Organic compositions to treat APOC3-related diseases
The present disclosure relates to compositions and methods for treating APOC3-related diseases such as: hypertriglyceridemia (e.g., Type V Hypertriglyceridemia), abnormal lipid metabolism, abnormal cholesterol metabolism, atherosclerosis, hyperlipidemia, diabetes, including Type 2 diabetes, obesity, cardiovascular disease, and coronary artery disease, among other disorders relating to abnormal metabolism or otherwise, using a therapeutically effective amount of a RNAi agent to APOC3.
1. A double-stranded RNAi agent for inhibiting expression of an APOC3 gene in a cell, comprising a first strand and a second strand, wherein said first strand is less than 30 nucleotides in length and comprises SEQ ID NO: 132, wherein the second strand is substantially complementary to the first strand, and wherein the 3′ end of the first strand terminates in a phosphate or modified internucleoside linker and further comprises, in 5′ to 3′ order: a spacer, a second phosphate or modified internucleoside linker, and a 3′ end cap.
2. The RNAi agent of claim 1 , wherein the first strand comprises at least one modified nucleotide or modified internucleoside linkage.
3. The RNAi agent of claim 2 , wherein the first strand and the second strand form a duplex region of about 15 to about 30 nucleotide base pairs.
4. The RNAi agent of claim 2 , wherein one or more nucleotides of the first strand or the second strand has been replaced by a spacer.
5. The RNAi agent of claim 2 , wherein the first strand comprises at least one 2′-modified nucleotide or modified phosphorothioate linkage.
6. The RNAi agent of claim 3 , wherein the spacer is selected from a sugar, alkyl, cycloalkyl, ribitol, 2′-deoxy-ribitol, diribitol, 2′-methoxyethoxy-ribitol, C3 [—(CH 2 ) 3 —], C4 [—(cH 2 ) 4 —, C5 [—(cH 2 ) 5 —, C6 [—(cH 2 ) 6 —, or 4-methoxybutane-1,3-diol.
7. The RNAi agent of claim 2 , wherein the RNAi agent is ligated to one or more diagnostic compound, reporter group, cross-linking agent, nuclease-resistance conferring moiety, natural or unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer, low- or medium-molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-binding agent, integrin-targeting molecule, polycationic, peptide, polyamine, peptide mimic, and/or transferrin.
8. The RNAi agent of claim 7 , wherein the RNAi agent is ligated to one or more carbohydrates.
9. The RNAi agent of claim 8 , wherein the carbohydrate comprises N-Acetylgalactosamine (GalNAc).
10. The RNAi agent of claim 9 , wherein the RNAi agent is ligated to an N-Acetylgalactosamine conjugate that comprises the structure represented by X1053:
11. The RNAi agent of claim 2 , wherein the 3′ end cap comprises:
wherein,
X is the 3′ end of the first strand of the RNAi agent;
q is 0, 1 or 2;
R 6 is phenyl which is unsubstituted or substituted with a group selected from benzoxy and 3,4-dihydroxybutyl;
R 7 is hydrogen or hydroxy-ethyl, wherein if R 7 is hydroxy-ethyl, the hydroxyl can be optionally functionalized as succinate or attached to a solid support;
R s is hydrogen or methoxy;
Y 1 is CH or N; and
Y 2 is N or CR 9 ; wherein R 9 is selected from hydrogen and methyl.
12. A pharmaceutical composition comprising one or more RNAi agents of claim 1 , and at least one pharmaceutically acceptable excipient.
13. A method of treating an APOC3-related disease in a subject, comprising administering to the subject a therapeutically effective amount of an RNAi agent of claim 1 .
14. The method of claim 13 , wherein the subject is a human and the APOC3-related disease is hypertriglyceridemia (e.g., Type V Hypertriglyceridemia), abnormal lipid metabolism, abnormal cholesterol metabolism, atherosclerosis, hyperlipidemia, diabetes, obesity, cardiovascular disease, or coronary artery disease.
15. The method of claim 13 , wherein the method further comprises administering an additional treatment.
16. The method of claim 15 , wherein the additional treatment comprises a second RNAi agent to APOC3.
17. A method of inhibiting the expression of APOC3 in a cell, comprising administering an RNAi agent according to claim 1 in an amount sufficient to inhibit expression of APOC3 in the cell.
18. A cell or vector containing the RNAi agent of claim 1 .