GJA1 isoforms protect against metabolic stress

Patent metadata

Field	Value
Publication number	US-11433116-B2
Application number	US-201716089890-A
Country	US
Kind code	B2
Filing date	Apr 13, 2017
Priority date	Apr 14, 2016
Publication date	Sep 6, 2022
Grant date	Sep 6, 2022

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.

First claim

The invention claimed is:

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.

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

3. 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.

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

5. 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.

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

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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

Assignees

• Cedars Sinai Medical Center

Inventors

• Shaw Robin
• Hong Tingting
• Fu Ying
• Xiao Shaohua
• Basheer Wassim

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• C07K14/705

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · 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

• A61K38/00

  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) · CPC title

• A61K38/177

  Receptors; Cell surface antigens; Cell surface determinants · CPC title