ESTABLISHED IMMUNITY PRECLUDES ADENOVIRUS-MEDIATED GENE-TRANSFER IN RAT CAROTID ARTERIES - POTENTIAL FOR IMMUNOSUPPRESSION AND VECTOR ENGINEERING TO OVERCOME BARRIERS OF IMMUNITY

Preclinical arterial gene transfer studies with adenoviral vectors are typically performed in laboratory animals that lack immunity to adeno virus. However, human patients are likely to have prior exposures to a denovirus that might affect: (a) the success of arterial gene transfer ; (b) the duration of recombinant gene expression; and (c) the likelih ood of a destructive immune response to transduced cells. We confirmed a high prevalence (57%) in adult humans of neutralizing antibodies to adenovirus type 5. We then used a rat model to establish a central ro le for the immune system in determining the success as well as the dur ation of recombinant gene expression after adenovirus-mediated gene tr ansfer into isolated arterial segments. Vector-mediated recombinant ge ne expression, which was successful in naive rats and prolonged by imm unosuppression, was unsuccessful in the presence of established immuni ty to adenovirus. 4 d of immunosuppressive therapy permitted arterial gene transfer and expression in immune rats, but at decreased levels. Ultraviolet-irradiated adenoviral vectors, which mimic advanced-genera tion vectors (seduced viral gene expression and relatively preserved c apsid function), were less immunogenic than were nonirradiated vectors . A primary exposure to ultraviolet-irradiated (but not nonirradiated) vectors permitted expression of a recombinant gene after redelivery o f the same vector. in conclusion, arterial gene transfer with current type 5 adenoviral vectors is unlikely to result in significant levels of gene expression in the majority of humans. Both immunosuppression a nd further engineering of the vector genome to decrease expression of viral genes show promise in circumventing barriers to adenovirus-media ted arterial gene transfer.