Adenovirus-AAV Combination Strategies for Gene Therapy
Krishna J. Fisher
Among the repertoire of eukaryotic viruses that have been genetically engineered for targeting therapeutic genes to somatic cells, adenovirus has captured considerable attention since the early 1990s. And, while much can be said about the strengths and weaknesses of adenovirus vectors for human gene therapy, a crossroads of sorts has been reached. Long since past are the days when deletion of the E1 region was hailed as a facile maneuver for disrupting the normal cascade of early and late gene expression, thereby rendering the virus tame. It now appears that these so-called first generation vectors exhibit many properties that are indicative of the wild type virus. The significance of this is best illustrated by the destructive immulogical forces that are mounted in response to adenovirus-mediated gene transfer, resulting in the purging of transduced cells. With these findings at hand, adenovirus vector development is faced with the challenge of striking a balance between two critical parameters: ablating adverse cellular responses to de novo synthesis of viral proteins or other trans-acting factors, while promoting stability of the recombinant viral chromosome.