TRANSIENT EXPRESSION OF GENES TRANSFERRED IN-VIVO INTO HEART USING FIRST-GENERATION ADENOVIRAL VECTORS - ROLE OF THE IMMUNE-RESPONSE

Gene therapy for heart diseases requires availability of an efficient vector for gene transfer into myocardium, Recombinant adenovirus expressing the Escherichia coli beta-galactosidase (beta-Gal) gene was shown to infect rat cardiocytes efficiently in vivo, However, a time course of gene expression showed that transgene expression was maximal during the first week following injection, then declined and disappeared by day 21, An immunosuppressive treatment prolonged beta-Gal expression for at least 21 days. On the contrary, a preimmunization of the animals by two intraperitoneal injections of the vector led to a decreased transgene expression 48 hr after intramyocardial injection and to a barely detectable expression at the sixth day, Appearance of adenovirus neutralizing antibodies in preimmunized animals could have contributed to such a refractoriness to further adenoviral infection, Finally, a neonatal intrathymic injection of the vector was able to induce longterm LacZ expression for more than 2 months after heart injection, although neutralizing as well as anti-beta-Gal antibodies were detected in sera of the animals, These results indicate that an immune response against first-generation replication-defective adenoviral vectors is a major cause of transient transgene expression, a cellular response being most probably responsible for ablation of transgene expression in immunocompetent animals.