A mouse model of arterial gene transfer - Antigen-specific immunity is a minor determinant of the early loss of adenovirus-mediated transgene expression

We developed a murine model of arterial gene transfer and used it to test t he role of antigen-specific immunity in the loss of adenovirus-mediated tra nsgene expression. Adenoviral vectors encoding either beta-galactosidase (b eta-gal) or green fluorescent protein were infused to the lumen of normal c ommon carotids of CD-1 and C57BL/6 mice and atherosclerotic carotids of Apo e(-/-) mice. At 3 days after gene transfer, significant reporter gene expre ssion was detected in all strains. Transgene expression was transient, with expression undetectable at 14 days. Next, a beta-gal-expressing vector was infused into carotids of ROSA26 mice (transgenic for, and therefore tolera nt of, beta-gal) and RAG-2(-/-) mice (deficient in recombinase-activating g ene [RAG]-2 and therefore lacking in antigen-specific immunity). beta-Gal e xpression was again high at 3 days but declined substantially (>90%) by 14 days. In vivo labeling with bromodeoxyuridine revealed that carotid endothe lial proliferation was increased dramatically by the gene-transfer procedur e alone, likely leading to the loss of episomal adenoviral DNA. Gene transf er to normal and atherosclerotic mouse carotids can be accomplished; howeve r, elimination of antigen-specific immune responses does not prevent the ea rly loss of adenovirus-mediated transgene expression. Efforts to prolong ad enovirus-mediated transgene expression in the artery wall must be redirecte d. These efforts will likely include strategies to avoid the consequences o f increased cell turnover. Nevertheless, despite the brevity of expression, this mouse model of gene transfer to normal and severely atherosclerotic a rteries will likely be useful for investigating the genetic basis of vascul ar disease and for developing gene therapies. The full text of this article is available at http://www.circresaha.org.