Reduction of Restenosis After Angioplasty in an Atheromatous Rabbit Model by Suicide Gene Therapy

• DOI: 10.1161/01.cir.96.2.408
• Publication Date: 2012-06-12T00:41:02Z
• Authors: P. Gabriel Steg; Ouafae Tahlil; Nathalie Aubailly; Jean-Michel Caillaud; Jean-François De...; Karine Berthelot; Aude Le Roux; Laurent Feldman; Michel Perricaudet; Patrice Denèfle; Didier Branellec
• Keywords: 0301 basic medicine; Cell Death; Arteriosclerosis; Gene Transfer Techniques; Genetic Therapy; Thymidine Kinase; 3. Good health; Disease Models, Animal; 03 medical and health sciences; Recurrence; Animals; Rabbits; Tunica Intima; Ganciclovir; Angioplasty, Balloon; Aorta

Background Gene delivery of the thymidine kinase (tk) gene combined with ganciclovir (GCV) limits intimal hyperplasia after abrasion of normal arteries. However, the low efficiency of adenoviral-mediated gene transfer to atherosclerotic arteries has raised concerns about the applicability of this strategy to the prevention of restenosis.

Methods and Results A replication-defective adenoviral vector expressing tk (Ad-RSVtk) demonstrated selective toxicity toward GCV-treated arterial smooth muscle cells, with oligonucleolytic cleavage suggesting apoptosis. In vivo, after demonstration of tk expression after Ad-RSVtk delivery, the combination of Ad-RSVtk followed by GCV was tested in a rabbit model of angioplasty of atheromatous iliac arteries. Angioplasty (8 atm, 20 minutes) was performed by use of a hydrogel balloon coated with Ad-RSVtk (4×10 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. Four weeks later, morphometric analysis demonstrated a reduced intima-to-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 vitro, Ad-RSVtk demonstrates selective toxicity toward GCV-treated arterial smooth muscle cells involving apoptosis. In vivo, GCV conditions reduction of neointimal formation after percutaneous delivery of Ad-RSVtk during angioplasty of atheromatous arteries.