Methods for treating pain

• US 20040258671A1
• Filed: 12/18/2003
• Published: 12/23/2004
• Est. Priority Date: 06/23/2003
• Status: Active Grant

• Current Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Original Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Inventors: Watkins, Linda May Rothblum
• Granted Patent: US 7,261,882 B2
• Time in Patent Office: Days
• US Class Current: 424/93.21
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 38/2026 IL-4
• CPC Class Codes: A61K 38/2066 IL-10
• CPC Class Codes: A61K 38/2086 IL-13 to IL-16
• CPC Class Codes: A61K 38/34 Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: A61K 48/0083 characterised by an aspect of the administration regime
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/32 fusions with soluble part of a cell surface receptor, "decoy receptors"
• CPC Class Codes: C07K 2319/75 containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/10343 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2750/14143 viral genome or elements thereof as genetic vector

Abstract

Methods of treating pain by delivery of anti-inflammatory cytokines, proinflammatory cytokine antagonists, and agents that act to reduce or prevent proinflammatory cytokine actions, to the nervous system are described. These agents can be delivered using gene therapy techniques. Alternatively, the agents can be delivered in protein compositions.

Claims

1. A method of treating pain in a vertebrate subject comprising administering to the nervous system of said subject a recombinant vector comprising a polynucleotide encoding an agent selected from the group consisting of an anti-inflammatory cytokine, a proinflammatory cytokine antagonist, and an agent that acts to reduce or prevent inflammatory cytokine actions, operably linked to expression control elements, under conditions that result in expression of said polynucleotide in vivo to reduce pain.

2. The method of claim 1, wherein the subject is administered a polynucleotide encoding an anti-inflammatory cytokine.

3. The method of claim 1, wherein said agent is selected from the group consisting of interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1ra), interleukin-4 (IL-4), interleukin-13 (IL-13), tumor necrosis factor soluble receptor (TNFsr), alpha-MSH, and transforming growth factor-beta 1 (TGF-β

1).

4. The method of claim 2, wherein said anti-inflammatory cytokine is IL-10.

5. The method of claim 4, wherein the IL-10 is fused to the Fc portion of an IgG.

6. The method of claim 2, wherein said vertebrate subject is a human and said anti-inflammatory cytokine is human IL-10.

7. The method of claim 1, wherein said recombinant vector is a recombinant virus.

8. The method of claim 7, wherein said recombinant virus is a recombinant adenovirus.

9. The method of claim 7, wherein said recombinant virus is a recombinant adeno-associated virion.

10. The method of claim 1, wherein said recombinant vector is plasmid DNA.

11. The method of claim 1, wherein said administering is by intraparenchymal delivery.

12. The method of claim 1, wherein said administering is by intrathecal delivery.

13. The method of claim 1, wherein said administering is by epidural delivery.

14. The method of claim 1, wherein the pain is neuropathic pain.

15. The method of claim 1, wherein the method further comprises subsequently administering at five days or less after the first administration, a recombinant vector comprising a polynucleotide encoding an agent selected from the group consisting of an anti-inflammatory cytokine, a proinflammatory cytokine antagonist, and an agent that acts to reduce or prevent inflammatory cytokine actions, operably linked to expression control elements, under conditions that result in expression of said polynucleotide in vivo to maintain reduced pain.

16. The method of claim 1, wherein the method further comprises subsequently administering at five days or less after the first administration, a therapeutically effective amount of a composition comprising an agent selected from the group consisting of an anti-inflammatory cytokine, a proinflammatory cytokine antagonist, and an agent that acts to reduce or prevent inflammatory cytokine actions to maintain reduced pain.

17. The method of claim 15, wherein the subsequent administration is done at three days or less after the first administration.

18. The method of claim 16, wherein the subsequent administration is done at three days or less after the first administration.

19. A method of treating pain in a mammalian subject comprising intrathecally administering to the central nervous system of said subject a recombinant virus or plasmid comprising a polynucleotide encoding IL-10, operably linked to expression control elements, under conditions that result in expression of said polynucleotide in vivo to reduce pain.

20. The method of claim 19, wherein the IL-10 is fused to the Fc portion of an IgG.

21. The method of claim 19, wherein said vertebrate subject is a human and said IL-10 is human IL-10.

22. The method of claim 19, wherein said subject is administered a recombinant virus.

23. The method of claim 22, wherein said recombinant virus is a recombinant adenovirus.

24. The method of claim 22, wherein said recombinant virus and is a recombinant adeno-associated virion.

25. The method of claim 19, wherein the method further comprises subsequently administering at five days or less after the first administration, a recombinant vector comprising a polynucleotide encoding IL-10, operably linked to expression control elements, under conditions that result in expression of said polynucleotide in vivo to maintain reduced pain.

26. The method of claim 19, wherein the method further comprises subsequently administering at five days or less after the first administration, a therapeutically effective amount of composition comprising IL-10 to maintain reduced pain.

27. The method of claim 25, wherein the subsequent administration is done at three days or less after the first administration.

