Concluding Remarks

HDAds offer a number of advantages as gene transfer vehicles for gene therapy. The absence of viral coding sequences results in significant reduction in chronic toxicity and prolongation of transgene expression. Their large cloning capacity permits insertion of large genes, inclusion of cis-acting regulatory elements for regulated transgene expression and, in some cases, insertion of genes in their genomic context for endogenous regulation, none of which may be possible with other viral vectors. The HDAd genome does not integrate into the host cell chromosomes but probably remains episomal within the nucleus. Although this precludes permanency and may be a serious limitation for transduction of rapidly dividing cell populations, it also minimizes the possibility of germline transmission or insertional mutagenesis, which may lead to oncogenic transformation, as may be possible with integrating vectors such as those based on retroviruses (92) or lentiviruses. Several important issues remain to be addressed before the full potential of this technology can be realized. Chief among these are improved methods for large-scale production, evaluation of acute toxicity following high-dose systemic delivery in a large animals, and the problem of host immune response to the therapeutic protein.

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