Gene therapy for transplant arteriosclerosis

Transplant arteriosclerosis is a thickening of the intima that develops in arteries of transplanted organs. Smooth muscle cell (SMC) replication plays a central role in it's pathogenesis. One strategy to selectively eliminate dividing cells is to express a herpesvirus thymidine kinase (tk) gene which phosphorylates the nucleoside analog, ganciclovir, into a toxic form which leads to cell killing. To evaluate a feasibility of transgene expression in arterial grafts, we performed ex vivo adenovirus (ADV)-mediated transfer of human placental alkaline phosphatase (hpAP) gene into aortas of donor rabbits, and then transplanted them into carotid artery of recipient rabbits. 2 days post-transplant luminal endothelial cells, adventitial cells, and medial SMCs expressed hpAP. 2 wk after surgery only SMCs demonstrated continuous hpAP expression. In the next series of experiments, we performed transplantation of ADV-tk infected grafts combined with systemic administration of ganciclovir. ADV-hpAP infected grafts were used as a control. 2 wk after transplantation, formation of intimai thickening in tk-overexpressing grafts was significantly reduced (p<0.01). A proportion of SMC among proliferating cells was decreased while the percent of replicating macrophages as well as undefined cells had grown. Thus, gene therapy targeting SMC proliferation may be used for a treatment of transplant arteriosclerosis.