Analysis of adenoviral transport mechanisms in the vessel wall and optimization of gene transfer using local delivery catheters

Local delivery devices have been used for adenovirus-mediated gene transfer to the arterial wall for the potential treatment of vascular proliferative diseases. However, low levels of adenoviral gene expression in vascular smooth muscle cells may pose a serious limitation to the success of these procedures in the clinic. In this study, we examined the mechanisms controlling adenoviral transport to the vessel wall, using both hydrogel-coated and infusion-based local delivery catheters, with the goal of enhancing in vivo gene transfer under clinically relevant delivery conditions. The following delivery parameters were tested in vivo: applied transmural pressure, viral solution volume and concentration, and delivery time. We found that viral particles are transported into the vessel wall in a manner consistent with diffusion rather than pressure-driven convection. Consistent with diffusion, viral concentration was shown to be the key variable for viral transport in the vessel wall and thus gene expression in vascular smooth muscle cells. A transduction level of 17.8 +/- 3.2% was achieved by delivering a low volume of concentrated adenoviral beta-galactosidase solution through an infusion balloon catheter at low pressure without an adverse effect on medial cellularity. Under these conditions, effective gene transfer was accomplished within a clinically relevant time frame of 2 min, indicating that longer delivery times may not be necessary to achieve efficient gene transfer.