REDUCTION OF RESTENOSIS AFTER ANGIOPLASTY IN AN ATHEROMATOUS RABBIT MODEL BY SUICIDE GENE-THERAPY

Background Gene delivery of the thymidine kinase (tk) gene combined wi th ganciclovir (GCV) limits intimal hyperplasia after abrasion of norm al arteries. However, the low efficiency of adenoviral-mediated gene t ransfer to atherosclerotic arteries has raised concerns about the appl icability of this strategy to the prevention of restenosis. Methods an d Results A replication-defective adenoviral vector expressing tk (Ad- RSVtk) demonstrated selective toxicity toward GCV-treated arterial smo oth muscle cells, with oligo-nucleolytic cleavage suggesting apoptosis . In vivo, after demonstration of tk expression after Ad-RSVtk deliver y, the combination of Ad-RSVtk followed by GCV was tested in a rabbit model of angioplasty of atheromatous iliac arteries. Angioplasty (8 at m, 20 minutes) was performed by use of a hydrogel balloon coated with Ad-RSVtk (4x10(9) plaque forming units). GCV was infused (25 mg.kg(-1) IV BID) from days 2 through 7 after angioplasty in 8 of 12 rabbits. F our weeks later, morphometric analysis demonstrated a reduced intima-t o-media ratio in the group receiving combination therapy compared with Ad-RSVtk alone (3.0+/-1.2 versus 5.2+0.5, P<.018). GCV per se had no effect on intimal hyperplasia after arterial injury. Conclusions In vi tro, Ad-RSVtk demonstrates selective toxicity toward GC-V-treated arte rial smooth muscle cells involving apoptosis. In vivo, GCV conditions reduction of neointimal formation after percutaneous delivery of Ad-RS Vtk during angioplasty of atheromatous arteries.