COMPOSITIONS AND METHODS FOR INCREASING VASCULARIZATION

• US 20100261654A1
• Filed: 05/01/2008
• Published: 10/14/2010
• Est. Priority Date: 05/01/2007
• Status: Active Grant

• Current Assignee: Inserm (institut national de la sant et de la recherche mdicale, Sinfonia Biotherapeutics AB
• Original Assignee: Biogen Idec MA Inc. (Biogen, Inc.), Inserm (institut national de la sant et de la recherche mdicale
• Inventors: Silvestre, Jean-Sebastien, Rossomando, Anthony, Tamarat, Radia
• Granted Patent: US 8,329,655 B2
• Time in Patent Office: Days
• US Class Current: 514/13.300
• CPC Class Codes: A61K 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• 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
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators

Abstract

Disclosed are methods of increasing vascularization in a tissue by administering a neublastin polypeptide to a mammal exhibiting impaired or inadequate blood flow in the tissue. The methods can be used to in the treatment or prevention of a disorder characterized by impaired or inadequate blood flow or to increase vascularization in an organ that has been transplanted into a subject.

Claims

1. A method of increasing vascularization in a tissue, the method comprising:

selecting a mammal exhibiting impaired or inadequate blood flow in a tissue; and

administering to the mammal an amount of a polypeptide effective to increase vascularization in the tissue, wherein the polypeptide comprises an amino acid sequence that is at least 80% identical to amino acids 15-113 of SEQ ID NO;

1, and wherein the polypeptide, when dimerized, binds to a complex containing GFRalpha3 and RET.

2. The method of claim 1, wherein the tissue is an ischemic tissue.

3. The method of claim 2, wherein the ischemic tissue is an ischemic muscle tissue.

4. The method of claim 1, wherein the heart of the mammal exhibits impaired blood flow and administration of the polypeptide increases vascularization of the heart.

5. The method of claim 1, wherein the mammal has suffered a stroke and exhibits impaired or inadequate blood flow in the tissue as a result of the stroke.

6. The method of claim 1, wherein the mammal has suffered a myocardial infarction and exhibits impaired or inadequate blood flow in the tissue as a result of the myocardial infarction.

7. The method of claim 1, wherein the mammal has a coronary artery disease and exhibits impaired or inadequate blood flow in the tissue as a result of the coronary artery disease.

8. The method of claim 1, wherein the mammal has received a transplanted organ and administration of the polypeptide increases vascularization in the transplanted organ.

9. The method of claim 8, wherein the transplanted organ is a heart.

10. The method of claim 8, wherein the transplanted organ is dermis.

11. The method of claim 1, wherein the mammal has an ischemic disease.

12. The method of claim 1, wherein the mammal has a cardiovascular disease.

13. The method of claim 1, wherein the tissue is located in an extremity of the mammal.

14. The method of claim 12 or 13, wherein the mammal has diabetes.

15. The method of claim 1, wherein the tissue comprises a skin lesion.

16. The method of claim 15, wherein the skin lesion is associated with a diabetic ulcer.

17. The method of claim 16, wherein the diabetic ulcer is a diabetic foot ulcer.

18. The method of claim 1, further comprising administering to the mammal one or more of an antithrombotic agent, a factor other than neublastin that increases vascularization, a cholesterol-lowering agent, a beta blocker, an anti-hypertensive agent, or an immunosuppressive agent.

19. The method of claim 1, further comprising determining whether increased vascularization has occurred subsequent to administration of the polypeptide.

20. The method of claim 1, wherein the polypeptide is administered to the mammal via systemic administration.

21. The method of claim 1, wherein the polypeptide is administered to the mammal via subcutaneous administration.

22. The method of claim 1, wherein herein the polypeptide is administered to the mammal via local administration.

23. The method of claim 1, wherein the amino acid sequence is at least 90% identical to amino acids 15-113 of SEQ ID NO:

1.

24. The method of claim 1, wherein the amino acid sequence is at least 95% identical to amino acids 15-113 of SEQ ID NO:

1.

25. The method of claim 1, wherein the amino acid sequence is at least 98% identical to amino acids 15-113 of SEQ ID NO:

1.

26. The method of claim 1, wherein the polypeptide comprises amino acids 15-113 of SEQ ID NO:

1, amino acids 15-113 of SEQ ID NO;

2, amino acids 15-113 of SEQ ID NO;

3, amino acids 15-113 of SEQ ID NO;

4, amino acids 15-113 of SEQ ID NO;

5, amino acids 15-113 of SEQ ID NO;

8, or amino acids 15-113 of SEQ ID NO;

9.

27. The method of claim 1, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:

1, the amino acid sequence of SEQ ID NO;

2, the amino acid sequence of SEQ ID NO;

3, the amino acid sequence of SEQ ID NO;

4, the amino acid sequence of SEQ ID NO;

5, the amino acid sequence of SEQ ID NO;

8, or the amino acid sequence of SEQ ID NO;

9.

28. The method of claim 1, wherein the polypeptide comprises amino acids 10-113 of SEQ ID NO:

1.

29. The method of claim 1, wherein the mammal has not been diagnosed with a neurological disorder.

30. The method of claim 1, wherein the mammal has not been diagnosed with an ocular disorder.

31. The method of claim 1, wherein the mammal is a human.