LOW-EFFICIENCY OF PERCUTANEOUS ADENOVIRUS-MEDIATED ARTERIAL GENE-TRANSFER IN THE ATHEROSCLEROTIC RABBIT

Recombinant adenoviruses are the most efficient vectors with which to perform arterial gene transfer, Previous in vivo studies of adenovirus -mediated arterial transfection, however, have been performed using no rmal or endothelium-denuded arteries, It is unclear whether these resu lts can be extended to atherosclerotic arteries, Accordingly, this stu dy was designed to (a) assess the feasibility of adenovirus-mediated g ene transfer to atherosclerotic lesions, and (b) compare the transfect ion efficiency, anatomic distribution of transfected cells, and durati on of transgene expression achieved in normal versus atherosclerotic a rteries. A recombinant adenovirus including a nuclear-targeted beta-ga lactosidase gene was percutaneously delivered to the iliac artery of n ormal (n = 25) and atherosclerotic (n = 25) rabbits, Transgene express ion, assessed by morphometric as well as chemiluminescent analyses, wa s documented in all normal and atherosclerotic arteries between 3 and 14 d after gene transfer, but was undetectable at later time points, T ransfected cells were identified as smooth muscle cells located in the media of normal arteries, and in the neointima and the vasa-vasora of atherosclerotic arteries, Two percent of medial cells, but only 0.2% of medial and neointimal cells expressed the transgene in normal and a therosclerotic arteries, respectively (P = 0.0001), Similarly, nuclear beta-galactosidase activity was higher in normal than in atherosclero tic arteries (3.2 vs, 0.8 mU/mg protein, P = 0.02), These findings ind icate that atherosclerosis reduces the transfection efficiency which c an be achieved with adenoviral vectors, and thus constitutes a potenti al limitation to adenovirus-based, arterial gene therapy.