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 inhibiting the expression of apolipoprotein C-III in cells or tissues comprising contacting said cells or tissues with a compound 10 to 25 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein C-III, wherein said compound specifically hybridizes with a 5′ untranslated region or coding region of said nucleic acid molecule encoding apolipoprotein C-III (SEQ ID NO: 4), so that expression of apolipoprotein C-III is inhibited by at least 45%.
2. A method of treating an animal having a disease or condition associated with apolipoprotein C-III or delaying the onset of a disease or condition associated with apolipoprotein C-III in an animal comprising administering to said animal a therapeutically or prophylactically effective amount of a compound 10 to 25 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein C-III, wherein said compound specifically hybridizes with a 5′ untranslated region or coding region of said nucleic acid molecule encoding apolipoprotein C-III (SEQ ID NO: 4), so that expression of apolipoprotein C-III is inhibited by at least 45%, thereby treating an animal having a disease or condition associated with apolipoprotein C-III or delaying the onset of a disease or condition associated with apolipoprotein C-III in an animal.
3. The method of claim 2 , wherein the condition involves abnormal lipid metabolism, abnormal cholesterol metabolism, atherosclerosis, abnormal metabolic condition, hyperlipidemia, diabetes, Type 2 diabetes, obesity, hypertriglyceridemia, and/or cardiovascular disease.
4. A method of modulating glucose levels in an animal comprising administering to said animal a compound 10 to 25 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein C-III, wherein said compound specifically hybridizes with a 5′ untranslated region or coding region of said nucleic acid molecule encoding apolipoprotein C-III (SEQ ID NO: 4), so that expression of apolipoprotein C-III is inhibited by at least 45%, thereby modulating glucose levels in an animal.
5. The method of claim 4 , wherein serum glucose levels are reduced.
6. The method of claim 4 , wherein fasted serum insulin levels in an animal are decreased.
7. The method of claim 1 , wherein the compound is 20 nucleobases in length.
8. The method of claim 1 , wherein the compound is 20 nucleotides in length, comprising ten 2′-deoxynucleotides, flanked on each side by five 2′-methoxyethyl nucleotides, wherein all internucleoside linkages are phosphorothioate, and all cytosine residues are 5-methylcytosines.
9. The method of claim 1 , wherein the compound comprises at least one modified internucleoside linkage, sugar moiety, or nucleobase.
10. The method of claim 1 , wherein the compound comprises at least one 2′-O-methoxyethyl sugar moiety.
11. The method of claim 1 , wherein the compound comprises at least one phosphorothioate internucleoside linkage.
12. The method of claim 1 , wherein the compound comprises at least one 5-methylcytosine.
13. The method of claim 2 , wherein the compound is 20 nucleobases in length.
14. The method of claim 2 , wherein the compound is 20 nucleotides in length, comprising ten 2′-deoxynucleotides, flanked on each side by five 2′-methoxyethyl nucleotides, wherein all internucleoside linkages are phosphorothioate, and all cytosine residues are 5-methylcytosines.
15. The method of claim 2 , wherein the compound comprises at least one modified internucleoside linkage, sugar moiety, or nucleobase.
16. The method of claim 2 , wherein the compound comprises at least one 2′-O-methoxyethyl sugar moiety.
17. The method of claim 2 , wherein the compound comprises at least one phosphorothioate internucleoside linkage.
18. The method of claim 2 , wherein the compound comprises at least one 5-methylcytosine.
19. The method of claim 4 , wherein the compound is 20 nucleobases in length.
20. The method of claim 4 , wherein the compound is 20 nucleotides in length, comprising ten 2′-deoxynucleotides, flanked on each side by five 2′-methoxyethyl nucleotides, wherein all internucleoside linkages are phosphorothioate, and all cytosine residues are 5-methylcytosines.
21. The method of claim 4 , wherein the compound comprises at least one modified internucleoside linkage, sugar moiety, or nucleobase.
22. The method of claim 4 , wherein the compound comprises at least one 2′-O-methoxyethyl sugar moiety.
23. The method of claim 4 , wherein the compound comprises at least one phosphorothioate internucleoside linkage.
24. The method of claim 4 , wherein the compound comprises at least one 5-methylcytosine.
25. A method of inhibiting the expression of apolipoprotein C-III in cells or tissues comprising contacting said cells or tissues with a compound 10 to 25 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein C-III, wherein said compound comprises at least an 8 consecutive nucleobase portion of SEQ ID NO:19, 20, 21, 22, 23, 25, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96, and wherein said compound specifically hybridizes with said nucleic acid molecule encoding apolipoprotein C-III, so that expression of apolipoprotein C-III is inhibited.
