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.
Palasis
M
M
Boston Scientific Corporation, Natick, MA 01760, USA. palasism@bsci.com
Luo
Z
Z
Barry
J J
JJ
Walsh
K
K
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002404:Catheterization / Q000379:methods*; D004730:Endothelium, Vascular / Q000502:physiology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics*; D007083:Iliac Artery / Q000187:drug effects / Q000502:physiology*; D007763:Lac Operon; D009130:Muscle, Smooth / Q000378:metabolism; D011312:Pressure; D011817:Rabbits; D013997:Time Factors; D014652:Vascular Diseases / Q000628:therapy*; D001616:beta-Galactosidase / Q000378:metabolism
D001616:beta-Galactosidase