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, wherein the siRNA comprises a double-stranded region of about 19 to about 25 nucleotides in length, and wherein the antisense strand comprises a 2′OMe-modified sequence set forth in SEQ ID NOS:3-58 and/or wherein the sense strand comprises a 2′OMe-modified sequence set forth in SEQ ID NOS:59-110.
2. A nucleic acid-lipid particle comprising:
(a) an siRNA of claim 1 ;
(b) a cationic lipid; and
(c) a non-cationic lipid.
3. The nucleic acid-lipid particle of claim 2 , wherein the non-cationic lipid is a mixture of a phospholipid and cholesterol or a derivative thereof.
4. The nucleic acid-lipid particle of claim 2 , further comprising a conjugated lipid that inhibits aggregation of particles.
5. 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 2 .
6. 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 2 .
7. 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 2 .
8. 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 2 .
9. 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 2 .
10. 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 2 .
11. 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 2 .
12. 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 2 .