Improved adenoviral vector for vascular gene therapy : beneficial effects on vascular function and inflammation.
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 beta-galactosidase. Both vectors efficiently transduced vascular endothelium; however, the E1/E4-AV vector gene-modified vessels showed higher beta-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.
Qian
H S
HS
Duke University Medical Center, Durham, NC, USA.
Channon
K
K
Neplioueva
V
V
Wang
Q
Q
Finer
M
M
Tsui
L
L
George
S E
SE
McArthur
J
J
D000256:Adenoviridae / Q000235:genetics*; D017498:Adenovirus E1 Proteins / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000235:genetics; D017504:Adenovirus E4 Proteins / Q000235:genetics; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000628:therapy; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014652:Vascular Diseases / Q000235:genetics / Q000628:therapy*; D014664:Vasodilation / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D017498:Adenovirus E1 Proteins; D017500:Adenovirus E1A Proteins; D017504:Adenovirus E4 Proteins; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D001616:beta-Galactosidase