Methods for the regulation of matrix metalloproteinase expression

• US 9,884,085 B2
• Filed: 06/24/2014
• Issued: 02/06/2018
• 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:
  US14/898,999
• Publication Number:
  US 20160151445A1
• Time in Patent Office: 1,323 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 38/07 Tetrapeptides
• CPC Class Codes: A61K 38/55 Protease inhibitors
• 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 of reducing MMP-9 expression and/or MMP-9 activity in a mammalian subject. The disclosure also provides methods of increasing TIMP-1 expression and/or TIMP-1 activity in a mammalian subject. The methods comprise administering a therapeutically effective amount of an aromatic-cationic peptide to a subject in need thereof.

Claims

1. A method for reducing matrix metalloproteinase 9 (MMP-9) gene expression in a mammalian subject in need thereof compared to MMP-9 gene expression in a healthy control subject, 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 aromatic-cationic peptide is administered about 0.5 hours to about 4 hours after the myocardial infarction.

3. The method of claim 1, wherein the reduction of MMP-9 gene expression prevents, ameliorates, or treats left ventricular (LV) remodeling.

4. The method of claim 1, wherein the reduction of MMP-9 gene expression increases LV function compared to a control subject not administered the aromatic-cationic peptide.

5. The method of claim 4, wherein increased LV function is determined by one or more physiological 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.

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

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

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

9. The method of claim 8, 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, an α

-receptor blocking drug, a sympathetic nerve inhibitor, digoxin, an inotrope, captopril, and an antihyperlipidemic drug.

10. A method for increasing tissue inhibitor of metalloproteinase 1 (TIMP-1) gene expression in a mammalian subject in need thereof compared to TIMP-1 gene expression in a healthy control subject, 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 any pharmaceutical salts thereof, wherein the subject has suffered a myocardial infarction.

11. The method of claim 10, wherein the aromatic-cationic peptide is administered about 0.5 hours to 4 hours after the myocardial infarction.

12. The method of claim 10, wherein the increase of TIMP-1 gene expression prevents, ameliorates, or treats LV remodeling.

13. The method of claim 10, wherein the increase in TIMP-1 gene expression increases LV function compared to a control subject not administered the aromatic-cationic peptide.

14. The method of claim 13, wherein increased LV function is determined by one or more physiological 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.

15. The method of claim 10, wherein the subject is a human.

16. The method of claim 10, wherein the peptide is administered orally, topically, systemically, intravenously, subcutaneously, intraperitoneally, or intramuscularly.

17. The method of claim 10, further comprising separately, sequentially or simultaneously administering a cardiovascular agent to the subject.

18. The method of claim 17, 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, an α

-receptor blocking drug, a sympathetic nerve inhibitor, digoxin, an inotrope, captopril, and an antihyperlipidemic drug.