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

• US 8,940,479 B2
• Filed: 01/14/2009
• Issued: 01/27/2015
• Est. Priority Date: 01/14/2008
• Status: Active Grant

• Current Assignee: Cornell University
• Original Assignee: Cornell University
• Inventors: Lee, Ann-Hwee, Glimcher, Laurie H.
• Primary Examiner(s): MCDONALD, JENNIFER SUE PITRAK
• Application Number:
  US12/812,811
• Publication Number:
  US 20110052669A1
• Time in Patent Office: 2,204 Days
• Field of Search: None
• US Class Current: 435/6
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: G01N 2333/4703 Regulators; Modulating activity
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 2800/044 Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity

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

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.

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.

24. The method of claim 1, 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.

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

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.

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.

16. The method of claim 2, 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.

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

35. The method of claim 2, 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.

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

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

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.

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.

17. The method of claim 3, wherein the nucleic acid molecule is a liposome:

XBP-1 siRNA complex.

21. The method of claim 3, wherein the nucleic acid molecule is a cholesterol:

XBP-1 siRNA complex.

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

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

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

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

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

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.

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.

18. The method of claim 4, wherein the nucleic acid molecule is a liposome:

XBP-1 siRNA complex.

22. The method of claim 4, wherein the nucleic acid molecule is a cholesterol:

XBP-1 siRNA complex.

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

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

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

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

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

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.

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.

19. The method of claim 5, wherein the nucleic acid molecule is a liposome:

XBP-1 siRNA complex.

23. The method of claim 5, wherein the nucleic acid molecule is a cholesterol:

XBP-1 siRNA complex.

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

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

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

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

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