# US 11,433,116 B2 · GJA1 isoforms protect against metabolic stress

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- Number: US 11,433,116 B2
- Document ID: US11433116B2
- Status: Granted
- Kind: B2
- Application number: 16/089,890
- Filed: 2017-04-13
- Published: 2019-04-25
- Granted: 2022-09-06
- Earliest claimed: 2016-04-14
- Assignees: Cedars-Sinai Medical Center
- Applicants: Cedars-Sinai Medical Center
- Inventors: Robin Shaw; TingTing Hong; Ying Fu; Shaohua Xiao; Wassim Basheer
- Web page: https://patentgrep.com/patent/US11433116B2

## CPC

- A61K 38/1709: {from mammals}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 38/17: from animals; from humans {(enzyme inhibitors A61K38/005)}
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C07K 14/47: from mammals
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- 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
- 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

The present invention describes methods of treating, preventing, reducing the likelihood of having, reducing the severity of and/or slowing the progression of a medical condition related to ischemia/reperfusion in a subject using GJA1-20k as a therapeutic agent. The invention further provides a method of protecting a cell from metabolic stress, using GJA1-20k. The invention also provides for a composition and/or gene expression vector comprising GJA1-20k.

## Claims

### Claim 1

A method of treating, reducing the likelihood of having, reducing the severity of and/or slowing the progression of a condition in a subject, comprising: providing a polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, or a polypeptide consisting of the GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3 fused to a cell penetrating peptide (CPP), or a gene expression vector comprising a sequence encoding the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, wherein the gene expression vector is configured for expressing the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3; and administering a therapeutically effective amount of the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, the polypeptide consisting of the GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3 fused to a cell penetrating peptide (CPP), the gene expression vector comprising the sequence encoding the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, to the subject, thereby treating, reducing the likelihood of having, reducing the severity of and/or slowing the progression of the condition in the subject, wherein the condition is metabolic stress, ischemia, or both.

### Claim 2 (depends on 1)

The method of claim 1, wherein the subject is one who has had a previous myocardial infarction.

### Claim 3 (depends on 1)

The method of claim 1, wherein the administration of the polypeptide consisting of the GJA1-20k polypeptide or the GJA1-20k polypeptide fused to the CPP results in a cardioprotective effect.

### Claim 4 (depends on 3)

The method of claim 3, wherein the cardioprotective effect comprises a reduction in basal mitochondrial dependent oxygen consumption and maximal respiratory capacity.

### Claim 5 (depends on 1)

The method of claim 1, wherein the administration of the gene expression vector comprising the sequence encoding the polypeptide consisting of GJA1-20k polypeptide results in a cardioprotective effect.

### Claim 6 (depends on 5)

The method of claim 5, wherein the cardioprotective effect comprises a reduction in basal mitochondrial dependent oxygen consumption and maximal respiratory capacity.

### Claim 7

A method of protecting a cell from metabolic stress, comprising:
providing
a polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, or
a polypeptide consisting of the GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3 fused to a cell penetrating peptide (CPP), or
a gene expression vector comprising a sequence encoding the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, wherein the gene expression vector is configured for expressing the GJA1-20k polypeptide having SEQ ID NOs:1, 2 or 3; and contacting the cell with
the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, or
polypeptide consisting of the GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3 fused to a cell penetrating peptide (CPP), or
the gene expression vector comprising the sequence encoding the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3, thereby protecting the cell from metabolic stress.

### Claim 8 (depends on 7)

The method of claim 7, wherein contacting the cell with the GJA1-20k polypeptide or the GJA1-20k polypeptide fused to a CPP results in a reduction in basal mitochondrial dependent oxygen consumption and maximal respiratory capacity.

### Claim 9 (depends on 7)

The method of claim 7, wherein contacting the cell with the gene expression vector comprising the sequence encoding the polypeptide consisting of GJA1-20k polypeptide having SEQ ID NOs: 1, 2 or 3 results in a reduction in basal mitochondrial dependent oxygen consumption and maximal respiratory capacity.

### Claim 10 (depends on 1)

The method of claim 1, wherein the subject has or is having a myocardial infarction, open heart surgery, cardiopulmonary bypass, coronary artery reperfusion, stroke, ischemic stroke, or nephrotoxicity.

### Claim 11 (depends on 1)

The method of claim 1, wherein treating, reducing the likelihood of having, reducing the severity of and/or slowing the progression of metabolic stress or ischemia results in treating, reducing the likelihood of having, reducing the severity of and/or slowing the progression of reperfusion injury in a subject who underwent or is undergoing reperfusion.

### Claim 12 (depends on 1)

The method of claim 1, wherein the polypeptide consisting of the GJA1-20k polypeptide, polypeptide consisting of the GJA1-20k polypeptide fused to the CPP, or the gene expression vector is provided in a composition.

### Claim 13 (depends on 7)

The method of claim 7, wherein the polypeptide consisting of the GJA1-20k polypeptide, polypeptide consisting of the GJA1-20k polypeptide fused to the CPP, or the gene expression vector is provided in a composition.