GENETIC-MODIFICATION OF THE VESSEL WALL - COMPARISON OF SURGICAL AND CATHETER-BASED TECHNIQUES FOR DELIVERY OF RECOMBINANT ADENOVIRUS

Background Gene transfer can potentially alter vessel wall biology and intervene in the pathogenesis of human disease. Although several methods for vector delivery have been described, systematic comparisons of these methods are unavailable. Therefore, this study compared three catheter-based strategies and a surgical technique to assess efficient and selective gene transfer to the vascular wall. Methods and Results The common carotid arteries and internal jugular veins of New Zealand White rabbits were infected with recombinant adenovirus encoding either firefly luciferase or a nuclear-localizing variant of beta-galactosidase. Delivery of recombinant virus was achieved by one of four methods: (1) instillation within a surgically isolated vessel segment (dwell), (2) a double-balloon catheter, (3) a perforated balloon catheter (Wolinsky), or (4) an angioplasty balloon catheter coated with a hydrophilic adsorbent polymer (Hydrogel). Vessel segments were analyzed 4 days after infection for luciferase and beta-galactosidase activity and for the extent of injury to the vessel wall. Luciferase activity in vessels infected using the double-balloon method was substantially greater than that achieved by catheter-based methods (P<.05). The dwell and double-balloon methods yielded selective expression in intimal cells, whereas arteries infected using perforated or Hydrogel-coated balloon catheters demonstrated expression primarily in medial cells. Tissue injury was most pronounced with the perforated balloon catheter. Conclusions Prototype catheters permit relatively efficient direct gene transfer to vascular endothelium; however, delivery methods for targeting the medial cells are inefficient. Modifications are needed to optimize direct gene transfer and minimize tissue injury.