A more recent version of this article appeared on May 11, 2001

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(Circulation Research. 2001;0:hh0901.090926.)
© 2001 American Heart Association, Inc.

Article

Improved Adenoviral Vector for Vascular Gene Therapy

Beneficial Effects on Vascular Function and Inflammation

Hu Sheng Qian, Keith Channon, Valentina Neplioueva, Qing Wang, Mitchell Finer, Lisa Tsui, Samuel E. George James McArthur

From Duke University Medical Center (H.S.Q., V.N., S.E.G.), Durham, NC; Department of Cardiovascular Medicine (K.C.), John Radcliffe Hospital, Oxford, UK; and Cell Genesys Inc (Q.W., M.F., L.T., J.M.), Foster City, Calif.

Correspondence to James McArthur, Cell Genesys Inc, Department of Preclinical Biology and Immunology, 344 Lakeside Dr, Foster City, CA 94404. E-mail to jamesm{at}cellgenesys.com

Abstract

Abstract—First-generation, E1-deleted adenoviral vectors (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 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 E1/E4-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 E1/E4-AV or an E1-AV vector encoding ß-galactosidase. Both vectors efficiently transduced vascular endothelium; however, the E1/E4-AV vector gene–modified vessels showed higher ß-galactosidase expression 10 days after gene transfer. Importantly, the E1/E4-AV vector produced substantially less endothelial cell activation, less inflammation, and reduced neointimal hyperplasia compared with the E1-AV vector–treated vessels. The E1-AV vector–transduced vessels also demonstrated significantly impaired endothelium-dependent relaxation whereas the E1/E4-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 E1/E4-AV vector is superior to the E1-AV vector for vascular gene therapy because of the prolonged transgene expression, reduced vascular inflammation, reduced intimal hyperplasia, and maintenance of normal vasomotor function.

Key Words: vascular gene therapy • adenoviral vectors

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