Gene delivery to in situ veins: Differential effects of adenovirus and adeno-associated viral vectors

Purpose: Gene transfer offers the potential to modify vein graft biology at the time of surgical implantation. Efficiency of gene delivery, stability of expression, and host responses are critical parameters for candidate vec tors. We compared the effects of intraluminal exposure with adenovirus (AD) and adeno-associated virus (AAV) vectors on transgene expression and monoc yte adhesion (MA) in treated vein segments. Methods: Adult New Zealand white rabbits (N = 51) were anesthetized, and th e jugular veins were cannulated bilaterally. Veins were gently distended wi th either vector (2.10(8) to 1.10(10) infective particles/mL) or vehicle (c ontrol) for 30 minutes, after which venous flow was restored. AD and AAV ve ctors encoding for the marker genes P-galactosidase (LacZ) and green fluore scent protein (GFP) were used. Vessels were explanted 2 to 40 days postinfe ction for analysis of gene expression (X-gal staining, reverse transcriptas e-polymerase chain reaction), MA, and immunohistochemistry. Ex vivo adhesio n assays used Cr-51-labeled THP-1 cells. Statistical significance was teste d by using analysis of variance with a P value less than .05. Results: All animals survived, and all treated veins were patent at sacrifi ce. Intraluminal exposure to AD at a titer of 1.10(9) resulted in near comp lete transduction of the endothelium at 2 days, with no detectable expressi on by day 14. At an equal titer of infectious particles, transgene expressi on was markedly less for AAV at 2 to 7 days, but improved at 2 weeks and pe rsisted to 40 days. MA was significantly increased 2 days after AD exposure (2.7-fold vs control, *P < .002); AAV treatment had no discernible effect on MA. Conclusion: AD-mediated gene transfer to vein segments resulted in robust, transient gene expression that disappeared after 2 weeks. In comparison, AA V-mediated gene delivery was less efficient, but resulted in delayed onset, persistent expression beyond 30 days. AD exposure induced an early increas e in MA to the vein surface that was not seen with AAV treatment. Current g enerations of both AD and AAV vectors have significant, albeit different, l imitations for vascular gene therapy.