Netrin-related compositions and uses

• US 20060019896A1
• Filed: 07/14/2005
• Published: 01/26/2006
• Est. Priority Date: 07/14/2004
• Status: Active Grant

• Current Assignee: University of Utah Research Foundation (State of Utah)
• Original Assignee: University of Utah Research Foundation (State of Utah)
• Inventors: Park, Kye Won, Li, Dean Y.
• Granted Patent: US 7,456,151 B2
• Time in Patent Office: Days
• US Class Current: 514/8.100
• CPC Class Codes: A61K 38/177 Receptors; Cell surface antigens; Cell surface determinants
• CPC Class Codes: A61K 38/179 for growth factors; for growth regulators
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/1858 Platelet-derived growth factor [PDGF]
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 38/1891 Angiogenesic factors; Angiogenin
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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

Abstract

The present invention provides methods and compositions for modulating proliferation, differentiation, migration, and adhesion of cardiovascular cell types.

Claims

1. A method for promoting angiogenesis, comprising administering an amount of a polypeptide effective to promote angiogenesis, wherein said polypeptide is a netrin polypeptide.

2. The method of claim 1, wherein said netrin polypeptide comprises an amino acid sequence encoded by a nucleic acid sequence that hybridizes under stringent conditions, including a wash step of 0.2×

at 65°

C., to a nucleic acid sequence represented in any of SEQ ID NO;

1, 3, 5, 7, 9, 11, 37, 39, 41, or 43, and wherein said amino acid sequence binds to a netrin receptor and retains a biological activity of native netrin.

3. The method of claim 1, wherein said netrin polypeptide is a modified netrin polypeptide.

4. The method of claim 1, further comprising administering one or more angiogenic factors.

5. The method of claim 4, wherein said angiogenic factor is selected from a VEGF polypeptide, a PDGF polypeptide, a FGF polypeptide, or an angiopoietin polypeptide.

6. The method of claim 5, wherein said angiogenic factor acts synergistically with said netrin polypeptide.

7. The method of claim 4, wherein said angiogenic factor is administered concomitantly with or consecutively to administration of said netrin polypeptide.

8. A method for inhibiting angiogenesis, comprising administering an amount of an agent effective to inhibit angiogenesis, wherein said agent inhibits expression or activity of a netrin polypeptide.

9. The method of claim 8, wherein said agent is selected from one or more of an anti-netrin antibody, an Unc5h receptor, an Unc5h receptor ectodomain, or an anti-neogenin antibody.

10. A method for promoting migration of endothelial cells or smooth muscle cells, comprising contacting said cells with an amount of a polypeptide effective to promote migration of said endothelial cells or smooth muscle cells, wherein said polypeptide is a netrin polypeptide.

11. The method of of claim 10, wherein said smooth muscle cells are vascular smooth muscle cells.

12. A method for promoting proliferation and/or migration of stem cells, comprising administering an amount of a polypeptide effective to promote proliferation and or migration of said stem cells, wherein said polypeptide is a netrin polypeptide.

13. The method of claim 12, wherein said stem cells are embryonic, fetal, or adult stem cells.

14. The method of claim 13, wherein said stem cells are hematopoietic stem cells or endothelial stem cells.

15. The method of claim 12, wherein said netrin polypeptide is a modified netrin polypeptide.

16. The method of claim 12, wherein said netrin polypeptide comprises an amino acid sequence encoded by a nucleic acid sequence that hybridizes under stringent conditions, including a wash step of 0.2×

at 65°

C., to a nucleic acid sequence represented in any of SEQ ID NO;

1, 3, 5, 7, 9, 11, 37, 39, 41, or 43, and wherein said amino acid sequence binds to a netrin receptor and retains a biological activity of native netrin.

17. The method of claim 12, wherein said method comprises promoting migration of stem cells to a site of injury.

18. A pharmaceutical composition that provides a netrin polypeptide for localized delivery, wherein said pharmaceutical composition comprises a netrin polypeptide attached to a biocompatible support or dissolved in a biocompatible matrix, and wherein said pharmaceutical composition retains one or more biological activities of the netrin polypeptide selected from any of:

(i) promoting angiogenesis;

(ii) promoting migration of vascular smooth muscle cells;

or

(iii) promoting migration of endothelial cells;

20. The pharmaceutical composition of claim 18, further comprising one or more angiogenic factors.

21. The pharmaceutical composition of claim 20, wherein said angiogenic factor is selected from a VEGF polypeptide, a PDGF polypeptide, a FGF polypeptide, or an angiopoietin polypeptide.

22. The pharmaceutical composition of claim 18, wherein said biocompatible matrix is a bandage, gauze pad, dressing, or suture.

24. The pharmaceutical composition of claim 18, wherein said biocompatible support is an intraluminal device.

25. The pharmaceutical composition of claim 24, wherein said intraluminal device is selected from a stent, catheter, or wire.

26. The pharmaceutical composition of claim 18, wherein said netrin polypeptide is a modified netrin polypeptide.

27. A method for treating an ischemic condition in an animal, comprising administering to an animal in need thereof an amount of the pharmaceutical composition of claim 18 effective to decrease ischemia in said animal.

28. The method of claim 27, further comprising administering one or more angiogenic factors.

31. A method of promoting wound healing, comprising administering to an animal in need thereof an amount of the pharmaceutical composition of claim 18 effective to promote angiogenesis in said animal, thereby promoting wound healing.

19. A pharmaceutical composition that provides an agent that inhibits the expression or activity of a netrin polypeptide, wherein said pharmaceutical composition comprises an agent attached to a biocompatible support or dissolved in a biocompatible matrix, and wherein said pharmaceutical composition retains the netrin inhibitory activity of the agent.

23. The pharmaceutical composition of claim 19, wherein said biocompatible matrix is a bandage, gauze pad, dressing, or suture.

29. A method for decreasing inflammation in an animal, comprising administering to an animal in need thereof an amount of the pharmaceutical composition of claim 19 sufficient to inhibit one or more of proliferation or migration of one or more inflammatory cell types in said animal, wherein said agent inhibits the expression or activity of a netrin polypeptide.

30. The method of claim 29, wherein said inflammatory cell types are selected from macrophages, lymphocytes, mast cells, platlets, or eosinophils.

34. A method for inhibiting growth or survival of a tumor, comprising administering an amount of an agent effective to inhibit angiogenesis, thereby inhibiting the growth or survival of the tumor, wherein said agent inhibits the expression or activity of a netrin polypeptide, and wherein said method comprises administering said agent as the pharmaceutical composition of claim 19.

35. A method of preventing or treating adhesions following surgery or medical wounding, comprising administering an amount of the pharmaceutical composition of claim 19 effective to inhibit angiogenesis, thereby inhibiting scar formation and adhesions following surgery or medical wounding, wherein said agent inhibits the expression or activity of a netrin polypeptide.

32. A method for inhibiting growth or survival of a tumor, comprising administering an amount of an agent effective to inhibit angiogenesis, thereby inhibiting the growth or survival of the tumor, wherein said agent inhibits the expression or activity of a netrin polypeptide.

33. The method of claim 32, wherein said agent is selected from one or more of an anti-netrin antibody, an Unc5h receptor, an Unc5h receptor ectodomain, or an anti-neogenin antibody.

36. A method for treating a neuropathy in an animal, comprising administering to an animal in need thereof an amount of a polypeptide effective to treat or prophylactically treat the neuropathy in said animal, wherein said polypeptide is a netrin polypeptide.

37. The method of claim 36, wherein the neuropathy is a peripheral neuropathy.

38. The method of claim 36, wherein the neuropathy is a diabetic neuropathy.