Myocardial remodeling after myocardial infarction begins immediately after the infarct and leads inexorably to left ventricular dilatation and failure, with dismal prognosis. This process is tightly regulated by intracellular changes and modulated at the gene level; it is compensatory at first, but can later become maladaptive. Intervention at the gene level, using a viral vector, is a promising therapeutic option. Adenovirus, the most popular vector, is limited by its short persistence in the cell due to host inflammatory reactions and direct cytopathic effects. The SV40 (simian virus 40) pseudovirion shows promise as a persisting, non inflammation-inducing vector. We plan to study its potential as a cardiac gene delivery vector. Our hypotheses are that SV40 will deliver efficiently a reporter gene to cardiac myocytes, that expression will persist for an extended period, and that no significant inflammatory or cytopathic reaction will develop. We will examine our hypothesis both in vitro in neonatal rat cardiomyocytes in culture, and in vivo, using a rat model and a catheter-based delivery system developed by us. This project will serve as a basis for therapeutic trials of SV40-gene delivery in different models of heart failure. In addition different pathways in the remodeling process can be studied specifically by altering gene expression using this vector.
| Mukherjee, Santanu; Abd-El-Latif, Mahmoud; Bronstein, Michal et al. (2007) High cooperativity of the SV40 major capsid protein VP1 in virus assembly. PLoS One 2:e765 |
