Compositions and methods for promoting nerve regeneration

• US 6,881,409 B2
• Filed: 09/04/2003
• Issued: 04/19/2005
• Est. Priority Date: 10/24/1997
• Status: Expired due to Fees

• Current Assignee: Oregon Health & Science University
• Original Assignee: Oregon Health & Science University
• Inventors: Gold, Bruce G.
• Primary Examiner(s): Kemmerer, Elizabeth
• Assistant Examiner(s): NICHOLS, CHRISTOPHER J
• Application Number:
  US10/656,701
• Publication Number:
  US 20040063610A1
• Time in Patent Office: 593 Days
• Field of Search: 424/145.1, 424/130.1, 514/183, 514/330, 514/423, 514/428, 514/465, 514/466, 514/1, 514/2
• US Class Current: 424/145.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 38/1883 Neuregulins, e.g.. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: G01N 2500/02 Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
• CPC Class Codes: G01N 33/5058 Neurological cells
• CPC Class Codes: G01N 33/743 Steroid hormones
• CPC Class Codes: Y10T 436/14 Heterocyclic carbon compound [i.e. , O, S, N, Se, Te, as only ring hetero atom]

Abstract

FK506 and geldanamycin promote nerve regeneration by a common mechanism that involves the binding of these compounds to polypeptide components of steroid receptor-complexes other than the steroid hormone binding portion of the complex (FKBP52 and hsp90, respectively). These and other agents cause hsp90 dissociation from steroid receptor complexes or block association of hsp90 with steroid receptor complexes.

Claims

1. A method of improving nerve growth into a partial transection of a spinal cord, comprising:

introducing into the transection NGF and a non-cellular gap filling agent that includes a therapeutically effective amount of a benzoquinone ansamycin that binds to a polypeptide component of a steroid receptor complex other than a steroid binding portion of the complex, wherein the NGF and benzoquinone ansamycin are present in a therapeutically sufficient amount to interfere with association or promote dissociation of hsp90 from the complex, and promote nerve growth into the spinal cord.

2. A method of promoting nerve growth a mammal having a partially transected spinal cord, the method comprising:

administering to the mammal a pharmaceutical composition comprising a nerve growth stimulating amount of a non-FKBP12-binding agent that binds to a polypeptide component of a steroid receptor complex other than a steroid hormone binding portion of the complex wherein the agent interferes with association or promotes dissociation of hsp90 with the complex and promotes nerve growth, thereby promoting nerve growth.

3. The method of claim 2 wherein the non-FKBP12-binding agent is administered in a gap-filling composition comprising the non-FKBP12-binding agent.

4. The method of claim 2, wherein the agent is selected from the group consisting of a non-FKBP12-binding FK506 analog, a benzoquinone ansamycin, a peptide comprising a sequence of a selected polypeptide component of the steroid receptor complex at a site of interaction between the selected component and another polypeptide component of the steroid receptor complex, an antibody that binds to a polypeptide component of the complex, and combinations thereof.

5. The method of claim 4, wherein the agent is a benzoquinone ansamycin.

6. The method of claim 5, wherein the benzoquinone ansamycin is a geldanamycin derivative.

7. The method of claim 2, wherein the agent binds to FKBP12 with an apparent K_d of greater than 10 μ

M.

8. The method of claim 7, wherein the agent binds FKBP12 with an apparent K_d of greater than 30 μ

M.

9. The method of claim 8, wherein the agent binds FKBP12 with an apparent K_d of greater than 100 μ

M.

10. The method of claim 2, wherein the agent is selected from the group consisting of a peptide comprising a sequence from a component of the steroid receptor complex which peptide inhibits assembly or promotes dissociation of the steroid receptor complex, an antibody that binds to a component of the steroid receptor complex and prevents assembly or promotes dissociation of the steroid receptor complex, a benzoquinone ansamycin, or an FK506 analog which binds to FKBP12 with a K_d of at least 10 μ

M, and combinations thereof.

11. The method of claim 2, further comprising grafting to the spinal cord an allograft or artificial nerve graft.

12. The method of claim 2, wherein the agent is in combination with a neurotrophic factor, other than the agent.

13. The method of claim 12, wherein the neurotrophic factor is NGF, estrogen, or dexamethasone.

14. The method of claim 2, further comprising administering a second neurotrophic agent in an amount that promotes nerve growth in combination with the pharmaceutical composition.

30. The method of claim 14, wherein the second neurotrophic agent is NGF, IGF-1, aFGF, bFGF, PDGF, BDNF, CNTF, GDNF, NT-3, or NT 4/5.

15. A method of promoting nerve repair in a mammal having a spinal cord injury, the method comprising:

administering to the mammal a pharmaceutical composition comprising a nerve repair stimulating amount of an agent, other than FK506, that binds to a polypeptide component of a steroid receptor complex other than a steroid hormone binding portion of the complex, and which promotes hsp90 dissociation or inhibits hsp90 association with the complex, and promotes repair of the injury, wherein the spinal cord injury is a partial transection.

16. The method of claim 15, further comprising grafting to the partial transection an allograft, and the agent is administered in a therapeutically sufficient amount that promotes growth of the nerve graft.

17. The method of claim 16, further comprising grafting an artificial nerve graft to the partial transection.

18. The method of claim 17, wherein the artificial nerve graft is a collagen nerve graft, and the agent is administered in a therapeutically sufficient amount that promotes growth of the partially transected spinal cord.

19. The method of claim 15, further comprising applying a therapeutically effective amount of the agent directly to an injured area of the spinal cord to promote nerve growth at the injured area.

20. The method of claim 19, wherein applying the agent directly to the injured area comprises contacting the partial transection with a therapeutically effective amount of the agent to promote nerve growth at the partial transection.

21. The method of claim 15, further comprising filling the partial transection with a gap filling material that includes a therapeutically sufficient amount of the agent to promote nerve growth into the spinal cord.

22. The method of claim 21, wherein the gap filling material comprises a cellular or non-cellular gap filling material.

23. The method of claim 22, wherein the gap filling material is a non-cellular gap filling material.

24. The method of claim 23, wherein the non-cellular gap filling material is collagen.

25. The method of claim 15, wherein the nerve repair stimulating agent is administered along a path for new nerve growth.

26. The method of claim 15, wherein the agent is:

(a) an FK506 analog

(b) a benzoquinone ansamycin

(c) a peptide comprising a sequence of a polypeptide component of the steroid receptor complex at a site of interaction between the selected component and another polypeptide component of the steroid receptor complex;

or

(d) an antibody that binds to a polypeptide component of the steroid receptor complex.

27. The method of claim 26 wherein the agent is non-immunosuppressive.

28. The method of claim 26, wherein the agent is an FK506 analog.

29. The method of claim 26, wherein the agent is a benzoquinone ansamycin.