IMMUNE-RESPONSES TO TRANSGENE-ENCODED PROTEINS LIMIT THE STABILITY OFGENE-EXPRESSION AFTER INJECTION OF REPLICATION-DEFECTIVE ADENOVIRUS VECTORS

The use of replication-defective adenoviruses (RDAd) for human gene th erapy has been limited by host immune responses that result in transie nt recombinant gene expression in vivo. It remained unclear whether th ese immune responses were directed predominantly against viral protein s or, alternatively, against foreign transgene-encoded proteins. In th is report, we have compared the stability of recombinant gene expressi on in adult immunocompetent mice following intramuscular (i.m.) inject ion with identical RDAd encoding self (murine) or foreign (human) eryt hropoietin. Our results demonstrate that immune responses directed aga inst foreign transgene-encoded proteins are the major determinants of the stability of gene expression following i.m. injection of RDAd. Mor eover, we demonstrate long-term recombinant gene expression in immunoc ompetent animals following a single i.m. injection of RDAd encoding a self protein. These findings are important for the design of future pr eclinical and clinical gene therapy trials.