Methods of inducing regulated pancreatic hormone production in non-pancreatic islet tissues

• US 20050090465A1
• Filed: 05/12/2004
• Published: 04/28/2005
• Est. Priority Date: 06/01/1999
• Status: Active Grant

• Current Assignee: Tel Hashomer Medical Research Infrastructure And Services Ltd.
• Original Assignee: Sarah Ferber
• Inventors: Ferber, Sarah
• Granted Patent: US 8,778,899 B2
• Time in Patent Office: Days
• US Class Current: 514/44.00A
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: C12N 15/85 for animal cells
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/10343 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2830/008 cell type or tissue specific enhancer/promoter combination
• CPC Class Codes: C12N 2830/85 mammalian

Abstract

Disclosed are methods and pharmaceutical compositions for inducing pancreatic hormone production.

Claims

1. A method of inducing endogenous PDX-1 expression in a cell, said method comprising introducing to said cell a composition comprising a PDX-1 inducer compound, in an amount sufficient to induce said endogenous PDX-1 expression in said cell.

2. The method of claim 1, wherein said PDX-1 inducer compound comprises a nucleic acid encoding a pancreatic and duodenal homobox 1 (PDX-1) polypeptide, a neuroD polypeptide or a betacellulin polypeptide

3. The method of claim 2, wherein said nucleic acid is operably linked to a promoter.

4. The method of claim 2, wherein said promoter is a cytomegalovirus (CMV) promoter, a BOS promoter, a transthyretin promoter, a glucose 6-phosphatase promoter, an albumin intestinal fatty acid binding protein promoter, a thyroglobulin promoter, a surfactant A promoter, a surfactant c promoter or a phosphoglycerate kinase 1 promoter.

5. The method of claim 2, wherein said nucleic acid is present in a plasmid.

6. The method of claim 2, wherein said nucleic acid is present in a viral vector.

7. The method of claim 6, wherein said viral vector is an adenovirus vector or a lentivirus vector.

8. The method of claim 7 wherein said adenovirus vector is a gutless recombinant adenovirus vector.

9. The method claim 1, wherein said cell is a non-pancreatic cell.

10. The method of claim 1, wherein said cell is an endodermal cell, an ectodermal cell or a mesodermal cell.

11. The method of claim 10, wherein said endodermal cell is a liver cell.

12. The method of claim 10, wherein said ectodermal cell is a skin cell.

13. The method of claim 10, wherein said mesodermal is a bone marrow cell.

14. The method of claim 1, wherein said cell is provided in vivo, in vitro or ex vivo from a mammalian subject.

15. The method of claim 1, further comprising contacting said cell with a transfection agent.

16. The method of claim 1, further comprising contacting said cell with a composition comprising nicotinamide, epidermal growth factor, activin A, hepatic growth factor, exendin, GLP-1 or betacellulin.

17. A method of inducing the expression of a pancreatic gene in a non-pancreatic cell, said method comprising introducing to said cell a composition comprising a nucleic acid encoding a pancreatic and duodenal homobox 1 (PDX-1) polypeptide, in an amount sufficient to induce said gene expression in said cell.

18. The method of claim 17, wherein said pancreatic gene is a pancreatic transcription factor.

19. The method of claim 18, wherein said pancreatic transcription factor is beta 2, ISL-2, Nkx6.1, Ngn3.1, or NKx2.2.

20. The method of claim 17, wherein said pancreatic gene is a endocrine gene or an exocrine gene.

21. The method of claim 20, wherein said endocrine gene is SCG2, SGNE1, CHGN, PTPRN, AMPH, NBEA, NeuroD or folistatin.

22. The method of claim 20 wherein said exocrine gene is serine protease inhibitor, Kazal type 1, Elastase, factor-p48, or regenerating islet-derived 1 alpha.

23. The method of claim 17, wherein said cell is an endodermal cell, an ectodermal cell or a mesodermal cell.

24. The method of claim 23, wherein said endodermal cell is a liver cell.

25. The method of claim 23, wherein said ectodermal cell is a skin cell.

26. The method of claim 23, wherein said mesodermal is a bone marrow cell.

27. The method of claim 17, wherein said cell is provided in vivo, in vitro or ex vivo from a mammalian subject.

28. A method of converting a non-pancreatic cell to a pancreatic cell, comprising contacting said non-pancreatic cell with a PDX-1 inducer compound in an amount to

a. induce the expression of endogenous PDX-1, an embryonic marker, insulin, glucogon, or somatostatin in said non-pancreatic cell or

b. repress the expression of C/EBPβ

, albumin or ADH-1 in said non-pancreatic cell.

29. The method of claim 28, wherein said PDX-1 inducer compound comprises a nucleic acid encoding a pancreatic and duodenal homobox 1 (PDX-1) polypeptide, a neuroD polypeptide or a betacellulin polypeptide.

30. The method of claim 28, wherein said embryonic marker is alpha-1 fetoprotein or Gata-4.

31. The method of claim 28, wherein said non-pancreatic cell is a differentiated cell.

32. The method of claim 31, wherein said differentiated cell is a liver cell, a skin cell or a bone marrow cell.

33. A method of alleviating a symptom of diabetes in a subject, said method comprising administering to a subject a composition comprising a nucleic acid encoding a pancreatic and duodenal homobox 1 (PDX-1) polypeptide.

34. The method of claim 33, wherein said diabetes is Type 1 or Type 2.