PRESERVATION OF THE NEUROMUSCULAR JUNCTION (NMJ) AFTER TRAUMATIC NERVE INJURY

• US 20140170162A1
• Filed: 12/18/2013
• Published: 06/19/2014
• Est. Priority Date: 12/18/2012
• Status: Abandoned Application

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Gupta, Ranjan
• Application Number:
  US14/133,414
• Publication Number:
  US 20140170162A1
• Time in Patent Office: Days
• US Class Current: 424/158.1
• 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 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/609 Amides, e.g. salicylamide labetalol, metoclopramide A61K31/166
• CPC Class Codes: A61K 31/65 Tetracyclines
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138

Abstract

The invention relates to treatment and/or prevention of nerve injury. In one embodiment, the present invention provides a method of preserving the neuromuscular junction (NMJ) in an individual by administering a therapeutically effective dosage of a composition comprising an inhibitor of Wnt3a, and an inhibitor of MMP3 to the individual. In another embodiment, the present invention provides a method of stabilizing NMJ after nerve injury by inhibiting the WNT and beta-catenin signaling pathway and preserving agrin.

Claims

1. A method of treating nerve injury in an individual, comprising:

providing a composition comprising one or more of the following;

agrin, an inhibitor of the matrix metalloproteinase 3 (MMP3) signaling pathway, an inhibitor of the WNT signaling pathway, and an inhibitor of the beta-catenin signaling pathway; and

administering a therapeutically effective dosage of the composition to the individual.

2. The method of claim 1, wherein the composition is administered in conjunction with surgical treatment.

3. The method of claim 1, wherein the individual is a human.

4. The method of claim 1, wherein the inhibitor of the MMP3 signaling pathway is an inhibitor of MMP3.

5. The method of claim 1, wherein the inhibitor of the WNT signaling pathway is an inhibitor of Wnt3a.

6. The method of claim 1, wherein the nerve injury is treated by preserving the neuromuscular junction (NMJ).

7. The method of claim 1, wherein administering the composition prevents degradation of the motor end plate after prolonged denervation.

8. The method of claim 1, wherein the composition is administered prior to nerve injury surgery.

9. The method of claim 1, wherein the composition is administered post nerve injury surgery.

10. The method of claim 1, wherein the composition is administered intravenously.

11. The method of claim 1, wherein the inhibitor of the MMP3 signaling pathway is selected from the following:

minocycline, MMP Inhibitor II, MMP Inhibitor V, CP 471474, MMP-3 Inhibitor I, MMP-3 Inhibitor II, MMP-3 Inhibitor III, MMP-3 Inhibitor IV, actinonin, MMP-3 Inhibitor V, MMP-3 Inhibitor VIII, MMP-13 Inhibitor I, NNGH, PD166793, UK 370106, UK 356618.

12. The method of claim 1, wherein the inhibitor of the MMP3 signaling pathway is an MMP3 siRNA molecule.

13. The method of claim 1, wherein the inhibitor of the WNT signaling pathway is an Wnt3a siRNA molecule.

14. The method of claim 1, wherein the inhibitor of the WNT signaling pathway is an inhibitor of the armadillo protein β

-catenin.

15. The method of claim 1, wherein the inhibitor of the WNT signaling pathway is an inhibitor of one or more of the following:

beta-catenin destruction complex, WNT/Beta-catenin signalsome, cadherin junctions, and hypoxi sensing system Hif-1alpha (hypoxia induced factor 1beta).

16. The method of claim 1, wherein the inhibitor of the WNT signaling pathway is one or more of the following:

XAV939, IWR1, IWP-1, IWP-2, JW74, JW55, okadaic acid, tautomycein, 2-[4-(4-fluoro-phenyl)piperazin-1-yl]-6-methylpyrimidin-4(3H)-one, niclosamide, cambinol, sulindac, filipin, bosutinib, imatinib, ethacrynic acid, PKF118-744, BC21, and Rp-8-Br-cAMP.

17. A composition comprising:

a therapeutically effective dosage of a composition comprising one or more of the following;

agrin, an inhibitor of the matrix metalloproteinase 3 (MMP3) signaling pathway, an inhibitor of the WNT signaling pathway, and an inhibitor of the beta-catenin signaling pathway; and

a pharmaceutically acceptable carrier.

18. The composition of claim 17, wherein the inhibitor of the MMP3 signaling pathway is an inhibitor of MMP3.

19. The composition of claim 18, wherein the inhibitor of MMP3 is an MMP3 antibody.

20. The composition of claim 18, wherein the inhibitor of MMP3 is selected from the following:

minocycline, MMP Inhibitor II, MMP Inhibitor V, CP 471474, MMP-3 Inhibitor I, MMP-3 Inhibitor II, MMP-3 Inhibitor III, MMP-3 Inhibitor IV, actinonin, MMP-3 Inhibitor V, MMP-3 Inhibitor VIII, MMP-13 Inhibitor I, NNGH, PD166793, UK 370106, UK 356618.

21. The composition of claim 17, wherein the inhibitor of the WNT signaling pathway is an inhibitor of Wnt3a.

22. The composition of claim 21, wherein the inhibitor of Wnt3a is an Wnt3a antibody.

23. The composition of claim 17, wherein the inhibitor of MMP3 signaling pathway is selected from the following:

XAV939, IWR1, IWP-1, IWP-2, JW74, JW55, okadaic acid, tautomycein, 2-[4-(4-fluoro-phenyl)piperazin-1-yl]-6-methylpyrimidin-4(3H)-one, niclosamide, cambinol, sulindac, filipin, bosutinib, imatinib, ethacrynic acid, PKF118-744, BC21, and Rp-8-Br-cAMP.

24. A method of preventing nerve injury in an individual, comprising:

providing a composition comprising one or more of the following;

agrin, an inhibitor of the matrix metalloproteinase 3 (MMP3) signaling pathway, an inhibitor of the WNT signaling pathway, and an inhibitor of the beta-catenin signaling pathway; and

administering a therapeutically effective dosage of the composition to the individual prior to nerve injury.

25. The method of claim 24, wherein the composition is administered intravenously.

26. A method of preserving the motor end plate after nerve injury in a subject, comprising:

providing a composition comprising MMP3 pathway specific siRNA, WNT pathway specific siRNA, and beta-catenin pathway specific siRNA; and

transfecting one or more cells of the subject with the composition.

27. The method of claim 26, wherein the composition comprises SEQ. ID. NO.:

1 and SEQ. ID. NO.;

2.

28. The method of claim 26, wherein the subject is a human.

29. The method of claim 26, wherein the subject is a rodent.