IP Library › Granted Patent US 8,940,479
Granted Patent B2
US 8,940,479 · App. 12/812,811 · Granted Jan 27, 2015

Methods for modulating de novo hepatic lipogenesis by modulating XBP-1 activity

Inventors: Ann-Hwee Lee (Chestnut Hill, MA); Laurie H. Glimcher (New York, NY)
Assignee: Cornell University
A61K31/70C12N15/113C12N2310/14G01N2333/4703G01N2500/04G01N2800/044
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Quick Facts
Patent No.
US 8,940,479
App. No.
12/812,811
Granted
Jan 27, 2015
Kind
B2
Abstract

The invention provides methods and compositions for modulating the expression, processing, post-translational modification, stability and/or activity of XBP-1 protein, or a protein in a signal transduction pathway involving XBP-I to treat dyslipidemias and steatosis disorders. The present invention also pertains to methods for identifying compounds that modulate the expression, processing, post-translational modification, and/or activity of XBP-I protein or a molecule in a signal transduction pathway involving XBP-1.

Claims (50)

1. A method of treating hyperlipidemia comprising administering a nucleic acid molecule that downmodulates XBP-1 gene expression to a subject having hyperlipidemia in an amount sufficient to downmodulate de novo hepatic lipogenesis, to thereby treat hyperlipidemia in the subject.

2. A method of treating atherosclerosis comprising administering a nucleic acid molecule that downmodulates XBP-1 gene expression to a subject having atherosclerosis in an amount sufficient to downmodulate de novo hepatic lipogenesis, to thereby treat atherosclerosis in the subject.

3. A method of treating hepatic steatosis comprising administering a nucleic acid molecule that downmodulates XBP-1 gene expression to a subject having hepatic steatosis in an amount sufficient to downmodulate de novo hepatic lipogenesis, to thereby treat hepatic steatosis in the subject.

4. A method of treating steatohepatitis comprising administering a nucleic acid molecule that downmodulates XBP-1 gene expression to a subject having steatohepatitis in an amount sufficient to downmodulate de novo hepatic lipogenesis, to thereby treat steatohepatitis in the subject.

5. A method of treating non-alcoholic hepatic steatohepatitis comprising administering a nucleic acid molecule that downmodulates XBP-1 gene expression to a subject having non-alcoholic hepatic steatohepatitis in an amount sufficient to downmodulate de novo hepatic lipogenesis, to thereby treat non-alcoholic hepatic steatohepatitis in the subject.

6. The method of claim 1 , wherein the nucleic acid molecule is selected from the group consisting of: a nucleic acid molecule that is antisense to a XBP-1 molecule, a XBP-1 siRNA molecule, a nucleic acid molecule encoding a dominant negative XBP-1 molecule, or combinations thereof.

7. The method of claim 1 , wherein the nucleic acid molecule is a liposome:XBP-1 siRNA complex.

8. The method of claim 1 , wherein the nucleic acid molecule is a cholesterol:XBP-1 siRNA complex.

9. The method of claim 7 , wherein the complex is administered at a dose of about 1-2.5 mg/kg.

10. The method of claim 1 , further comprising administering to the subject a hypolipidemic agent.

11. The method of claim 10 , wherein the hypolipidemic agent is a statin.

12. The method of claim 2 , wherein the nucleic acid molecule is selected from the group consisting of: a nucleic acid molecule that is antisense to a XBP-1 molecule, a XBP-1 siRNA molecule, a nucleic acid molecule encoding a dominant negative XBP-1 molecule, or combinations thereof.

13. The method of claim 3 , wherein the nucleic acid molecule is selected from the group consisting of: a nucleic acid molecule that is antisense to a XBP-1 molecule, a XBP-1 siRNA molecule, a nucleic acid molecule encoding a dominant negative XBP-1 molecule, or combinations thereof.

14. The method of claim 4 , wherein the nucleic acid molecule is selected from the group consisting of: a nucleic acid molecule that is antisense to a XBP-1 molecule, a XBP-1 siRNA molecule, a nucleic acid molecule encoding a dominant negative XBP-1 molecule, or combinations thereof.

15. The method of claim 5 , wherein the nucleic acid molecule is selected from the group consisting of: a nucleic acid molecule that is antisense to a XBP-1 molecule, a XBP-1 siRNA molecule, a nucleic acid molecule encoding a dominant negative XBP-1 molecule, or combinations thereof.

