LIPOFECTIN-MEDIATED VERSUS ADENOVIRUS-MEDIATED GENE-TRANSFER IN-VITRO AND IN-VIVO - COMPARISON OF CANINE AND PORCINE MODEL SYSTEMS

Background: Restenosis after coronary angioplasty might be prevented by locally delivered gene therapy in conjunction with percutaneous transluminal coronary angioplasty (PTCA), since this approach should provide a sustained source of therapeutic protein within the dilated lesion. However, the potential application of gene therapy is limited by the technical barrier of efficiently transferring genes to vascular cells. Methods: We used cultured coronary smooth muscle cells of human, porcine, and canine origin to evaluate three methods of gene transfer: recombinant adenovirus, liposomal complexes (Lipofectin), and Lipofectin supplemented with hemagglutinin. We then compared Lipofectin- and adenovirus-mediated direct gene transfer in canine and porcine coronary arteries. Results: The lipofection of cultured smooth muscle cells was enhanced by adding hemagglutinin, yielding luciferase levels that were 631-fold (human), ninefold (porcine), and sevenfold (canine) higher than with Lipofectin alone. However, the recombinant adenovirus directed even higher levels of gene expression, yielding luciferase levels that were 113 000-fold (human), 450-fold (porcine), and 230-fold (canine) higher than with Lipofectin alone. After percutaneous transluminal local delivery to intact canine coronary arteries, the adenovirus produced 55 times more luciferase than did Lipofectin. In living porcine coronary arteries, adenovirus produced 95 times more luciferase than did Lipofectin. Conclusion: Recombinant adenovirus produces far more recombinant protein than does Lipofectin after percutaneous transluminal direct gene transfer to canine and porcine coronary arteries. Adenoviral vectors may therefore prove useful in evaluating the potential of gene therapy in large animal models of coronary restenosis.