Induction of insulin expression

• US 20040002447A1
• Filed: 06/04/2002
• Published: 01/01/2004
• Est. Priority Date: 06/04/2002
• Status: Abandoned Application

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Itkin-Ansari, Pamela, Levine, Fred
• Application Number:
  US10/162,952
• Publication Number:
  US 20040002447A1
• Time in Patent Office: Days
• US Class Current: 514/9
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/336 having three-membered rings, e.g. oxirane, fumagillin
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/15 Depsipeptides; Derivatives thereof
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C12N 2501/70 Enzymes
• CPC Class Codes: C12N 5/0676 Pancreatic cells
• CPC Class Codes: G01N 33/5052 involving B-cells

Abstract

The present invention provides compositions and methods for inducing insulin expression in cells by contacting the cells with a histone deacetylase inhibitor.

Claims

1. A method for inducing insulin gene expression in cells, the method comprising the steps of:

(i) providing a cell that expresses a PDX-1 polynucleotide; and

(ii) contacting the cell with a histone deacetylase inhibitor, thereby inducing insulin gene expression in the cells.

2. The method of claim 1, wherein the contacting step results in an induction of insulin expression at least two-fold compared to a cell not contacted by the histone deacetylase inhibitor.

3. The method of claim 1, wherein the cell further expresses a heterologous PDX-1 polynucleotide.

4. The method of claim 1, wherein the cell expresses a NeuroD polynucleotide.

5. The method of claim 4, wherein the cell expresses a heterologous NeuroD polynucelotide.

6. The method of claim 1, wherein the cell is a pancreatic β

-cell.

7. The method of claim 6, wherein the β

-cells are human β

-cells.

8. The method of claim 1, wherein the cell produces a detectable amount of insulin prior to contacting the cell with the histone deacetylase inhibitor.

9. The method of claim 1, wherein the inhibitor is selected from the group consisting of butyrates, hydroxamic acids, cyclic peptides and benzamides.

10. The method of claim 1, wherein the inhibitor is selected from the group consisting of valproic acid, 4-phenylbutyrate, sodium butyrate, trichostatin A, suberoyl anilide hydroxamic acid (SAHA), oxamflatin, trapoxin B, FR901228, apicidin, chlamydocin, depuecin, scriptaid, depsipeptide, and N-acetyldinaline

11. The method of claim 1, further comprising contacting the cells with a GLP-1 receptor agonist.

12. The method of claim 11, wherein the GLP-1 receptor agonist is a GLP-1 analog.

13. The method of claim 11, wherein the GLP-1 receptor agonist has an amino acid sequence of a naturally occurring peptide.

14. The method of claim 13, wherein the GLP-1 receptor agonist is GLP-1, exendin-3, or exendin-4.

15. The method of claim 1, wherein the cells express a recombinant oncogene.

16. The method of claim 15, wherein the cells express more than one recombinant oncogene.

17. The method of claim 1, wherein the cells express a recombinant telomerase gene.

18. A method of identifying a compound that modulates β

-cell function, the method comprising the steps of contacting a cell with a compound in the presence of a histone deactylase inhibitor, wherein the cell expresses a PDX-1 polynucleotide; and

determining the effect of the compound on β

-cell function.

19. The method of claim 18, wherein β

-cell function comprises insulin expression.

20. The method of claim 18, wherein insulin expression increases when the cell is contacted with the compound.

21. The method of claim 18, wherein the inhibitor is selected from the group consisting of butyrates, hydroxamic acids, cyclic peptides and benzamides.

22. The method of claim 18, wherein the inhibitor is selected from the group consisting of valproic acid, 4-phenylbutyrate, sodium butyrate, trichostatin A, suberoyl anilide hydroxamic acid (SAHA), oxamflatin, trapoxin B, FR901228, apicidin, chlamydocin, depuecin, scriptaid, depsipeptide, and N-acetyldinaline

23. The method of claim 18, wherein the β

-cell expresses a NeuroD/BETA2 polynucleotide.

24. The method of claim 18, further comprising contacting the β

-cell with a GLP-1 receptor agonist.

25. The method of claim 24, wherein the GLP-1 receptor agonist is a GLP-1 analog.

26. The method of claim 24, wherein the GLP-1 receptor agonist has an amino acid sequence of a naturally occurring peptide.

27. The method of claim 26, wherein the GLP-1 receptor agonist is GLP-1, exendin-3, or exendin-4.

28. The method of claim 18, wherein the β

-cell is a human cell.

29. A culture of cells expressing PDX-1, wherein the culture comprises a histone deacetylase inhibitor.

30. The culture of claim 29, wherein the cells express a heterologous PDX-1 polynucleotide.

31. The culture of claim 29, wherein insulin expression of the cells is at least two-fold higher than cells in a culture lacking the histone deacetylase inhibitor.

32. The culture of claim 29, wherein the inhibitor is selected from the group consisting of butyrates, hydroxamic acids, cyclic peptides and benzamides.

33. The culture of claim 29, wherein the inhibitor is selected from the group consisting of valproic acid, 4-phenylbutyrate, sodium butyrate, trichostatin A, suberoyl anilide hydroxamic acid (SAHA), oxamflatin, trapoxin B, FR901228, apicidin, chlamydocin, depuecin, scriptaid, depsipeptide, and N-acetyldinaline

34. The culture of claim 29, wherein the cell expresses a NeuroD polynucleotide.

35. The culture of claim 34, wherein the cell expresses a heterologous NeuroD polynucelotide.

36. The culture of claim 29, further comprising a GLP-1 receptor agonist.

37. The culture of claim 36, wherein the GLP-1 receptor agonist is a GLP-1 analog.

38. The culture of claim 36, wherein the GLP-1 receptor agonist has an amino acid sequence of a naturally occurring peptide.

39. The culture of claim 38, wherein the GLP-1 receptor agonist is GLP-1, exendin-3, or exendin-4.

40. The culture of claim 29, wherein the cells are β

-cells.

41. The culture of claim 40, wherein the β

-cells are human β

-cells.

42. The culture of claim 29, wherein the β

-cells express a recombinant oncogene.

43. The culture of claim 42, wherein the β

-cells express more than one recombinant oncogene.

44. The culture of claim 40, wherein the β

-cells express a recombinant telomerase gene.