CIRCUMVENTING THE IMMUNE-RESPONSE TO ADENOVIRUS-MEDIATED GENE-THERAPY

Adenovirus-mediated gene transfer experiments have demonstrated an exc eptional efficiency of virus uptake and gene expression in a variety o f in vivo models. Unfortunately, the efficiency of gene delivery is no t accompanied by long-term gene expression. Maximal gene expression pe aks during the first week of infection followed by a rapid decline to near baseline levels within several weeks. Data from several laborator ies implicate host cellular and humoral immune responses as being resp onsible for the limited duration of expression and for the inability t o successfully readminister a gene using adenovirus vectors. In this s tudy we have examined two strategies which, independently or in combin ation, circumvent aspects of the host immune response against adenovir us-mediated gene therapy. The first strategy explores induction of imm une tolerance in the experimental host as a method to increase the dur ation of gene expression and as a method to allow readministration of adenovirus expression vectors. Our second strategy is directed at the need to readminister adenoviral vectors to immune competent adult anim als. We have demonstrated that a sequential exposure of rats to at lea st two other adenovirus serotypes does not compromise our ability to s uccessfully administer an Ad5-based CAT expression vector. The charact erization of serotype-specific neutralizing response indicates that th e construction and use of Ad expression vectors from different serotyp es will facilitate a useful adenovirus-based strategy allowing multipl e administrations of a target gene.