26. A method of treating an animal having a disease or condition associated with apolipoprotein C-III or delaying the onset of a disease or condition associated with apolipoprotein C-III in an animal comprising administering to said animal a therapeutically or prophylactically effective amount of a compound 10 to 25 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein C-III, wherein said compound comprises at least an 8 consecutive nucleobase portion of SEQ ID NO:19, 20, 21, 22, 23, 25, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96, and wherein said compound specifically hybridizes with said nucleic acid molecule encoding apolipoprotein C-III, so that expression of apolipoprotein C-III is inhibited, thereby treating an animal having a disease or condition associated with apolipoprotein C-III or delaying the onset of a disease or condition associated with apolipoprotein C-III in an animal.
27. The method of claim 26 , wherein the condition involves abnormal lipid metabolism, abnormal cholesterol metabolism, atherosclerosis, abnormal metabolic condition, hyperlipidemia, diabetes, Type 2 diabetes, obesity, hypertriglyceridemia, and/or cardiovascular disease.
28. A method of modulating glucose levels in an animal comprising administering to said animal a compound 10 to 25 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein C-III, wherein said compound comprises at least an 8 consecutive nucleobase portion of SEQ ID NO:19, 20, 21, 22, 23, 25, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96, and wherein said compound specifically hybridizes with said nucleic acid molecule encoding apolipoprotein C-III, so that expression of apolipoprotein C-III is inhibited, thereby modulating glucose levels in an animal.
29. The method of claim 28 , wherein serum glucose levels are reduced.
30. The method of claim 28 , wherein fasted serum insulin levels in an animal are decreased.
31. The method of claim 25 , wherein the compound is 20 nucleobases in length.
32. The method of claim 25 , wherein the compound is 20 nucleotides in length, comprising ten 2′-deoxynucleotides, flanked on each side by five 2′-methoxyethyl nucleotides, wherein all internucleoside linkages are phosphorothioate, and all cytosine residues are 5-methylcytosines.
33. The method of claim 25 , wherein the compound comprises at least one modified internucleoside linkage, sugar moiety, or nucleobase.
34. The method of claim 25 , wherein the compound comprises at least one 2′-O-methoxyethyl sugar moiety.
35. The method of claim 25 , wherein the compound comprises at least one phosphorothioate internucleoside linkage.
36. The method of claim 25 , wherein the compound comprises at least one 5-methylcytosine.
37. The method of claim 26 , wherein the compound is 20 nucleobases in length.
38. The method of claim 26 , wherein the compound is 20 nucleotides in length, comprising ten 2′-deoxynucleotides, flanked on each side by five 2′-methoxyethyl nucleotides, wherein all internucleoside linkages are phosphorothioate, and all cytosine residues are 5-methylcytosines.
39. The method of claim 26 , wherein the compound comprises at least one modified internucleoside linkage, sugar moiety, or nucleobase.
40. The method of claim 26 , wherein the compound comprises at least one 2′-O-methoxyethyl sugar moiety.
41. The method of claim 26 , wherein the compound comprises at least one phosphorothioate internucleoside linkage.
42. The method of claim 26 , wherein the compound comprises at least one 5-methylcytosine.
43. The method of claim 28 , wherein the compound is 20 nucleobases in length.
44. The method of claim 28 , wherein the compound is 20 nucleotides in length, comprising ten 2′-deoxynucleotides, flanked on each side by five 2′-methoxyethyl nucleotides, wherein all internucleoside linkages are phosphorothioate, and all cytosine residues are 5-methylcytosines.
45. The method of claim 28 , wherein the compound comprises at least one modified internucleoside linkage, sugar moiety, or nucleobase.
46. The method of claim 28 , wherein the compound comprises at least one 2′-O-methoxyethyl sugar moiety.
47. The method of claim 28 , wherein the compound comprises at least one phosphorothioate internucleoside linkage.
48. The method of claim 28 , wherein the compound comprises at least one 5-methylcytosine.