Compositions and methods for cardiac regeneration
The invention relates to the use of a CITED4 polypeptide and/or a microRNA-222 or precursor (e.g., pre-miR-222) or mimic thereof, for treating a cardiovascular disease or pathological condition, such as heart failure, myocardial infarction, and for promoting post-myocardial infarction cardiac remodeling in heart tissue.
1. A method of promoting physiological cardiomyocyte growth or proliferation in vivo, the method comprising administering to an adult subject in need thereof a viral vector encoding a CITED4 (CBP/p300-Interacting Transactivator with ED-rich carboxy-terminal Domain 4) polypeptide or fusion protein thereof under the transcriptional control of a promoter,
wherein the promoter is a cardiac-specific promoter, a muscle-specific promoter, a CMV immediate early gene promoter, an SV40 early promoter, a Rous sarcoma virus long terminal repeat, a rat insulin promoter, or a glyceraldehyde-3-phosphate dehydrogenase promoter;
wherein the viral vector is an adenoviral vector or an adeno-associated viral (AAV) vector; and,
wherein the viral vector is administered to the adult subject intravenously or by direct injection into cardiac tissue.
2. A method of treating a heart disease treatable by cardiomyocyte regeneration and/or proliferation, the method comprising administering to an adult subject in need thereof a viral vector encoding a CITED4 (CBP/p300-Interacting Transactivator with ED-rich carboxy-terminal Domain 4) polypeptide or fusion protein thereof under the transcriptional control of a promoter,
wherein the promoter is a cardiac-specific promoter, a muscle-specific promoter, a CMV immediate early gene promoter, an SV40 early promoter, a Rous sarcoma virus long terminal repeat, a rat insulin promoter, or a glyceraldehyde-3-phosphate dehydrogenase promoter;
wherein the viral vector is an adenoviral vector or an adeno-associated viral (AAV) vector; and,
wherein the viral vector is administered to the adult subject intravenously or by direct injection into cardiac tissue.
3. The method of claim 1 , wherein expression or activity of the CITED4 polypeptide or fusion protein thereof is increased in a cardiomyocyte or a precursor thereof in the adult subject.
4. The method of claim 1 , wherein the AAV vector is AAV1, AAV2, or AAV9.
5. The method of claim 2 , wherein the AAV vector is AAV1, AAV2, or AAV9.
6. The method of claim 2 , wherein expression or activity of the CITED4 polypeptide or fusion protein thereof is increased in a cardiomyocyte or a precursor thereof in the adult subject.
7. The method of claim 2 , wherein the heart disease is myocardial infarction or ischemic injury; adverse remodeling after ischemic injury or infarction; myocarditis; heart failure, cardiomyopathy; or valvular heart disease.
8. The method of claim 2 , wherein therapeutic efficacy is achieved by alleviating at least one symptom of the heart disease, or by inhibiting or retarding the worsening of the symptom.
9. The method of claim 8 , wherein therapeutic efficacy is measured by a decrease in a symptom of heart failure, an augment in functional status, a decrease in natriuretic peptide level, and/or beneficial reverse left ventricular (LV) remodeling.
10. The method of claim 1 , further comprising administering to the subject a second cardiac therapy.
11. The method of claim 10 , wherein said second cardiac therapy is selected from the group consisting of a β blocker, an ionotrope, a diuretic, ACE-I, All antagonist, BNP, a Ca 2+ -blocker, an endothelin receptor antagonist, and an HDAC inhibitor.
12. The method of claim 2 , wherein the heart disease is myocardial infarction, and wherein fibrosis and/or apoptosis in the infarct zone is reduced.
13. The method of claim 2 , further comprising administering to the subject a second cardiac therapy.
14. The method of claim 13 , wherein said second cardiac therapy is selected from the group consisting of a β blocker, an ionotrope, a diuretic, ACE-I, All antagonist, BNP, a Ca 2+ -blocker, an endothelin receptor antagonist, and an HDAC inhibitor.
15. The method of claim 1 , wherein said adult subject is a human.
16. The method of claim 2 , wherein said adult subject is a human.
17. The method of claim 1 , wherein said viral vector is said AAV vector, and wherein said AAV vector is delivered to the adult subject via intracoronary infusion.
18. The method of claim 2 , wherein said viral vector is said AAV vector, and wherein said AAV vector is delivered to the adult subject via intracoronary infusion.
19. The method of claim 10 , wherein said second cardiac therapy is an antiarrhythmic agent, a sodium channel blocker, an antihypertensive agent, an anti-angiotensin II agent, a sympatholytic, a cardiovasculator therapeutic agent, an agent for the treatment of congestive heart failure, an antianginal agent, a surgery, or a combination thereof.
20. The method of claim 13 , wherein said second cardiac therapy is an antiarrhythmic agent, a sodium channel blocker, an antihypertensive agent, an anti-angiotensin II agent, a sympatholytic, a cardiovasculator therapeutic agent, an agent for the treatment of congestive heart failure, an antianginal agent, a surgery, or a combination thereof.