Improved adenoviral vector for vascular gene therapy - Beneficial effects on vascular function and inflammation

First-generation, El-deleted adenoviral vectors (Delta E1-AV) can transduce the vascular endothelium with high efficiency, but their use is limited by the resulting acute endothelial injury and the long-term development of in timal hyperplasia. To reduce the impact of viral proteins on the gene-modif ied cells, a second-generation adenoviral vector with an additional pair of deletions in the E4 region was developed. To determine whether this Delta E1/Delta E4-AV vector would be useful for vascular gene transfer, we direct ly compared the efficiency of gene transfer to uninjured rabbit carotid art eries using either an Delta E1/Delta E4-AV or an Delta E1-AV vector encodin g beta -galactosidase. Both vectors efficiently transduced Vascular endothe lium; however, the Delta E1/Delta E4-AV vector gene-modified vessels showed higher beta -galactosidase expression 10 days after gene transfer. Importa ntly, the Delta E1/Delta E4-AV vector produced substantially less endotheli al cell activation, less inflammation, and reduced neointimal hyperplasia c ompared with the Delta E1-AV vector-treated vessels. The Delta E1-AV vector -transduced vessels also demonstrated significantly impaired endothelium-de pendent relaxation whereas the Delta E1/Delta E4-AV vector did not impact v asomotor function, even at doses of virus in 5-fold excess of the amount re quired for > 90% transduction of the endothelium. We conclude that the Delt a E1/Delta E4-AV vector is superior to the Delta E1-AV vector for vascular gene therapy because of the prolonged transgene expression, reduced vascula r inflammation, reduced intimal hyperplasia, and maintenance of normal vaso motor function.