Inclusion of the E3 region in an adenoviral vector decreases inflammation and neointima formation after arterial gene transfer

Adenoviral vectors are promising agents for vascular gene transfer. Their use, however, is limited by inflammatory host responses, neointima formation, and brevity of transgene expression. Inclusion of the immunomodulatory adenoviral E3 genes in a vector might prevent inflammation and neointima formation and prolong transgene expression. We compared 2 adenoviral vectors in a model of in vivo gene transfer to rabbit arteries. Both vectors expressed a luciferase reporter gene. One vector (AdE3Luc) contained the adenovirus early 3 (E3) region and the other (AdRSVLuc) lacked E3. Expression of E3 genes by AdE3Luc was confirmed in vitro and in vivo. Arteries transduced with AdE3Luc had substantially and significantly less inflammation (fewer T cells and lower levels of vascular cell adhesion molecule-1 and intercellular adhesion molecule 1 expression) and decreased neointima formation 14 days after gene transfer. Luciferase expression from the 2 vectors was equivalent, however, at both 3 and 14 days after gene transfer. Expression of E3 had no systemic immunosuppressive effects, as measured by peripheral blood counts and by assays for serum antibodies to adenovirus. We conclude that expression of E3 significantly decreases adenovirus-induced arterial wall inflammation and neointima formation. Because inflammation and neointima formation are major barriers to the clinical application of adenoviral vectors, use of E3-containing vectors improves the promise of adenovirus-mediated arterial gene transfer.