IMPROVED ADENOVIRAL VECTORS FOR HEPATIC GENE THERAPY

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DESCRIPTION: Recombinant adenovirus vectors offer potential for human gene therapy because of their ability to transduce many tissues at high efficiency in vivo. The enthusiasm for use of these vectors has been tempered by a powerful immunologic response directed against vector containing cells because of the low level synthesis of vector derived antigens. The fact that adenovirus-mediated gene transfer is persistent in animals lacking antigen-dependent immunity establishes the need to produce a less antigenic vector. Dr. Kay and his colleagues recently developed a method for creating high titer adenovirus vectors that were devoid of vector genomic sequences responsible for producing the immune response. Unexpectedly, these deleted vectors, although efficient at gene transfer, with minimal or no toxicity, do not persist in vivo in immunocompetent or immunodeficient animals. This occurred because these deleted vectors could not replicate their genome in transduced cells in vitro and in vivo. Thus it is hypothesized that persistence of adenoviral DNA is inherently related to its ability to replicate. The major goals of this proposal are: 1) to determine the minimal number of adenovirus genes needed for stability and place these back into the vector to make a minimal vector that can persist; 2) determine the mechanism(s) allowing for vector genome persistence; 3) determine the acute toxicity and antigen-dependent immunological responses directed against the new vector; and 4) develop the deleted vector system to produce an integrating vector system. The results of these studies will have important implications for the development of adenoviruses for gene therapy.