High density lipoprotein binding protein (Hdlbp/Vigilin) iRNA compositions and methods of use thereof
The invention relates to double stranded ribonucleic acid (dsRNA) agents and compositions targeting a High Density Lipoprotein Binding Protein (Hdlbp/Vigilin) gene, as well as methods of inhibiting expression of Hdlbp/Vigilin and methods of treating subjects having a disorder of lipid metabolism, such as mixed hyperlipidemia, hypertriglyceridemia or hypercholesterolemia, using such dsRNA agents and compositions.
1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a High Density Lipoprotein Binding Protein (Hdlbp/Vigilin) gene, wherein said dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of any one of nucleotides 373-395; 374-396; 381-403; 395-417; 440-462; 670-692; 852-874; 888-910; 905-927; 913-935; 1223-1245; 1246-1268; 1247-1269; 1248-1270; 1256-1278; 1267-1289; 1801-1823; 1908-1930; 1916-1938; 1919-1941; 2023-2045; 2071-2093; 2127-2149; 2128-2150; 2136-2158; 2137-2159; 2138-2160; 2225-2247; 2231-2253; 2232-2254; 2240-2262; 2242-2264; 2243-2265; 2245-2267; 2543-2565; 2544-2566; 2549-2571; 3017-3039; 3088-3110; 4271-4293; 4404-4426; 4405-4427; 4408-4430; 4411-4433; or 4416-4438 of the nucleotide sequence of SEQ ID NO:5, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the corresponding nucleotide sequence of SEQ ID NO:11.
2. The dsRNA agent of claim 1 , wherein said dsRNA agent comprises at least one nucleotide comprising a nucleotide modification.
3. The dsRNA agent of a claim 1 , wherein substantially all of the nucleotides of said sense strand and substantially all of the nucleotides of said antisense strand comprise a nucleotide modification; or all of the nucleotides of said sense strand and all of the nucleotides of said antisense strand comprise a nucleotide modification.
4. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a High Density Lipoprotein Binding Protein (Hdlbp/Vigilin) gene, wherein said dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of any one of nucleotides 373-395; 374-396; 381-403; 395-417; 440-462; 670-692; 852-874; 888-910; 905-927; 913-935; 1223-1245; 1246-1268; 1247-1269; 1248-1270; 1256-1278; 1267-1289; 1801-1823; 1903-1925; 1908-1930; 1916-1938; 1919-1941; 2023-2045; 2071-2093; 2127-2149; 2128-2150; 2136-2158; 2137-2159; 2138-2160; 2225-2247; 2231-2253; 2232-2254; 2240-2262; 2242-2264; 2243-2265; 2245-2267; 2543-2565; 2544-2566; 2549-2571; 3017-3039; 3088-3110; 4271-4293; 4404-4426; 4405-4427; 4408-4430; 4411-4433; or 4416-4438 of the nucleotide sequence of SEQ ID NO:5, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the corresponding nucleotide sequence of SEQ ID NO:11,
wherein substantially all of the nucleotides of said sense strand and substantially all of the nucleotides of said antisense strand comprise a nucleotide modification, and
wherein said sense strand is conjugated to a ligand attached at the 3′-terminus.
5. The dsRNA agent of claim 4 , wherein all of the nucleotides of said sense strand and all of the nucleotides of said antisense strand comprise a nucleotide modification.
6. The dsRNA agent of claim 1 or 4 , wherein the sense strand and the antisense strand are each independently 17-25 nucleotides in length.
7. The dsRNA agent of claim 1 or 4 , wherein the sense strand and the antisense strand are each independently no more than 30 nucleotides in length.
8. The dsRNA agent of claim 1 or 4 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or at least one strand comprises a 3′ overhang of at least 2 nucleotides.
9. The dsRNA agent of claim 1 , further comprising a ligand.
10. The dsRNA agent of claim 1 or 4 , wherein said agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.
11. A cell containing the double stranded RNAi agent of claim 1 or 4 .
12. A pharmaceutical composition for inhibiting expression of an Hdlbp/Vigilin gene comprising the double stranded RNAi agent of claim 1 or 4 .
13. A method of inhibiting expression of a High Density Lipoprotein Binding Protein (Hdlbp/Vigilin) gene in a cell, the method comprising:
(a) contacting the cell with the double stranded RNAi agent of claim 1 or 4 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of an Hdlbp/Vigilin gene, thereby inhibiting epression of the Hdlbp/Vigilin gene in the cell.
14. The method of claim 13 , wherein said cell is within a subject.
15. A method of treating a subject having a disorder that would benefit from a reduction in expression of a High Density Lipoprotein Binding Protein (Hdlbp/Vigilin) gene, comprising administering to the subject a therapeutically effective amount of the double stranded RNAi agent of claim 1 or 4 , thereby treating said subject.
16. The method of claim 14 or 15 , wherein the subject is human.
17. The method of claim 15 , wherein the disorder is a disorder of lipid metabolism.
18. The method of claim 17 , wherein the disorder of lipid metabolism is a hyperlipidemia.
19. The method of claim 15 , further comprising administering an additional therapeutic agent to the subject.
20. The method of claim 15 , wherein the double stranded RNAi agent is administered to the subject at a dose of about 0.01 mg/kg to about 50 mg/kg.
21. The method of claim 15 , wherein the double stranded RNAi agent is administered to the subject subcutaneously.
22. The dsRNA agent of claim 1 or 4 , wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5′-UAUGAUAAUGGUCUCUGAAUUGC-3′ (SEQ ID NO:104).
23. The dsRNA agent of claim 1 or 4 , wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence 5′-AAUUCAGAGACCAUUAUCAUA-3′ (SEQ ID NO:58).
24. The dsRNA agent of claim 23 , wherein the sense strand comprises the nucleotide sequence 5′-AAUUCAGAGACCAUUAUCAUA-3′ (SEQ ID NO:58) and the antisense strand comprises the nucleotide sequence of 5′-UAUGAUAAUGGUCUCUGAAUUGC-3 ‘ (SEQ ID NO:104).
25. The dsRNA agent of claim 24 , wherein the sense strand comprises the nucleotide sequence 5’-asasuucaGfaGfAfCfcauuaucaua-3′ (SEQ ID NO:150) and the antisense strand comprises the nucleotide sequence of 5′-usAfsugaUfaAfUfggucUfcUfgaauusgsc-3′ (SEQ ID NO:196),
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U; dT is 2′-deoxythymidine; and s is a phosphorothioate linkage.