Improved Adenoviral Vector for Vascular Gene Therapy

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Abstract
—First-generation, E1-deleted adenoviral vectors (ΔE1-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 intimal hyperplasia. To reduce the impact of viral proteins on the gene-modified cells, a second-generation adenoviral vector with an additional pair of deletions in the E4 region was developed. To determine whether this ΔE1/ΔE4-AV vector would be useful for vascular gene transfer, we directly compared the efficiency of gene transfer to uninjured rabbit carotid arteries using either an ΔE1/ΔE4-AV or an ΔE1-AV vector encoding β-galactosidase. Both vectors efficiently transduced vascular endothelium; however, the ΔE1/ΔE4-AV vector gene–modified vessels showed higher β-galactosidase expression 10 days after gene transfer. Importantly, the ΔE1/ΔE4-AV vector produced substantially less endothelial cell activation, less inflammation, and reduced neointimal hyperplasia compared with the ΔE1-AV vector–treated vessels. The ΔE1-AV vector–transduced vessels also demonstrated significantly impaired endothelium-dependent relaxation whereas the ΔE1/ΔE4-AV vector did not impact vasomotor function, even at doses of virus in 5-fold excess of the amount required for >90% transduction of the endothelium. We conclude that the ΔE1/ΔE4-AV vector is superior to the ΔE1-AV vector for vascular gene therapy because of the prolonged transgene expression, reduced vascular inflammation, reduced intimal hyperplasia, and maintenance of normal vasomotor function.

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