Modulation of apolipoprotein C-III expression
View Patent ↗Compounds, compositions and methods are provided for modulating the expression of apolipoprotein C-III. The compositions comprise oligonucleotides, targeted to nucleic acid encoding apolipoprotein C-III. Methods of using these compounds for modulation of apolipoprotein C-III expression and for diagnosis and treatment of disease associated with expression of apolipoprotein C-III are provided.
1. A method of treating an animal having hyperlipidemia, said method comprising:
administering to an animal suffering from hyperlipidemia an antisense compound comprising an antisense oligonucleotide, wherein said antisense oligonucleotide specifically hybridizes within nucleotides 3253-3558 of SEQ ID NO:4 and consists of 15 to 30 linked nucleosides, thereby reducing hyperlipidemia in said animal.
2. A method of delaying the onset of hyperlipidemia in an animal, said method comprising:
administering to an animal at risk for developing hyperlipidemia an antisense compound comprising an antisense oligonucleotide, wherein said antisense oligonucleotide specifically hybridizes within nucleotides 3253-3558 of SEQ ID NO:4 and consists of 15 to 30 linked nucleosides, thereby delaying the onset of hyperlipidemia.
3. The method of claim 2 wherein the animal is a human.
4. A method of lowering cholesterol levels in an animal comprising:
administering to an animal in need of a reduction in cholesterol levels an antisense compound comprising an antisense oligonucleotide, wherein said antisense oligonucleotide specifically hybridizes within nucleotides 3253-3558 of SEQ ID NO:4 and consists of 15 to 30 linked nucleosides, wherein said administering results in reduced cholesterol levels in said animal.
5. The method of claim 4 wherein the animal is a human.
6. The method of claim 4 wherein the cholesterol levels are plasma cholesterol levels.
7. The method of claim 4 wherein the cholesterol levels are serum cholesterol levels.
8. A method of lowering triglyceride levels in an animal comprising:
administering to an animal in need of a reduction in triglyceride levels an antisense compound comprising an antisense oligonucleotide, wherein said antisense oligonucleotide specifically hybridizes within nucleotides 3253-3558 of SEQ ID NO:4 and consists of 15 to 30 linked nucleosides, wherein said administering results in reduced triglyceride levels in said animal.
9. The method of claim 8 wherein the animal is a human.
10. The method of claim 8 wherein the triglyceride levels are plasma triglyceride levels.
11. The method of claim 8 wherein the triglyceride levels are serum triglyceride levels.
12. The method of any one of claims 1 , 2 , 4 or 8 , wherein said antisense oligonucleotide comprises at least one modified internucleoside linkage, sugar moiety, or nucleobase.
13. The method of claim 12 , wherein said modified internucleoside linkage is a phosphorothioate linkage.
14. The method of claim 12 , wherein said modified sugar moiety is a 2′-O-methoxyethyl sugar moiety.
15. The method of claim 12 , wherein said modified nucleobase is a 5-methylcytosine.
16. The method of any one of claims 1 , 2 , 4 or 8 , wherein said antisense compound consists of an antisense oligonucleotide.
17. The method of any one of claims 1 , 2 , 4 , or 8 , wherein said antisense oligonucleotide is fully complementary to SEQ ID NO: 4.
18. The method of any one of claims 1 , 2 , 4 , or 8 , wherein said antisense oligonucleotide consists of 18, 19, 20, 21, or 22 linked nucleosides.
19. The method of any one of claims 1 , 2 , 4 , or 8 , wherein said antisense oligonucleotide consists of 20 linked nucleosides.
20. The method of any one of claims 1 , 2 , 4 , or 8 , wherein said antisense compound demonstrates a reduction in apolipoprotein C-III mRNA levels of at least 45% when applied in vitro to cultured HepG2 cells at a concentration of 50 to 300 nM.
21. The method of any one of claims 1 , 2 , 4 , or 8 , wherein said antisense oligonucleotide comprises a plurality of 2′-deoxynucleotides flanked on each side by at least one 2′-O-methoxyethyl nucleotide.
22. The method of claim 1 , wherein said animal is a human.
23. The method of claim 1 , 2 , 4 , or 8 , wherein said antisense oligonucleotide specifically hybridizes within nucleotides 3253-3380, 3417-3445, 3445-3491, or 3509-3558 of SEQ ID NO: 4.
24. The method of claim 1 , 2 , 4 , or 8 , wherein said antisense oligonucleotide consists of:
a gap segment consisting often linked 2′-deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar moiety, and wherein each internucleoside linkage is a phosphorothioate linkage.
25. The method of claim 24 , wherein said antisense oligonucleotide comprises at least one cytosine that is a 5-methylcytosine.
26. The method of claim 25 , wherein each cytosine is a 5-methylcytosine.
27. The method of claim 26 , wherein the antisense oligonucleotide is fully complementary to SEQ ID NO: 4.
28. The method of claim 1 , 2 , 4 , or 8 , further comprising measuring serum apolipoprotein C-III levels in the serum of said animal.