MK2 inhibitor compositions and methods to enhance neurite outgrowth, neuroprotection, and nerve regeneration

Patent metadata

Field	Value
Publication number	US-9890195-B2
Application number	US-84481510-A
Country	US
Kind code	B2
Filing date	Jul 27, 2010
Priority date	Jul 27, 2009
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

Abstract

The described invention provides compositions comprising at least one peptide of formula I for enhancing neurite outgrowth, neuroprotection, and nerve regeneration, and methods of use thereof.

First claim

What is claimed is:

1. A method for improving or enhancing neurite outgrowth following a nerve injury in a subject in need thereof, the method comprising:
(a) providing a therapeutic amount of a composition comprising:
(i) a MAPKAP kinase 2 inhibitor peptide of amino acid sequence YARAAARQARAKALARQLGVAA [SEQ ID NO: 33];
(ii) a carrier; and

(b) administering the composition to the subject in need thereof;
wherein the therapeutic amount is effective
1. to enhance or improve outgrowth of at least one neurite process from a neuron cell body; and
2. to increase neurite length by at least 10% relative to neurite length of a neuron that has not been treated with the composition.

2. The method according to claim 1 , wherein the composition is a pharmaceutical composition.

3. The method according to claim 1 , wherein the neurite process is an axon.

4. The method according to claim 1 , wherein the neurite process is a dendrite.

5. The method according to claim 1 , wherein the composition inhibits production of at least one inflammatory cytokine following the nerve injury.

6. The method according to claim 5 , wherein the at least one inflammatory cytokine is at least one of IL-1 beta, IL-6, and TNF-alpha.

7. The method according to claim 5 , wherein the at least one inflammatory cytokine is produced by activated microglia and astrocytes following the nerve injury.

8. The method according to claim 1 , wherein the concentration of the MAPKAP kinase 2 inhibitor peptide in the therapeutic composition is from 0.001 nM to less than 3 mM.

9. The method according to claim 1 , wherein the composition is in a unit-dosage container or in a multi-dosage container.

10. A method for improving or enhancing nerve regeneration following a nerve injury in a subject in need thereof, the method comprising:
(a) providing a therapeutic amount of a composition comprising:
(i) a MAPKAP kinase 2 inhibitor peptide of amino acid sequence of YARAAARQARAKALARQLGVAA [SEQ ID NO: 33];
(ii) a carrier; and

(b) administering the composition to the subject in need thereof;
wherein the therapeutic amount is effective
1. to enhance or improve outgrowth of at least one neurite process from a neuron cell body; and
2. to increase regrowth of a neurite process of a neuron by at least 10% in length relative to regrowth of a neurite process of a neuron that has not been treated with the composition.

11. The method according to claim 10 , wherein the composition increases neurite regrowth by inhibiting expression of at least on inflammatory cytokine from activated microglia.

12. The method according to claim 11 , wherein the at least one inflammatory cytokine is at least one of IL-1 beta, IL-6, and TNF-alpha.

13. The method according to claim 11 , wherein the at least one inflammatory cytokine is produced by activated microglia and astrocytes following nerve injury.

14. The method according to claim 10 , wherein the concentration of the MAPKAP kinase 2 inhibitor peptide in the therapeutic composition is from 0.001 nM to less than 3 mM.

15. A method for protecting against progression of a neuronal injury in a subject in need thereof, the method comprising:
(a) providing a therapeutic amount of a composition comprising:
(i) a MAPKAP kinase 2 inhibitor peptide of amino acid sequence of YARAAARQARAKALARQLGVAA [SEQ ID NO: 33];

and
(ii) a carrier; and

(b) administering the composition to the subject in need thereof;
wherein the therapeutic amount is effective
1. to enhance or improve outgrowth of at least one neurite process form a neuron cell body;
2. to reduce or inhibit at least one manifestation of progression of the neuronal injury in at least one neuronal cell population affected by the neuronal injury; and
3. to increase survival of the at least one neuronal cell population affected by the neuronal injury.

16. The method according to claim 15 , wherein the neuronal injury is a neurapraxia type injury.

17. The method according to claim 15 , wherein the injury is an axonotmesis type injury.

18. The method according to claim 15 , wherein the injury is a neurotmesis type injury.

19. The method according to claim 15 , wherein the injury results from an acute disorder.

20. The method according to claim 19 , wherein the acute disorder is a stroke, a spinal cord injury, or a traumatic brain injury.

21. The method according to claim 15 , wherein the at least one manifestation of progression of the neuronal injury in at least one neuronal cell population is apoptotic cell death.

22. The method according to claim 15 , wherein the at least one manifestation of progression of the neuronal injury in at least one neuronal cell population is microglial activation.

23. The method according to claim 15 , wherein the at least one manifestation of progression of the neuronal injury in at least one neuronal cell population is inflammation.

24. The method according to claim 15 , wherein the at least one manifestation of progression of the neuronal injury in at least one neuronal cell population is formation of a scar.

25. The method according to claim 15 , wherein the neuronal cell population is a cortical cell population.

26. The method according to claim 15 , wherein the neuronal cell population is a mixed cortical cell population.

27. The method according to claim 26 , wherein the mixed cortical cell population comprises neurons, microglia, and astrocytes.

28. The method according to claim 15 , wherein the composition protects at least one neuron from progression of a neuronal injury by inhibiting expression of at least one inflammatory cytokine from activated microglia.

29. The method according to claim 28 , wherein the at least one inflammatory cytokine is at least one of IL-1 beta, IL-6, and TNF-alpha.

Assignees

• Panitch Alyssa
• Otto Kevin
• Onunkwo Nnadozie
• Woolley Andrew
• Purdue Research Foundation

Inventors

• Panitch Alyssa
• Otto Kevin
• Onunkwo Nnadozie
• Woolley Andrew

Classifications

• A61L15/32

  Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin {(A61L15/225 takes precedence)} · CPC title

• C07K14/001

  by chemical synthesis · CPC title

• A61L2430/32

  for nerve reconstruction · CPC title

• A61L2300/41

  Anti-inflammatory agents, e.g. NSAIDs · CPC title

• A61L27/227

  Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24 · CPC title