Cardiomyocytes in the adult mammal exhibit little if any capacity to undergo cell division. Consequently cardiomyocyte loss due to injury or disease is irreversible. The ability to utilize intracardiac grafting as a means to replace scarred, nonfunctional myocardium in a diseased heart with viable, functional cardiomyocytes would have significant therapeutic value. In addition, long-term delivery of recombinant molecules (as for example cardioprotective proteins, angiogenic factors, inotropic peptides or neurotrophins) via genetically engineered myocyte grafts could be of therapeutic value for individuals with myocardial ischemia or congestive heart failure. The local delivery of such molecules may also significantly reduce the arrhythmogenic potential of compromised myocardium without the complications which arise from systemic delivery. Preliminary experiments from this laboratory have established the feasibility of intra-cardiac grafting using a variety of cell types. These studies demonstrate that the myocardium can serve as a stable platform for cells which have been manipulated in vitro, and suggest that intra-cardiac grafts may provide a useful means for the local, long-term delivery of recombinant molecules to the heart. In this application we propose to extend these findings in an effort to develop models which test the feasibility of utilizing intra-cardiac grafting to effect both myocardial replacement and therapeutic delivery of recombinant molecules. We propose two Specific Aims. They are: (1) To develop models which test the feasibility of intracardiac grafting as a means to effect myocardial repair. (2) Develop models which test the feasibility of intra-cardiac grafting as a means to effect long term delivery of recombinant protein to the myocardium. In each instance, feasibility of the approach will first be established in mice. Once successful, similar grafting procedures will be attempted in dogs, where the in house availability of well established methods to assess both cardiovascular function and arrhythmogenic predilection can be employed to ascertain the functional significance of the grafting maneuver. These experiments will be performed in collaboration with the other components of this SCOR program.
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