Compositions and methods for silencing apolipoprotein C-III expression
The present invention provides compositions comprising therapeutic nucleic acids such as interfering RNA that target apolipoprotein C-III (APOC3) gene expression, lipid particles comprising one or more (e.g., a cocktail) of the therapeutic nucleic acids, methods of making the lipid particles, and methods of delivering and/or administering the lipid particles (e.g., for the treatment of lipid diseases or disorders such as atherosclerosis or a dyslipidemia such as hypertriglyceridemia or hypercholesterolemia).
1. A composition comprising a small-interfering RNA (siRNA) that silences apolipoprotein C-III (APOC3) gene expression, wherein the siRNA comprises a sense strand and a complementary antisense strand, and wherein the siRNA comprises a double-stranded region of about 19 to about 25 nucleotides in length, and wherein the antisense strand comprises a sequence set forth in SEQ ID NO:770 and/or wherein the sense strand comprises a sequence set forth in SEQ ID NO:769.
2. The composition of claim 1 , wherein the antisense strand and/or sense strand comprises at least one modified nucleotide in the double-stranded region.
3. The composition of claim 2 , wherein less than about 30% of the nucleotides in the double-stranded region comprise modified nucleotides.
4. The composition of claim 2 , wherein the modified nucleotide is a 2′-O-methyl (2′OMe) nucleotide.
5. A nucleic acid-lipid particle comprising:
(a) an siRNA of claim 1 ;
(b) a cationic lipid; and
(c) a non-cationic lipid.
6. The nucleic acid-lipid particle of claim 5 , wherein the non-cationic lipid is a mixture of a phospholipid and cholesterol or a derivative thereof.
7. The nucleic acid-lipid particle of claim 5 , further comprising a conjugated lipid that inhibits aggregation of particles.
8. A method for introducing an siRNA that silences APOC3 gene expression into a cell, the method comprising:
contacting the cell with a nucleic acid-lipid particle of claim 5 .
9. A method for silencing APOC3 gene expression in a mammal in need thereof, the method comprising:
administering to the mammal a nucleic acid-lipid particle of claim 5 .
10. A method for the in vivo delivery of an siRNA that silences APOC3 gene expression, the method comprising:
administering to a mammal a nucleic acid-lipid particle of claim 5 .
11. A method for treating and/or ameliorating one or more symptoms associated with atherosclerosis or dyslipidemia in a mammal in need thereof, the method comprising:
administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle of claim 5 .
12. A method for reducing susceptibility to atherosclerosis or dyslipidemia in a mammal in need thereof, the method comprising:
administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle of claim 5 .
13. A method for preventing or delaying the onset of atherosclerosis or dyslipidemia in a mammal in need thereof, the method comprising:
administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle of claim 5 .
14. A method for lowering triglyceride levels in a mammal in need thereof, the method comprising:
administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle of claim 5 .
15. A method for lowering cholesterol levels in a mammal in need thereof, the method comprising:
administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle of claim 5 .