Compositions and methods of treating root avulsion injury

Patent metadata

Field	Value
Publication number	US-10898550-B2
Application number	US-201916381826-A
Country	US
Kind code	B2
Filing date	Apr 11, 2019
Priority date	Oct 9, 2014
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

A method of treating root avulsion injury in a subject in need thereof includes administering to the subject a therapeutic agent that inhibits one or more of catalytic activity, signaling, and function of PTPσ.

First claim

Having described the invention, we claim:

1. A method of treating root avulsion injury in a subject in need thereof, the method comprising:
administering to the subject a therapeutic agent that inhibits one or more of catalytic activity, signaling, and function of PTPσ, wherein the therapeutic agent comprises a therapeutic peptide, the therapeutic peptide comprising an amino acid sequence with at least 70% identity to SEQ ID NO:32 or SEQ ID NO:63.

2. The method of claim 1 , wherein the amino acid sequence has at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% identity to SEQ ID NO:32 or SEQ ID NO:63.

3. The method of claim 1 , wherein the therapeutic peptide comprises a substitution of an amino acid of at least one of residue 4, 5, 6, 7, 9, 10, 12, or 13 of SEQ ID NO: 32 for another amino acid, wherein the amino acid residue 4E is substituted with D or Q, amino acid residue 5R is substituted with H, L or K, amino acid residue 6L is substituted with I, V or M, amino acid residue 7K is substituted with R or H, amino acid residue 9N is substituted with E or D, amino acid residue 10D is substituted with E or N, amino acid residue 12L is substituted with I, V or M, and/or amino acid residue 13K is substituted with R or H; or
the therapeutic peptide comprises a substitution of an amino acid of at least one of residue 7, 8, 9, 10, 12, or 13 of SEQ ID NO: 63 for another amino acid, wherein the amino acid residue 7E is substituted with D or Q, amino acid residue 8R is substituted with H, L or K, amino acid residue 9L is substituted with I, V or M, amino acid residue 10K is substituted with R or H, amino acid residue 12N is substituted with E or D, and/or amino acid residue 13D is substituted with E or N.

4. The method of claim 1 , wherein the therapeutic peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-25, 32, and 63.

5. The method of claim 1 , wherein the therapeutic agent further comprises a transport moiety linked to the therapeutic peptide and facilitates uptake of the therapeutic peptide by a nerve cell being treated.

6. The method of claim 5 , wherein the transport moiety is an HIV Tat transport moiety.

7. The method of claim 5 , wherein the transport moiety is linked to the therapeutic peptide by a peptide linker.

8. The method of claim 5 , wherein the therapeutic agent comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:33-58.

9. The method of claim 1 , wherein the therapeutic agent is administered systemically to the subject being treated.

10. The method of claim 1 , further comprising connecting an avulsed end in a peripheral nerve to a portion of the central nervous system.

11. The method of claim 1 , wherein the therapeutic agent is administered at an amount effective to increase survival rate of injured motoneurons, enhance regrowth across inhibitory central nervous system scar into re-implanted spinal roots, regenerate axons, decrease muscle atrophy, and/or promote motor functional recovery.

12. A method of treating denervation-induced muscle atrophy in a subject in need thereof; the method comprising:
administering to the subject a therapeutic agent that inhibits one or more of catalytic activity, signaling, and function of PTPσ, wherein the therapeutic agent comprises a therapeutic peptide, the therapeutic peptide comprising an amino acid sequence with at least 70% identity to SEQ ID NO:32 or SEQ ID NO:63.

