Polymer conjugated glycosylated neublastin

1. A dimer comprising a first neublastin polypeptide and a second neublastin polypeptide, wherein: (a) at least one of the polypeptides is glycosylated; (b) at least one of the polypeptides is conjugated at its N-terminus to a water-soluble synthetic polymer; and (c) neither of the polypeptides is conjugated to a water-soluble synthetic polymer at a position other than the N-terminus.

2. The dimer according to claim 1 , wherein the first neublastin polypeptide is selected from the group consisting of NBN113 (SEQ ID NO:2), NBN140 (SEQ ID NO:6), NBN116 (SEQ ID NO:7), NBN112 (SEQ ID NO:8), NBN111 (SEQ ID NO:9), NBN110 (SEQ ID NO:10), NBN109 (SEQ ID NO:11), NBN108 (SEQ ID NO:12), NBN107 (SEQ ID NO:13), NBN106 (SEQ ID NO:14), NBN105 (SEQ ID NO: 15), NBN104 (SEQ ID NO: 16), NBN103 (SEQ ID NO: 17), NBN102 (SEQ ID NO:18), NBN101 (SEQ ID NO:19), NBN100 (SEQ ID NO:20) and NBN99 (SEQ ID NO:21).

3. The dimer according to claim 1 , wherein the amino acid sequence of the first neublastin polypeptide and the second neublastin polypeptide are the same.

4. The dimer of claim 3 , wherein the amino acid sequence of the first neublastin polypeptide is NBN104 (SEQ ID NO:16).

5. The dimer of claim 1 , wherein the water-soluble synthetic polymer is a polyalkylene glycol moiety.

6. The dimer of claim 5 , wherein the N-terminal amino acid of the first neublastin polypeptide and the N-terminal amino acid of the second neublastin polypeptide each is conjugated to a polyalkylene glycol moiety.

7. The dimer according to claim 6 , wherein the average total molecular weight of the polyalkylene glycol moiety or moieties conjugated to the dimer is 10-50 kDa.

8. The dimer of claim 7 , wherein the average total molecular weight of the polyalkylene glycol moiety or moieties conjugated to the dimer is 15-45 kDa.

9. The dimer of claim 8 , wherein the average total molecular weight of the polyalkylene glycol moiety or moieties conjugated to the dimer is 20-40 kDa.

10. The dimer according to claim 5 , wherein the polyalkylene glycol moiety is linear.

11. The dimer according to claim 5 , wherein the polyalkylene glycol is branched.

12. The dimer of claim 5 , wherein the polyalkylene glycol moiety is a polyethylene glycol (PEG) moiety.

13. A composition comprising the dimer of claim 1 and a pharmaceutically acceptable carrier.

14. A method of treating neuropathic pain in a mammal, comprising administering to the mammal a therapeutically effective amount of the dimer of claim 1 .

15. The method of claim 14 , wherein the mammal is a human.

16. The method of claim 15 , wherein the route of administration is intravenous, intramuscular or subcutaneous.

17. The method claim 14 , wherein the therapeutically effective amount is from 0.1 μg/kg to 1000 μg/kg.

18. The method of claim 17 , wherein the therapeutically effective amount is from 1 μg/kg to 100 μg/kg.

19. The method of claim 18 , wherein the therapeutically effective amount is from 1 μg/kg to 30 μg/kg.

20. The method of claim 19 , wherein the therapeutically effective amount is from 3 μg/kg to 10 μg/kg.

21. A method of treating tactile allodynia in a mammal, comprising administering to the mammal a therapeutically effective amount of the dimer of claim 1 .

22. A method of treating thermal hyperalgesia, comprising administering to the mammal a therapeutically effective amount of the dimer of claim 1 .

23. A method of activating the RET receptor in a mammal, comprising administering to the mammal an effective amount of the dimer of claim 1 .

24. A method of treating neuropathic pain, tactile allodynia or thermal hyperalgesia in a mammal, comprising co-administering to the mammal an effective amount of the dimer of claim 1 and an analgesic agent.

25. A dimer comprising a first neublastin polypeptide and a second neublastin polypeptide, wherein: (a) at least one of the polypeptides is glycosylated; (b) at least one of the polypeptides is conjugated at its N-terminus to a polyethylene glycol moiety; and (c) neither of the polypeptides is conjugated to a polyethylene glycol moiety at a position other than the N-terminus, and wherein the amino acid sequence of the first neublastin polypeptide and the second neublastin is NBN104 (SEQ ID NO:16).

26. A composition comprising the dimer of claim 25 and a pharmaceutically acceptable carrier.

27. A method of treating neuropathic pain in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 25 .

28. A method of activating the RET receptor in a human, comprising administering to the human an effective amount of the dimer of claim 25 .

29. A method of treating a peripheral neuropathy in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 25 .

30. A method of treating painful diabetic neuropathy in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 25 .

31. The dimer of claim 25 , wherein the N-terminal amino acid of the first neublastin polypeptide and the N-terminal amino acid of the second neublastin polypeptide each is conjugated to a polyethylene glycol moiety.

32. A composition comprising the dimer of claim 31 and a pharmaceutically acceptable carrier.

33. A method of treating neuropathic pain in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 31 .

34. A method of activating the RET receptor in a human, comprising administering to the human an effective amount of the dimer of claim 31 .

35. A method of treating a peripheral neuropathy in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 31 .

36. A method of treating painful diabetic neuropathy in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 31 .

37. A dimer comprising a first neublastin polypeptide and a second neublastin polypeptide, wherein: (a) at least one of the polypeptides is glycosylated; (b) at least one of the polypeptides is conjugated at its N-terminus to a polyethylene glycol moiety; and (c) neither of the polypeptides is conjugated to a polyethylene glycol moiety at a position other than the N-terminus, and wherein the amino acid sequence of the first neublastin polypeptide and the second neublastin is NBN113 (SEQ ID NO:2).

38. The dimer of claim 37 , wherein the N-terminal amino acid of the first neublastin polypeptide and the N-terminal amino acid of the second neublastin polypeptide each is conjugated to a polyethylene glycol moiety.

39. A composition comprising the dimer of claim 37 and a pharmaceutically acceptable carrier.

40. A method of treating neuropathic pain in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 37 .

41. A method of activating the RET receptor in a human, comprising administering to the human an effective amount of the dimer of claim 37 .

42. A method of treating a peripheral neuropathy in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 37 .

43. A method of treating painful diabetic neuropathy in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 37 .

44. A composition comprising the dimer of claim 38 and a pharmaceutically acceptable carrier.

45. A method of treating neuropathic pain in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 38 .

46. A method of activating the RET receptor in a human, comprising administering to the human an effective amount of the dimer of claim 38 .

47. A method of treating a peripheral neuropathy in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 38 .

48. A method of treating painful diabetic neuropathy in a human, comprising administering to the human a therapeutically effective amount of the dimer of claim 38 .