Methods and compositions for regulating SRCA2A expression levels in myocardial infarction

• US 9,877,997 B2
• Filed: 06/24/2014
• Issued: 01/30/2018
• Est. Priority Date: 06/26/2013
• Status: Active Grant

• Current Assignee: Stealth BioTherapeutics, Inc. (Morningside Group Ltd.)
• Original Assignee: Stealth BioTherapeutics Corp. (Morningside Group Ltd.)
• Inventors: Wilson, D. Travis, Kloner, Robert A.
• Primary Examiner(s): Ha, Julie
• Assistant Examiner(s): Hellman, Kristina M
• Application Number:
  US14/899,007
• Publication Number:
  US 20160120931A1
• Time in Patent Office: 1,316 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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.

Claims

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-NH₂, 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.