Cardiac Regenerative Therapy with Cyclin A2

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$499,998.00
Award Year:
2009
Program:
STTR
Phase:
Phase I
Contract:
1R41HL088867-01A1
Agency Tracking Number:
HL088867
Solicitation Year:
n/a
Solicitation Topic Code:
n/a
Solicitation Number:
n/a
Small Business Information
VENTRINOVA, INC.
VENTRINOVA, INC., 1 Columbus Place, New York, NY, 10019
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
783142131
Principal Investigator:
HINA CHAUDHRY
(212) 241-4082
HINA.CHAUDHRY@MSSM.EDU
Business Contact:
SARDAR CHAUDHRY
() -
hina.chaudhry@mssm.edu
Research Institution:
MOUNT SINAI SCHOOL OF MEDICINE OF NYU

MOUNT SINAI SCHOOL OF MEDICINE
OF NEW YORK UNIVERSITY
NEW YORK, NY, 10029 6574

Nonprofit college or university
Abstract
DESCRIPTION (provided by applicant): The morbidity and mortality due to cardiovascular disease is attributed to the lack of significant replicative potential of adult mammalian cardiomyocytes. Thus myocyte loss in response to ischemic injury typically resu lts in scar formation and a decline of cardiac function that is usually irreversible. The cessation of myocyte proliferation is associated with an arrest of the cell cycle. Cyclin A2 is the sole cyclin regulating two major transitions of the cell cycle, bo th G1/S and G2/M. It is also the only cyclin to be completely silenced in mammalian hearts after birth. We have previously demonstrated in a transgenic mouse model that constitutive expression of cyclin A2 in the mouse myocardium elicits mitoses in postnat al hearts. Furthermore, we have shown that cyclin A2 is critical in mediating cardiac regeneration after myocardial infarction (MI) is induced in the transgenic mice. The regenerative ability of cyclin A2 appears to involve enhanced proliferation of endoge nous cardiac progenitor cells, in addition to potential dedifferentiation of mature cardiomyocytes in the peri-infarct zone. We have also demonstrated that exogenously administered cDNA encoding cyclin A2 via adenoviral vector can ameliorate cardiac functi on post-MI in genetically naive adult rats with a significant increase in all proliferative indices examined. We now aim to explore whether cyclin A2 will affect cardiac repair after MI in a large animal model. These are critical pre-clinical studies that will form the basis of future human clinical trials. We will utilize both adenoviral cyclin A2 driven by the CMV promoter and a novel adeno-associated vector (AAV9) to deliver cyclin A2 cDNA to the infarcted porcine heart in a cardiac-specific manner. We w ill test both direct myocardial injection and antegrade coronary infusion methods. We will perform analyses of cardiac function in animals that receive cyclin A2 compared to those that receive null vectors. We will examine the effects of cyclin A2 on endog enous cardiac progenitor cells, and determine whether cyclin A2 can regulate proliferation of these cells in the porcine model. We will also examine the effect of cyclin A2 on the mature cardiomyocytes of the peri-infarct and distal zones. Our proposal off ers a new and exciting approach to cardiac regeneration in the face of controversial results of stem cell transplantation as a method to achieve myogenesis. As cardiovascular disease remains the number one killer in the western world, cyclin A modulation m ay have a major impact on the spectrum of human disease. PUBLIC HEALTH RELEVANCE: Congestive heart failure is the leading cause of hospitalization in the U.S. and cardiovascular disease remains the number one killer in the western world. The morbidity and mortality of cardiovascular disease is due to the fact that the heart cannot regenerate after an injury such as myocardial infarction (MI). We have found that cyclin A2, a key developmental gene, is able to regenerate heart cells in small animal models of MI. We will now test the ability of cyclin A2 to regenerate the heart after MI in large animals as a basis for the future design of human clinical trials.

* information listed above is at the time of submission.

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