COMPOSITIONS COMPRISING NECROSIS INHIBITORS, SUCH AS NECROSTATINS, ALONE OR IN COMBINATION, FOR PROMOTING AXON REGENERATION AND NERVE FUNCTION, THEREBY TREATING CNS DISORDERS

• US 20160151442A1
• Filed: 11/02/2015
• Published: 06/02/2016
• Est. Priority Date: 10/21/2011
• Status: Active Grant

• Current Assignee: Children's Medical Center Corporation, Massachusetts Eye And Ear Infirmary (Foundation of The Massachusetts Eye and EAR Infirmary Incorporated)
• Original Assignee: Massachusetts Eye And Ear Infirmary (Foundation of The Massachusetts Eye and EAR Infirmary Incorporated)
• Inventors: Vavvas, Demetrios G.
• Granted Patent: US 10,022,419 B2
• Time in Patent Office: Days
• 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 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 38/005 Enzyme inhibitors protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/05 Dipeptides
• 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 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

Provided are methods for promoting axon regeneration of a Central Nervous System (CNS) neuron and promoting nerve function following injury to a CNS neuron, for example, brain and/or spinal cord injury. Axon regeneration in a CNS neuron or nerve function following injury to a CNS neuron can be promoted by administering a necrosis inhibitor either alone or in combination with an apoptosis inhibitor to a subject suffering from a CNS disorder, wherein a symptom of the CNS disorder is axon degeneration.

Claims

1. A method for promoting axon regeneration in a CNS neuron, the method comprising:

exposing the CNS neuron to an effective amount of a necrosis inhibitor and an effective amount of an apoptosis inhibitor thereby to promote the regeneration of the axon.

2. The method of claim 1, wherein the neuron is ex vivo.

3. The method of claim 1, wherein the neuron is in vivo.

11. The method of claim 1, wherein the CNS neuron is selected from the group consisting of a sensory neuron, a motor neuron, a cortical neuron, a pyramidal neuron, a cerebellar neuron, a hippocampal neuron, and a midbrain neuron.

17. The method of claim 1, wherein the necrosis inhibitor is a necrostatin.

19. The method of claim 17, wherein the necrostatin is selected from the group consisting of necrostatin-1, necrostatin-2, necrostatin-3, necrostatin-4, necreostatin-5, and necrostatin-7, or a combination thereof.

20. The method of claim 17, wherein from about 0.05 mg to about 2 mg of necrostatin is administered.

21. The method of claim 1, wherein the apoptosis inhibitor is a pan-caspase inhibitor.

22. The method of claim 21, wherein the pan-caspase inhibitor is zVAD, IDN-6556 or a combination thereof.

24. The method of claim 17, wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered locally.

25. The method of claim 17, wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered systemically.

26. The method of claim 17, wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered sequentially or simultaneously.

4. (canceled)

5. A method of preserving the viability of a CNS neuron, the method comprising:

administering to a subject in need thereof an effective amount of a necrosis inhibitor and an effective amount of an apoptosis inhibitor thereby to preserve the viability of the CNS neuron.

6. The method of claim 5, wherein after treatment with the necrosis inhibitor and the apoptosis inhibitor, the CNS neuron is capable of supporting axonal regeneration.

8. The method of claim 5, further comprising, after the administration of a necrosis inhibitor and an apoptosis inhibitor, measuring neuron function within the subject.

9. The method of claim 8, wherein the neuron function is an indication of axon regeneration in the neuron.

10. The method of claim 5, wherein, after administration of the necrosis inhibitor and the apoptosis inhibitor, the neuron function of the CNS neuron is preserved or improved relative to the neuron function prior to administration of the necrosis inhibitor and the apoptosis inhibitor.

7. (canceled)

12-14. -14. (canceled)

15. A method of promoting axon regeneration in a CNS neuron, the method comprising:

reducing the production and/or activity of a RIP-1 kinase and/or a RIP-3 kinase in the CNS neuron thereby to promote axon regeneration in a CNS neuron.

16. The method of claim 15, wherein the reduction in the production and/or activity of the RIP-1 kinase and/or the RIP-3 kinase is achieved by administering an effective amount of a RIP kinase inhibitor.

18. The method of claim 16, wherein the RIP kinase inhibitor is a necrostatin.

23. (canceled)

27-44. -44. (canceled)