a carbohydrate, ammo sugar, cholesterol, polypeptide or lipid.
17 . The RNAi oligonucleotide of claim 1 , wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 717, and the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 718.
18 . A pharmaceutical composition comprising:
(i) the RNAi oligonucleotide of claim 1 , or a pharmaceutically acceptable salt thereof; and
(ii) a pharmaceutically acceptable carrier, delivery agent or excipient.
19 . The pharmaceutical composition of claim 18 , wherein the pharmaceutically acceptable carrier comprises water.
20 . The pharmaceutical composition of claim 18 , wherein the pharmaceutically acceptable carrier comprises phosphate buffered saline.