Methods and compositions for inducing neural plasticity

Patent metadata

Field	Value
Publication number	US-12138300-B2
Application number	US-201917272393-A
Country	US
Kind code	B2
Filing date	Aug 29, 2019
Priority date	Sep 5, 2018
Publication date	Nov 12, 2024
Grant date	Nov 12, 2024

Abstract

A method of promoting compensatory plasticity of spared neural cells after a neural injury includes contacting the spared neural cells with an effective amount of a therapeutic agent comprising a therapeutic peptide, wherein the therapeutic peptide comprises an amino acid sequence with at least 70% identity to SEQ ID NO:32.

First claim

The invention claimed is:

1. A method of promoting compensatory plasticity of spared neural cells of a subject's brain after a neural injury, comprising:
systemically administering to the subject after the neural injury an effective amount of a therapeutic agent comprising a therapeutic peptide and a transport moiety linked to the therapeutic peptide that facilitates uptake of the therapeutic peptide by a cell, wherein the therapeutic peptide comprises an amino acid sequence with at least 70% identity to SEQ ID NO: 32,
wherein the neural injury is caused by cerebral focal ischemia, cerebral global ischemia, acute ischemic stroke, malignant stroke, chronic stroke disease, thrombus, or embolism, and the therapeutic peptide induces compensatory neurite outgrowth in the spared neural cells.

2. The method of claim 1 , wherein the spared neural cells are neural stem cells.

3. The method of claim 1 , wherein the spared neural cells comprise oligodendrocyte progenitor cells (OPCs) and/or glial precursor cells (GPCs).

4. The method of claim 1 , wherein the spared neural cells are neurons.

5. The method of claim 1 , wherein the neurite outgrowth comprises axonal sprouting of the spared neural cells, dendrite sprouting of the spared neural cells, or dendrite branching of the spared neural cells.

6. The method of claim 1 , wherein the peptide induces compensatory migration of spared neural cells toward the neural injury.

7. The method of claim 1 , wherein the amino acid sequence has at least 78% identity to SEQ ID NO: 32.

8. 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.

9. 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 and 32.

10. The method of claim 1 , wherein the transport moiety is an HIV Tat transport moiety.

11. The method of claim 1 , wherein the transport moiety is linked to the therapeutic peptide by a peptide linker.

12. The method of claim 1 , wherein the therapeutic agent comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 35-61.

13. The method of claim 1 , wherein the spared neural cells are contacted with the therapeutic agent within 7 days post injury.

14. A method of treating a neural injury in a subject in need thereof, comprising:
promoting compensatory plasticity in spared neural cells after the neural injury according to claim 1 .

15. The method of claim 14 , wherein the subject is a human or other non-human mammal.

16. The method of claim 1 , wherein the therapeutic agent is systemically administered after an acute treatment window of the neural injury to promote functional recovery and/or inhibit chronic atrophy of the brain of the subject.

17. The method of claim 16 , wherein the therapeutic agent is systemically administered to the subject at least 12 hours after the neural injury.

18. The method of claim 1 , wherein the stroke comprises chronic stroke disease and the therapeutic agent is systemically administered at an amount effective to promote functional recovery and/or inhibit chronic atrophy of the brain of the subject.

19. The method of claim 10 , wherein the therapeutic peptide comprises an amino acid sequence with at least 70% identity to SEQ ID NO: 62.

20. The method of claim 19 , wherein the therapeutic peptide comprises an amino acid sequence of SEQ ID NO: 62.

21. A method for inducing compensatory plasticity in a subject comprising:
systemically administering to the subject an effective amount of a therapeutic agent comprising a therapeutic peptide, wherein the therapeutic peptide comprises an amino acid sequence with at least 70% identity to SEQ ID NO: 32,
wherein the subject has suffered a stroke caused by cerebral focal ischemia, cerebral global ischemia, acute ischemic stroke, malignant stroke, chronic stroke disease, thrombus, or embolism; and
wherein the systemic administration is carried out in a manner that the therapeutic peptide induces compensatory neurite outgrowth in spared neural cells.

22. The method of claim 21 , wherein the compensatory neurite outgrowth is axonal sprouting in the spared neural cells.

23. The method of claim 21 , wherein the compensatory neurite outgrowth is dendrite sprouting in the spared neural cells.

24. The method of claim 21 , wherein the systemic administration increases synaptic contact with neighboring, surrounding, or distant neural cells.

25. The method of claim 21 , wherein the spared neural cells are oligodendrocyte progenitor cells and/or glial precursor cells.

26. The method of claim 21 , wherein the spared neural cells are nestin+ and DCX− neural stem cells or nestin+, apt2− neural stem cells.

27. The method of claim 21 , wherein the therapeutic peptide comprises an amino acid sequence of SEQ ID NO: 62.

Assignees

• Univ Case Western Reserve

Inventors

• Silver Jerry
• Luo Yu
• Luo Fucheng

Classifications

• C12Y301/03048

  Protein-tyrosine-phosphatase (3.1.3.48) · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61P25/28

  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 title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C07K2319/10

  containing a tag for extracellular membrane crossing, e.g. TAT or VP22 · CPC title