TREATMENTS FOR NEUROLOGICAL DISORDERS

• US 20090221495A1
• Filed: 02/27/2007
• Published: 09/03/2009
• Est. Priority Date: 02/27/2006
• Status: Active Grant

• Current Assignee: Sinfonia Biotherapeutics AB, Arizona Board of Regents (University of Arizona)
• Original Assignee: Gloriana Therapeutics, Inc.
• Inventors: Porreca, Frank, Rossomando, Anthony, Sah, Dinah Wen-Yee
• Granted Patent: US 10,328,125 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 38/1883 Neuregulins, e.g.. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system

Abstract

Disclosed are methods of improving impaired proprioception, treating brachial plexus injuries, regenerating large and small nerve fibers, treating dorsal root nerve injuries, and improving sensory neural responses in a subject by administration of a neublastin polypeptide.

Claims

1. A method of improving impaired proprioception in a subject, the method comprising administering to a subject that exhibits impaired proprioception an amount of a polypeptide effective to improve proprioception in the subject, 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 GFRα

3 and RET.

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

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

39. The method of claim 1, wherein the polypeptide is administered to the subject via intravenous administration.

40. The method of claim 1, wherein the polypeptide is administered locally to damaged neural tissue.

41. The method of claim 1, wherein the subject is a human.

54. 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.

55. 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.

56. 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.

57. 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.

58. 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.

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

1.

2. A method of regenerating nerve fibers in a subject, the method comprising administering to a subject that has suffered damage to or loss of nerve fibers an amount of a polypeptide effective to regenerate nerve fibers, 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 GFRα

3 and RET.

3. The method of claim 2, wherein the nerve fibers are large nerve fibers.

4. The method of claim 2, wherein the nerve fibers are small nerve fibers.

5. The method of claim 2, wherein the subject has suffered damage to or loss of dorsal root nerve fibers.

6. The method of claim 2, wherein the subject has suffered damage to or loss of nerve fibers distal to the dorsal root ganglia.

7. The method of claim 2, wherein the nerve fibers are nerve fibers of the skin and the administration of the polypeptide results in skin reinnervation.

8. The method of claim 2, wherein the polypeptide is administered to the subject within 48 hours following the damage to or loss of nerve fibers.

9. The method claim 2, wherein the polypeptide is administered to the subject within seven days following the damage to or loss of nerve fibers.

10. The method of claim 2, wherein the polypeptide is administered to the subject within one month following the damage to or loss of nerve fibers.

11. The method of claim 2, wherein the polypeptide is administered to the subject in two or more doses following the damage to or loss of nerve fibers.

12. The method of claim 2, wherein administration of the polypeptide to the subject is terminated within six months following the damage to or loss of nerve fibers.

13. The method of claim 2, wherein administration of the polypeptide to the subject is terminated within one month following the damage to or loss of nerve fibers.

14. The method of claim 2, wherein administration of the polypeptide to the subject is terminated within two weeks following the damage to or loss of nerve fibers.

15. The method of claim 2, wherein the damage to or loss of nerve fibers is a result of a nerve crush injury.

16. The method of claim 2, wherein the damage to or loss of nerve fibers is a result of a nerve cut injury.

17. A method of improving an impaired sensory neural response in a subject, the method comprising administering to a subject that exhibits an impaired sensory neural response an amount of a polypeptide effective to improve the impaired response, 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 GFRα

3 and RET.

18. The method of claim 17, wherein the impaired sensory neural response is a result of damage to or loss of dorsal root nerve fibers.

19. The method of claim 17, wherein the impaired sensory neural response is a result of damage to or loss of nerve fibers distal to the dorsal root ganglia.

20. The method of claim 17, wherein the impaired sensory neural response is characterized by a loss of sensitivity to noxious mechanical or thermal stimuli.

21. A method of treating a brachial plexus injury in a subject, the method comprising administering to a subject that has suffered a brachial plexus injury an effective amount of a polypeptide that comprises an amino acid sequence that is at least 80% identical to amino acids 15-113 of SEQ ID NO:

1, wherein the polypeptide, when dimerized, binds to a complex containing GFRα

3 and RET.

22. The method of claim 21, wherein the polypeptide is administered to the subject within 48 hours following the brachial plexus injury.

23. The method of claim 21, wherein the polypeptide is administered to the subject within seven days following the brachial plexus injury.

24. The method of claim 21, wherein the polypeptide is administered to the subject within one month following the brachial plexus injury.

25. The method of claim 21, wherein the polypeptide is administered to the subject in two or more doses following the brachial plexus injury.

26. The method of claim 21, wherein administration of the polypeptide to the subject is terminated within six months following the brachial plexus injury.

27. The method of claim 21, wherein administration of the polypeptide to the subject is terminated within one month following the brachial plexus injury.

28. The method of claim 21, wherein administration of the polypeptide to the subject is terminated within two weeks following the brachial plexus injury.

29. A method of treating a dorsal root nerve injury in a subject, the method comprising administering to a subject that has suffered loss of synaptic function as a result of a dorsal root nerve injury an amount of a polypeptide effective to promote reentry of nerve fibers through the dorsal root entry zone into the spinal cord, 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 GFRα

3 and RET.

30. The method of claim 29, wherein the polypeptide is administered to the subject within 48 hours following the dorsal root nerve injury.

31. The method of claim 29, wherein the polypeptide is administered to the subject within seven days following the dorsal root nerve injury.

32. The method of claim 29, wherein the polypeptide is administered to the subject within one month following the dorsal root nerve injury.

33. The method of claim 29, wherein the polypeptide is administered to the subject in two or more doses following the dorsal root nerve injury.

34. The method of claim 29, wherein administration of the polypeptide to the subject is terminated within six months following the dorsal root nerve injury.

35. The method of claim 29, wherein administration of the polypeptide to the subject is terminated within one month following the dorsal root nerve injury.

36. The method of claim 29, wherein administration of the polypeptide to the subject is terminated within two weeks following the dorsal root nerve injury.

42. A method of regenerating nerve fibers, the method comprising contacting neural tissue that has suffered damage to or loss of nerve fibers with an amount of a polypeptide effective to regenerate nerve fibers, 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 GFRα

3 and RET.

43. The method of claim 42, wherein the nerve fibers are large nerve fibers.

44. The method of claim 42, wherein the nerve fibers are small nerve fibers.

45. The method of claim 42, wherein the neural tissue comprises dorsal root ganglia.

46. The method of claim 42, wherein the neural tissue comprises nerve fibers distal to the dorsal root ganglia.

47. The method of claim 42, wherein the nerve fibers are nerve fibers of the skin.

48. The method of claim 42, wherein the neural tissue is contacted with the polypeptide within 48 hours following the damage to or loss of nerve fibers.

49. The method of claim 42, wherein the neural tissue is contacted with the polypeptide within seven days following the damage to or loss of nerve fibers.

50. The method of claim 42, wherein the neural tissue is contacted with the polypeptide within one month following the damage to or loss of nerve fibers.

51. The method of claim 42, wherein the neural tissue is contacted with the polypeptide in two or more doses following the damage to or loss of nerve fibers.

52. The method of claim 42, wherein the damage to or loss of nerve fibers is the result of a nerve crush injury.

53. The method of claim 42, wherein the damage to or loss of nerve fibers is the result of a nerve cut injury.