Transgene expression in the coronary circulation: transcatheter gene delivery

Therapeutic and research applications of direct gene transfer in the coronary vasculature are limited by varying transgene activity found in the vessel wall. It remains to be determined whether this is due to difficulties in delivery of recombinant DNA into the coronary arteries or if it relates to the state of recipient cells in the arterial wall. Accordingly, using a clinically applicable protocol, we have examined the time course of transgene (luciferase) expression in porcine coronary vasculature following transcatheter gene transfer (1 day to 4 weeks). Liposome-mediated transfection by means of a transcatheter approach resulted in detectable luciferase activity in all transfected vessels at 1 day after gene delivery. However, the activity of a reporter gene rapidly declined at 7 days thereafter, with only 33% of coronary arteries demonstrating luciferase activity. Comparable levels of transgene sequences were present in transfected vessels, although no correlation with luciferase activity was found. To further determine possible mechanisms responsible for rapidly declining transgene expression in vivo, cell proliferation was induced in the vessel wall by means of either balloon denudation or by intramural injections of platelet derived growth factor BB (PDGF-BB) into the porcine coronary vasculature at the time of gene transfer. Luciferase activity was significantly augmented (23-fold) following mitogenic stimulation in vivo as compared with the control transfected coronary arteries. These data demonstrate that a practical transcatheter approach provides an effective route to deliver recombinant DNA sequences into the coronary arterial wall.(ABSTRACT TRUNCATED AT 250 WORDS)