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 normal or endothelium-denuded arteries, It is unclear whether these results can be extended to atherosclerotic arteries, Accordingly, this study was designed to (a) assess the feasibility of adenovirus-mediated gene transfer to atherosclerotic lesions, and (b) compare the transfection efficiency, anatomic distribution of transfected cells, and duration of transgene expression achieved in normal versus atherosclerotic arteries. A recombinant adenovirus including a nuclear-targeted beta-galactosidase gene was percutaneously delivered to the iliac artery of normal (n = 25) and atherosclerotic (n = 25) rabbits, Transgene expression, assessed by morphometric as well as chemiluminescent analyses, was documented in all normal and atherosclerotic arteries between 3 and 14 d after gene transfer, but was undetectable at later time points, Transfected 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 atherosclerotic arteries, respectively (P = 0.0001), Similarly, nuclear beta-galactosidase activity was higher in normal than in atherosclerotic arteries (3.2 vs, 0.8 mU/mg protein, P = 0.02), These findings indicate that atherosclerosis reduces the transfection efficiency which can be achieved with adenoviral vectors, and thus constitutes a potential limitation to adenovirus-based, arterial gene therapy.