16. The method of claim 2 , wherein the nucleic acid molecule is a liposome:XBP-1 siRNA complex.

17. The method of claim 3 , wherein the nucleic acid molecule is a liposome:XBP-1 siRNA complex.

18. The method of claim 4 , wherein the nucleic acid molecule is a liposome:XBP-1 siRNA complex.

19. The method of claim 5 , wherein the nucleic acid molecule is a liposome:XBP-1 siRNA complex.

20. The method of claim 2 , wherein the nucleic acid molecule is a cholesterol:XBP-1 siRNA complex.

21. The method of claim 3 , wherein the nucleic acid molecule is a cholesterol:XBP-1 siRNA complex.

22. The method of claim 4 , wherein the nucleic acid molecule is a cholesterol:XBP-1 siRNA complex.

23. The method of claim 5 , wherein the nucleic acid molecule is a cholesterol:XBP-1 siRNA complex.

24. The method of claim 1 , wherein the nucleic acid molecule is a XBP-1 siRNA molecule.

25. The method of claim 2 , wherein the nucleic acid molecule is a XBP-1 siRNA molecule.

26. The method of claim 3 , wherein the nucleic acid molecule is a XBP-1 siRNA molecule.

27. The method of claim 4 , wherein the nucleic acid molecule is a XBP-1 siRNA molecule.

28. The method of claim 5 , wherein the nucleic acid molecule is a XBP-1 siRNA molecule.

29. The method of claim 1 , wherein the nucleic acid molecule is a nucleic acid molecule that is antisense to a XBP-1 molecule.

30. The method of claim 2 , wherein the nucleic acid molecule is a nucleic acid molecule that is antisense to a XBP-1 molecule.

31. The method of claim 3 , wherein the nucleic acid molecule is a nucleic acid molecule that is antisense to a XBP-1 molecule.

32. The method of claim 4 , wherein the nucleic acid molecule is a nucleic acid molecule that is antisense to a XBP-1 molecule.

33. The method of claim 5 , wherein the nucleic acid molecule is a nucleic acid molecule that is antisense to a XBP-1 molecule.

34. The method of claim 1 , wherein the nucleic acid molecule is a nucleic acid molecule encoding a dominant negative XBP-1 molecule.

35. The method of claim 2 , wherein the nucleic acid molecule is a nucleic acid molecule encoding a dominant negative XBP-1 molecule.

36. The method of claim 3 , wherein the nucleic acid molecule is a nucleic acid molecule encoding a dominant negative XBP-1 molecule.

37. The method of claim 4 , wherein the nucleic acid molecule is a nucleic acid molecule encoding a dominant negative XBP-1 molecule.

38. The method of claim 5 , wherein the nucleic acid molecule is a nucleic acid molecule encoding a dominant negative XBP-1 molecule.

39. The method of claim 16 , wherein the complex is administered at a dose of about 1-2.5 mg/kg.

40. The method of claim 17 , wherein the complex is administered at a dose of about 1-2.5 mg/kg.

41. The method of claim 18 , wherein the complex is administered at a dose of about 1-2.5 mg/kg.

42. The method of claim 19 , wherein the complex is administered at a dose of about 1-2.5 mg/kg.

43. The method of claim 2 , further comprising administering to the subject a hypolipidemic agent.

44. The method of claim 3 , further comprising administering to the subject a hypolipidemic agent.

45. The method of claim 4 , further comprising administering to the subject a hypolipidemic agent.

46. The method of claim 5 , further comprising administering to the subject a hypolipidemic agent.

47. The method of claim 43 , wherein the hypolipidemic agent is a statin.

48. The method of claim 44 , wherein the hypolipidemic agent is a statin.

49. The method of claim 45 , wherein the hypolipidemic agent is a statin.

50. The method of claim 46 , wherein the hypolipidemic agent is a statin.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 11, 2013
From: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
To: CORNELL UNIVERSITY
Reel/Frame 030778/0677 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 14, 2010
From: GLIMCHER, LAURIE; LEE, ANN-HWEE
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 024984/0123 →
CONFIRMATORY LICENSE Recorded Aug 11, 2010
From: HARVARD UNIVERSITY
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 024825/0080 →
Continuity (3)
Provisional Application 61011070 · Jan 14, 2008
Provisional Application 61191049 · Sep 5, 2008
Related Publication 20110052669A1 · Mar 3, 2011