Methods for modulating expression of RBP4
Methods are provided for modulating RBP4 by administering a RBP4-specific modulator. Also provided are methods for treating cardiovascular and metabolic disorders in a subject or delaying or preventing risk factors thereof through the modulation of RBP4. The present invention is also directed to methods of decreasing lipid levels in a subject or for preventing or delaying the onset of a rise in lipid levels in a subject, comprising administering to said subject a RBP4-specific inhibitor.
1. A method of treating or ameliorating a cardiovascular disease in an animal diagnosed as having cardiovascular disease, comprising administering to the animal a therapeutically effective amount of a Retinol-Binding Protein 4 (RBP4) inhibitor, wherein the RBP4 inhibitor is a nucleic acid capable of inhibiting RBP4 by at least 24%, thereby treating or ameliorating the cardiovascular disease in the animal.
2. The method of claim 1 , wherein the cardiovascular disease is obesity, atherosclerosis, dyslipidemia, coronary heart disease, or a combination thereof.
3. The method of claim 2 , wherein the dyslipidemia is hyperlipidemia.
4. The method of claim 3 , wherein the hyperlipidemia is hypercholesterolemia.
5. The method of claim 1 , wherein the administering results in a reduction of cholesterol levels.
6. A method of decreasing cholesterol levels in a human diagnosed as being in need of decreasing cholesterol levels comprising administering a Retinol-Binding Protein 4 (RBP4) inhibitor to the human diagnosed as being in need of decreasing cholesterol levels, wherein the RBP4 inhibitor is a nucleic acid capable of inhibiting RBP4 by at least 24%, thereby decreasing cholesterol levels in the human.
7. The method of claim 6 , wherein the nucleic acid is a modified oligonucleotide.
8. The method of claim 7 , wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides.
9. The method of claim 8 , wherein said modified oligonucleotide is a single-stranded oligonucleotide.
10. The method of claim 9 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to human RBP4.
11. The method of claim 9 , wherein at least one internucleoside linkage is a modified internucleoside linkage.
12. The method of claim 11 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
13. The method of claim 9 , wherein at least one nucleoside contains a modified sugar.
14. The method of claim 13 , wherein the modified sugar comprises a 2′-O-methoxyethyl sugar moiety.
15. The method of claim 13 , wherein the modified sugar is a bicyclic nucleic acid sugar moiety.
16. The method of claim 9 , wherein at least one nucleoside comprises a modified nucleobase.
17. The method of claim 15 , wherein the bicyclic nucleic acid sugar moiety comprises a 4′-CH(CH3)-O-2′ bridge.
18. The method of claim 1 , wherein the administering comprises parenteral administration.
19. The method of claim 18 , wherein the parenteral administration comprises subcutaneous or intravenous administration.
20. The method of claim 1 , comprising co-administering the RBP4 inhibitor and at least one additional therapy.
21. The method of claim 20 , wherein the RBP4 inhibitor and the additional therapy are administered concomitantly.
22. The method of claim 20 , wherein the RBP4 inhibitor and the additional therapy are administered in the same formulation.
23. A method comprising identifying an animal having a cardiovascular disease and administering to said animal a therapeutically effective amount of a composition comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence complementary to SEQ ID NO: 1, 2, 3, 4, 5, 6 or 7 as measured over the entirety of said modified oligonucleotide, wherein the modified oligonucleotide is capable of inhibiting Retinol-Binding Protein 4 (RBP4) by at least 24%, thereby treating the cardiovascular disease.
24. The method of claim 16 , wherein the modified nucleobase is a 5-methylcytosine.
25. The method of claim 9 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleotides;
a 5′ wing segment consisting of linked nucleosides; and
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, and wherein each nucleoside of each wing segment comprises a modified sugar.
26. The method of claim 25 , wherein the oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides; and
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, wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage, and wherein each cytosine in said modified oligonucleotide is a 5-methylcytosine.
27. The method of claim 1 , wherein the animal is a human.
28. The method of claim 23 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.
29. The method of claim 28 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
30. The method of claim 23 , wherein at least one nucleoside of the modified oligonucleotide contains a modified sugar.
31. The method of claim 30 , wherein the modified sugar comprises a 2′-O-methoxyethyl sugar moiety.
32. The method of claim 31 , wherein the modified sugar is a bicyclic nucleic acid sugar moiety.
33. The method of claim 32 , wherein the bicyclic nucleic acid sugar moiety comprises a 4′-CH(CH3)-O-2′ bridge.
34. The method of claim 23 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified nucleobase.
35. The method of claim 1 , wherein the nucleic acid comprises a modification selected from the group consisting of a modified internucleoside linkage, a modified sugar moiety, and a modified nucleobase.