# US 2021/0330757 A1 · Methods and compositions for inducing neural plasticity

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- Number: US 2021/0330757 A1
- Document ID: US20210330757A1
- Status: Published application
- Kind: A1
- Application number: 17/272,393
- Filed: 2019-08-29
- Published: 2021-10-28
- Earliest claimed: 2018-09-05
- Assignees: Case Western Reserve University
- Applicants: Case Western Reserve University
- Inventors: Jerry Silver; Yu Luo; Fucheng Luo
- Web page: https://patentgrep.com/patent/US20210330757A1

## CPC

- A61K 38/465: {acting on ester bonds (3.1), e.g. lipases, ribonucleases}
- A61K 38/005: {Enzyme inhibitors (protease inhibitors A61K38/55)}
- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61P 25/00: Drugs for disorders of the nervous system
- C12N 9/16: acting on ester bonds (3.1)
- C12Y 301/03048: Protein-tyrosine-phosphatase (3.1.3.48)
- A61K 9/0019: {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)}
- C07K 2319/10: containing a tag for extracellular membrane crossing, e.g. TAT or VP22
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## 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.

## Claims

### Claim 1

A method of promoting compensatory plasticity of spared neural cells after a neural injury, comprising:
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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1, 2, 3)

The method of any one of claims 1-3, wherein the peptide induces compensatory neurite outgrowth of the spared neural cells.

### Claim 6 (depends on 5)

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

### Claim 7 (depends on 5)

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

### Claim 8 (depends on 1, 2, 3, 4)

The method of any one of claims 1-4, wherein the peptide induces compensatory migration of spared neural cells toward the neural injury.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7, 8)

The method of any one of claims 1-8, wherein the neural injury is in the central nervous system.

### Claim 10 (depends on 9)

The method of claim 9, wherein the neural injury is in the brain.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1-10, wherein the neural injury is caused by traumatic brain injury (TBI), multiple sclerosis (MS), Alzheimer's disease, ischemia, stroke, aneurysm, cerebral hemorrhage, thrombus, or embolism.

### Claim 12 (depends on 11)

The method of claim 11, wherein the TBI is a concussion.

### Claim 13 (depends on 11)

The method of claim 11, wherein the ischemia is focal ischemia or global ischemia.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

The method of any one of claims 1-13, wherein the amino acid sequence has at least 78%, at least 85%, or at least 92% identity to SEQ ID NO:32.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The method of any one of claims 1-14, 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.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

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

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

The method of any one of claims 1-16, wherein the therapeutic agent further comprises a transport moiety linked to the therapeutic peptide and facilitates uptake of the therapeutic peptide by a cell.

### Claim 18 (depends on 17)

The method of claim 17, wherein the transport moiety is an HIV Tat transport moiety.

### Claim 19 (depends on 17, 18)

The method of claim 17 or 18, wherein the transport moiety is linked to the therapeutic peptide by a peptide linker.

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The method of claims 1-14, wherein the therapeutic agent comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 35-61.

### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)

The method of any of claims 1-20, wherein the spared neural cells are contacted with the therapeutic agent within 7 days post injury.

### Claim 22

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 by 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.

### Claim 23 (depends on 22)

The method of claim 22, wherein the spared neural cells are neural stem cells.

### Claim 24 (depends on 22)

The method of claim 22, wherein the spared neural stem cells comprise oligodendrocyte progenitor cells (OPCs) and/or glial precursor cells (GPCs).

### Claim 25 (depends on 22)

The method of claim 22, wherein the spared neural cells are neurons.

### Claim 26 (depends on 22, 23, 24, 25)

The method of one of claims 22-25, wherein the peptide induces compensatory neurite outgrowth in the spared neural cells.

### Claim 27 (depends on 26)

The method of claim 26, wherein the neurite outgrowth comprises axonal sprouting in the spared neural cells.

### Claim 28 (depends on 26)

The method of claim 26, wherein the neurite outgrowth comprises dendrite sprouting or branching in the spared neural cells.

### Claim 29 (depends on 22, 23, 24)

The method of any one of claims 22-24, wherein the peptide induces compensatory migration of spared neural cells toward the neural injury.

### Claim 30 (depends on 22, 23, 24, 25, 26, 27, 28, 29)

The method of any one of claims 22-29, wherein the neural injury is in the central nervous system.

### Claim 31 (depends on 30)

The method of claim 30, wherein the neural injury is in the brain.

### Claim 32 (depends on 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)

The method of any one of claims 22-31, wherein the neural injury is caused by traumatic brain injury (TBI), multiple sclerosis (MS), Alzheimer's disease, ischemia, stroke, aneurysm, cerebral hemorrhage, thrombus, or embolism.

### Claim 33 (depends on 34)

The method of claim 34, wherein the TBI is a concussion.

### Claim 34 (depends on 34)

The method of claim 34, wherein the ischemia is focal ischemia or global ischemia.

### Claim 35 (depends on 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)

The method of any one of claims 22-34, wherein the amino acid sequence has at least at least 78%, at least 85%, or at least 92% identity to SEQ ID NO: 32.

### Claim 36 (depends on 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

The method of any one of claims 22-35, 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.

### Claim 37 (depends on 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

The method of any one of claims 22-35, wherein the therapeutic peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:1-25 and 32.

### Claim 38 (depends on 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37)

The method of any one of claims 22-37, wherein the therapeutic agent further comprises a transport moiety linked to the therapeutic peptide and facilitates uptake of the therapeutic peptide by a cell.

### Claim 39 (depends on 38)

The method of claim 38, wherein the transport moiety is an HIV Tat transport moiety.

### Claim 40 (depends on 38, 39)

The method of claim 38 or 39, wherein the transport moiety is linked to the therapeutic peptide by a peptide linker.

### Claim 41 (depends on 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

The method of any one of claims 22-35, wherein the therapeutic agent comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:35-61.

### Claim 42 (depends on 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41)

The method of any one of claims 22-41, wherein the spared neural cells are contacted with the therapeutic agent within 7 days post injury.

### Claim 43 (depends on 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42)

The method of any one of claims 22-42, wherein the subject is a human or other non-human mammal.

### Claim 44 (depends on 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

The method of any one of claim 22-43, wherein the therapeutic agent is administered systemically, intrathecally, or intravitreally to the subject.