28. The method of claim 26, wherein the subsequent administration is done at three days or less after the first administration.

29. A method of treating existing pain in a vertebrate subject comprising intrathecally administering to said subject a therapeutically effective amount of a composition comprising an agent selected from the group consisting of an anti-inflammatory cytokine, a proinflammatory cytokine antagonist, and an agent that acts to reduce or prevent inflammatory cytokine actions.

30. The method of claim 29, wherein the subject is administered an anti-inflammatory cytokine.

31. The method of claim 29, wherein said agent is one or more agents selected from the group consisting of interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1ra), interleukin-4 (IL-4), interleukin-13 (IL-13), tumor necrosis factor soluble receptor (TNFsr), alpha-MSH, and transforming growth factor-beta 1 (TGF-β

1).

32. The method of claim 30, wherein said anti-inflammatory cytokine is IL-10.

33. The method of claim 32, wherein the IL-10 is fused to the Fc portion of an IgG.

34. The method of claim 32, wherein said vertebrate subject is a human and said anti-inflammatory cytokine is human IL-10.

35. The method of claim 29, wherein the method further comprises subsequently administering at five days or less after the first administration, a recombinant vector comprising a polynucleotide encoding an agent selected from the group consisting of an anti-inflammatory cytokine, a proinflammatory cytokine antagonist, and an agent that acts to reduce or prevent inflammatory cytokine actions, operably linked to expression control elements, under conditions that result in expression of said polynucleotide in vivo to maintain reduced pain.

36. The method of claim 29, wherein the method further comprises subsequently administering at five days or less after the first administration, a therapeutically effective amount of a composition comprising an agent selected from the group consisting of an anti-inflammatory cytokine, a proinflammatory cytokine antagonist, and an agent that acts to reduce or prevent inflammatory cytokine actions to maintain reduced pain.

37. The method of claim 35, wherein the subsequent administration is done at three days or less after the first administration.

38. The method of claim 36, wherein the subsequent administration is done at three days or less after the first administration.

39. A method of treating existing pain in a vertebrate subject comprising:

(a) administering to the nervous system of said subject a first composition comprising a therapeutically effective amount of interleukin-10 (IL-10); and

(b) administering to the nervous system of said subject a second composition comprising a therapeutically effective amount of IL-10 at five days or less after the first administration.

40. The method of claim 39, wherein the first composition and the second composition are the same.

41. The method of claim 39, wherein the first composition and the second composition are different.

42. The method of claim 39, wherein the IL-10 in the first composition and/or in the second composition is fused to the Fc portion of an IgG.

43. The method of claim 39, wherein said vertebrate subject is a human and the IL-10 in the first compositions and/or the second composition is human IL-10.

44. The method of claim 39, wherein the second composition is administered at three days or less after the first composition.

45. A method of treating existing pain in a vertebrate subject comprising:

(a) administering to the nervous system of said subject a first composition comprising a therapeutically effective amount of interleukin-10 (IL-10); and

(b) administering to the nervous system of said subject a second composition comprising a recombinant vector comprising a polynucleotide encoding IL-10, operably linked to expression control elements, under conditions that result in expression of said polynucleotide in vivo, wherein said second composition is administered at five days or less after the first composition is administered.

46. The method of claim 45, wherein the IL-10 in the first composition and/or in the second composition is fused to the Fc portion of an IgG.

47. The method of claim 45, wherein said vertebrate subject is a human and the IL-10 in the first compositions and/or the second composition is human IL-10.

48. The method of claim 45, wherein the second composition is administered at three days or less after the first composition.

49. A method of treating existing pain in a vertebrate subject comprising administering to said subject a therapeutically effective amount of a composition comprising an interleukin-10 (IL-10) polypeptide.

50. The method of claim 49, wherein the IL-10 polypeptide is fused to the Fc portion of an IgG.

51. The method of claim 49, wherein said vertebrate subject is a human and said IL-10 is human IL-10.

52. The method of claim 49, wherein said administering is by intrathecal delivery.

53. The method of claim 49, wherein said administering is by epidural delivery.

54. The method of claim 49, wherein the pain is neuropathic pain.

55. The method of claim 49, wherein the method further comprises subsequently administering at five days or less after the first administration, a recombinant vector comprising a polynucleotide encoding an agent selected from the group consisting of an anti-inflammatory cytokine, a proinflammatory cytokine antagonist, and an agent that acts to reduce or prevent inflammatory cytokine actions, operably linked to expression control elements, under conditions that result in expression of said polynucleotide in vivo to maintain reduced pain.

56. The method of claim 49, wherein the method further comprises subsequently administering at five days or less after the first administration, a therapeutically effective amount of a composition comprising an agent selected from the group consisting of an anti-inflammatory cytokine, a proinflammatory cytokine antagonist, and an agent that acts to reduce or prevent inflammatory cytokine actions to maintain reduced pain.

57. The method of claim 55, wherein the subsequent administration is done at three days or less after the first administration.

58. The method of claim 56, wherein the subsequent administration is done at three days or less after the first administration.