ADENOVIRAL VECTOR-MEDIATED GENE-TRANSFER INTO SHEEP ARTERIES USING A DOUBLE-BALLOON CATHETER

The potential for catheter-based in vivo delivery of genetic material to the arterial wall is incompletely explored. We evaluated the level of recombinant protein production as well as the anatomic distribution and duration of gene expression following adenoviral vector-mediated gene transfer into sheep arteries via a double balloon catheter. Catheters were positioned in the carotid or femoral arteries of 20 sheep via a combined percutaneous and surgical approach, and virions infused over a 30-min period. Three days later, recombinant gene expression was identified in approximately 30% (range 0-80%) of the luminal endothelial cells within the targeted area of the artery. Persistent recombinant protein expression was identified histochemically for up to 4 weeks, although the number of positive cells decreased steadily. High levels of both beta-galactosidase (beta-Gal) activity and protein (mean 20 mU and 44 ng per vessel) were measured in vessel extracts 3 days after gene transfer, again decreasing significantly over a 4-week period. Transgene expression was limited almost entirely to the intima and adventitia; adventitial gene transfer occurred virtually exclusively along the vasa vasorum. In comparison to previous studies of catheter-based gene transfer, adenoviral vectors delivered by double balloon catheter resulted in a particularly high efficiency of endothelial cell gene transfer. The efficiency and amount of recombinant gene expression achieved in this study suggest that catheter-based gene delivery may eventually be applicable to the treatment of focal human arterial disease.