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(Circulation. 1997;96:408-411.)
© 1997 American Heart Association, Inc.

Articles

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

P. Gabriel Steg, MD; Ouafae Tahlil, MS; Nathalie Aubailly, DVM; Jean-Michel Caillaud, MD; Jean-François Dedieu, PhD; Karine Berthelot, BSc; Aude Le Roux, PhD; Laurent Feldman, MD, PhD; Michel Perricaudet, PhD; Patrice Denèfle, PhD; ; Didier Branellec, PhD

From INSERM U-460, Faculté Xavier Bichat, Paris, France (P.G.S., O.T., L.F.); Rhône Poulenc Rorer-Gencell, France (N.A., J.-M.C., J.-F.D., K.B., P.D., D.B.); and UA 1301 CNRS, Institut Gustave Roussy, Villejuif, France (A.Le R., M.P.).

Correspondence to P. Gabriel Steg, Hôpital Bichat, 46 Rue Henri Huchard, 75877 Paris Cedex 18, France.

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 (4x10⁹ 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.

Key Words: atherosclerosis • genes • restenosis

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