Methods for nerve repair
View Patent ↗The subject invention pertains to compositions and methods for promoting repair of damaged nerve tissue. The compositions and methods of the subject invention can be employed to restore the continuity of nerve interrupted by disease, traumatic events or surgical procedures. Compositions of the subject invention comprise one or more chondroitin sulfate proteoglycan (CSPG)-degrading enzymes that promote axonal penetration into damaged nerve tissue. The invention also concerns methods for promoting repair of damaged nerve tissue using the present compositions and nerve tissue treated according to such methods. The invention also pertains to kits for nerve repair.
1. A method for increasing axon growth across a site of damage in a damaged nerve of the peripheral nervous system, wherein said damaged nerve is partially or completely severed at the site of damage, and has a portion proximal to the site of damage and a portion distal to the site of damage, and wherein said method comprises:
applying at least one chondroitin sulfate proteoglycan-degrading (CSPG-degrading) enzyme selected from the group consisting of chondroitinase ABC, chondroitinase A, chondroitinase C and chondroitinase AC to the damaged nerve in vivo, and
coapting the proximal portion with the distal portion;
wherein axon growth from the proximal portion to the distal portion, across the site of damage, is increased compared to axon growth in a damaged nerve to which a CSPG-degrading enzyme has not been applied.
2. The method of claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme comprises chondroitinase ABC.
3. The method of claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme comprises chondroitinase A.
4. The method of claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme comprises chondroitinase C.
5. The method according to claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme comprises chondroitinase AC.
6. The method of claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme is applied at the site of damage.
7. The method of claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme is applied adjacent to the site of damage.
8. The method, according to claim 1 , wherein said coapting occurs via a nerve graft between the proximal portion and the distal portion.
9. The method, according to claim 1 , wherein said proximal portion and said distal portion are directly coapted.
10. The method, according to claim 1 , wherein regenerating axons regrow within basal lamina of the distal nerve.
11. The method according to claim 1 , wherein coapting comprises suturing the damaged nerve.
12. The method according to claim 1 , wherein coapting comprises applying a tissue adhesive to the damaged nerve.
13. The method according to claim 12 , wherein the tissue adhesive is a biological glue.
14. The method according to claim 12 , wherein the tissue adhesive is selected from the group consisting of fibrin glue and platelet gel.
15. The method according to claim 1 , wherein said method further comprises applying a biologically active agent to the damaged nerve.
16. The method according to claim 15 , wherein the biologically active agent is a growth factor.
17. The method according to claim 16 , wherein the growth factor is selected from the group consisting of nerve growth factor, fibroblast growth factor-1, fibroblast growth factor-2, epidermal growth factor, ciliary neurotrophic factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4, neurotrophin-5, insulin-like growth factor-1, insulin-like growth factor-2, transforming growth factor, glial growth factor-2, vascular endothelial growth factor, granulocyte-macrophage colony stimulating factor, and lymphocyte infiltrating factor/cholinergic differentiating factor.
18. The method according to claim 1 , wherein said method further comprises applying cells to the damaged nerve to treat the damaged nerve in combination with the enzyme.
19. The method according to claim 18 , wherein the cells are stem cells.
20. The method according to claim 18 , wherein the cells are Schwann cells.
21. The method according to claim 1 , wherein the nerve damage comprises a disruption in the continuity of at least one of the nerve sheaths of the damaged nerve selected from the group consisting of basal lamina, perineurium, and epineurium.
22. The method according to claim 1 , wherein the nerve damage is a neurotmesis.
23. The method according to claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme is applied to the site of coaptation.
24. The method according to claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme is applied to the proximal portion of the damaged nerve, to the distal portion of the damaged nerve, or to both the proximal portion and distal portion of the damaged nerve.
25. The method according to claim 24 , wherein said method further comprises applying a tissue adhesive to the proximal portion of the damaged nerve, to the distal portion of the damaged nerve, or to both the proximal portion and distal portion of the damaged nerve.
26. The method according to claim 24 , wherein said method further comprises suturing together the proximal portion and distal portion of the damaged nerve.
27. The method according to claim 1 , wherein, upon application to the damaged nerve, the chondroitin sulfate proteoglycan-degrading enzyme causes degradation of chondroitin-4-sulfate, chondroitin-6-sulfate, or both chondroitin-4-sulfate and chondroitin-6-sulfate within the damaged nerve.
28. The method according to claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme decreases the latency of axonal ingress into the distal portion of the nerve compared to a nerve that has not been treated with the chrondroitan sulfate proteoglycan-degrading enzme.
29. The method according to claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme increases the rate of axonal ingress into the distal portion of the damaged nerve compared to a nerve that has not been treated with the chrondroitan sulfate proteoglycan-degrading enzme.
30. The method according to claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme is applied topically to the damaged nerve.
31. The method according to claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme is injected into the damaged nerve.
32. The method according to claim 31 , wherein the chondroitin sulfate proteoglycan-.degrading enzyme is injected into the proximal portion of the damaged nerve, the distal portion of the damaged nerve, or both the proximal portion and distal portion of the damaged nerve.
33. The method according to claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme is applied with a pharmaceutically acceptable carrier.
34. The method according to claim 33 , wherein the pharmaceutically acceptable carrier is selected from the group consisting of liquids, gels, foams, solids, and polymers.
35. The method according to claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme is applied via a pharmaceutically acceptable carrier selected from the group consisting of membranes, sponges, fibrous structures, powders, fleeces, and particles.
36. The method according to claim 33 , wherein the pharmaceutically acceptable carrier is a controlled release system.
37. The method according to claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme is a chondroitinase, and wherein the chondroitinase is applied to the damaged nerve within a concentration range from about 10 units/mL to about 1000 units/mL.
38. The method according to claim 37 , wherein the chondroitinase is applied to the damaged nerve within a concentration range from about 100 units/mL to about 500 units/mL.
39. The method according to claim 1 , wherein the chondroitin sulfate proteoglycan-degrading enzyme is produced by bacteria.
40. The method according to claim 1 , wherein the damaged nerve is mammalian nerve.
41. The method according to claim 40 , wherein the damaged nerve is a human nerve.