Gene Therapy for Heart Transplantation‐Associated Coronary Arteriosclerosisa

Abstract: Cardiac allograft arteriosclerosis, which limits the long-term survival of recipients, cannot be prevented by conventional therapies. The arteriopathy is characterized by diffuse intimal thickening made up of proliferative smooth muscle cells. To test the hypothesis that cell cycle-regulatory genes play crucial roles in the development of this arteriopathy in vivo gene therapy targeting cell division cycle (cdc) 2 kinase was attempted in murine cardiac allografts using hemagglutinating virus of Japan (HVJ)-liposome method. Antisense cdc 2 kinase oligodeoxynucleotide (ODN) was transfected into the allografts by intraluminal injection during the operation and the allografts were harvested at 4 weeks after transplantation. Coronary intimal thickening had developed in sense ODN-treated allografts and ICAM-1 and VCAM-1 were enhanced in these arteries. PDGF mRNA was also detected. Antisense cdc 2 kinase ODN inhibited intimal hyperplasia. These data indicate that antisense cdc 2 kinase modulates gene expression and inhibits smooth muscle cell proliferation of graft arteries.