Methods and compositions for regulating SRCA2A expression levels in myocardial infarction

Patent metadata

Field	Value
Publication number	US-9877997-B2
Application number	US-201414899007-A
Country	US
Kind code	B2
Filing date	Jun 24, 2014
Priority date	Jun 26, 2013
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

Abstract

The disclosure provides methods and compositions for increasing SERCA2a expression levels in a mammalian subject in need thereof. The methods comprise administering to the subject a therapeutic amount of an aromatic-cationic peptide to subjects in need thereof. In some embodiments, the aromatic-cationic peptide is D-Arg-2′6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof such as acetate or trifluoroacetate salt. In some embodiments, the subject has suffered a myocardial infarction.

First claim

What is claimed is:

1. A method for increasing sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) gene expression in a mammalian subject in need thereof, comprising administering to the mammalian subject a therapeutically effective amount of an aromatic-cationic peptide, wherein the aromatic-cationic peptide comprises D-Arg-2′6′-Dmt-Lys-Phe-NH 2 , or a pharmaceutically acceptable salt thereof, wherein the subject has suffered a myocardial infarction.

2. The method of claim 1 , wherein the myocardial infarction results from hypertension, ischemic heart disease, exposure to a cardiotoxic compound, myocarditis, thyroid disease, viral infection, gingivitis, drug abuse, alcohol abuse, pericarditis, atherosclerosis, vascular disease, hypertrophic cardiomyopathy, acute myocardial infarction, left ventricular systolic dysfunction, coronary bypass surgery, starvation, an eating disorder, or a genetic defect.

3. The method of claim 1 , wherein the aromatic-cationic peptide is administered about 0.5 hours to 4 hours after the myocardial infarction.

4. The method of claim 1 , wherein the increase of SERCA2a gene expression prevents, ameliorates, or treats left ventricular (LV) remodeling.

5. The method of claim 1 , wherein the increase of SERCA2a gene expression increases LV function compared to a control subject not administered the aromatic-cationic peptide.

6. The method of claim 5 , wherein increased LV function is determined by one or more physiological measures factors from the group consisting of reduced LV stroke volume, improved LV ejection fraction, improved fractional shortening, reduced infarct expansion, improved hemodynamics, and reduced lung volumes.

7. The method of claim 1 , wherein the subject is a human.

8. The method of claim 1 , wherein the peptide is administered orally, topically, systemically, intravenously, subcutaneously, intraperitoneally, or intramuscularly.

9. The method of claim 1 , further comprising separately, sequentially or simultaneously administering a cardiovascular agent to the subject.

10. The method of claim 9 , wherein the cardiovascular agent is selected from the group consisting of an anti-arrhthymia agent, a vasodilator, an anti-anginal agent, a corticosteroid, a cardioglycoside, a diuretic, a sedative, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II antagonist, a thrombolytic agent, a calcium channel blocker, a throboxane receptor antagonist, a radical scavenger, an anti-platelet drug, a β-adrenaline receptor blocking drug, α-receptor blocking drug, a sympathetic nerve inhibitor, digoxin, an inotrope, captopril, and an antihyperlipidemic drug.

Assignees

• Stealth Biotherapeutics Corp
• Stealth Biotherapeutics Corp

Inventors

• Wilson D Travis
• Kloner Robert A

Classifications

• A61K38/07

  Tetrapeptides · CPC title

• A61K31/573

  substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone · 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

• A61K31/401

  Proline; Derivatives thereof, e.g. captopril · CPC title

• A61K38/06 Primary

  Tripeptides · CPC title