13. The method of claim 12 , wherein the therapeutic peptide comprises a substitution of an amino acid of at least one of residue 4, 5, 6, 7, 9, 10, 12, or 13 of SEQ ID NO: 32 for another amino acid, wherein the amino acid residue 4E is substituted with D or Q, amino acid residue 5R is substituted with H, L or K, amino acid residue 6L is substituted with I, V or M, amino acid residue 7K is substituted with R or H, amino acid residue 9N is substituted with E or D, amino acid residue 10D is substituted with E or N, amino acid residue 12L is substituted with I, V or M, and/or amino acid residue 13K is substituted with R or H; or
the therapeutic peptide comprises a substitution of an amino acid of at least one of residue 7, 8, 9, 10, 12, or 13 of SEQ ID NO: 63 for another amino acid, wherein the amino acid residue 7E is substituted with D or Q, amino acid residue 8R is substituted with H, L or K, amino acid residue 9L is substituted with I, V or M, amino acid residue 10K is substituted with R or H, amino acid residue 12N is substituted with E or D, and/or amino acid residue 13D is substituted with E or N.

14. The method of claim 12 , wherein the therapeutic peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-25, 32, and 63.

15. The method of claim 12 , wherein the therapeutic agent further comprises a transport moiety linked to the therapeutic peptide and facilitates uptake of the therapeutic peptide by a nerve cell being treated.

16. The method of claim 15 , wherein the transport moiety is an HIV Tat transport moiety.

17. The method of claim 12 , wherein the therapeutic agent is administered systemically to the subject being treated.

18. The method of claim 12 , wherein the muscle atrophy results from a traumatic nerve injury or a neurodegenerative motor neuron disease.

19. A method of promoting muscle reinnervation in a subject in need thereof; the method comprising:
administering to the subject a therapeutic agent that inhibits one or more of catalytic activity, signaling, and function of PTPσ, wherein the therapeutic agent comprises a therapeutic peptide, the therapeutic peptide comprising an amino acid sequence with at least 70% identity to SEQ ID NO:32 or SEQ ID NO:63.

20. The method of claim 19 , wherein the therapeutic peptide comprises a substitution of an amino acid of at least one of residue 4, 5, 6, 7, 9, 10, 12, or 13 of SEQ ID NO: 32 for another wherein the therapeutic peptide comprises a substitution of an amino acid of at least one of residue 4, 5, 6, 7, 9, 10, 12, or 13 of SEQ ID NO: 32 for another amino acid, wherein the amino acid residue 4E is substituted with D or Q, amino acid residue 5R is substituted with H, L or K, amino acid residue 6L is substituted with I, V or M, amino acid residue 7K is substituted with R or H, amino acid residue 9N is substituted with E or D, amino acid residue 10D is substituted with E or N, amino acid residue 12L is substituted with I, V or M, and/or amino acid residue 13K is substituted with R or H; or
the therapeutic peptide comprises a substitution of an amino acid of at least one of residue 7, 8, 9, 10, 12, or 13 of SEQ ID NO: 63 for another amino acid, wherein the amino acid residue 7E is substituted with D or Q, amino acidresidue 8R is substituted with H, L or K, amino acid residue 9L is substituted with I, V or M, amino acid residue 10K is substituted with R or H, amino acid residue 12N is substituted with E or D, and/or amino acid residue 13D is substituted with E or N.

21. The method of claim 19 , wherein the therapeutic peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-25, 32, and 63.

22. The method of claim 19 , wherein the therapeutic agent further comprises a transport moiety linked to the therapeutic peptide and facilitates uptake of the therapeutic peptide by a nerve cell being treated.

23. The method of claim 22 , wherein the transport moiety is an HIV Tat transport moiety.

24. The method of claim 19

Assignees

• Case Western Resereve Univ
• Versitech Ltd
• Univ Case Western Reserve

Inventors

• Silver Jerry
• Lang Bradley T
• Cregg Jared M
• Weng Yi-Lan
• Li Heng
• Wu Wutian

Classifications

• A61K2039/5158

  Antigen-pulsed cells, e.g. T-cells · CPC title

• A61K38/005

  Enzyme inhibitors (protease inhibitors A61K38/55) · CPC title

• C12Y301/03048

  Protein-tyrosine-phosphatase (3.1.3.48) · CPC title

• A61K2039/55522

  Cytokines; Lymphokines; Interferons · CPC title

• A61K38/465 Primary

  acting on ester bonds (3.1), e.g. lipases, ribonucleases · CPC title