Introduction

The emergence of recombinant DNA as a tool to study medicine quickly promulgated the concept of cloned genes as therapeutics. As originally conceived, the concept of gene therapy was simply to introduce a wild-type copy of a deficient gene into cells to restore function in trans (1-4). Viewed in this way, the technical challenge was to efficiently deliver the gene to the appropriate cell and have it expressed for sufficient time, or readminister as often as needed, for the therapeutic application. Adenovirus (Ad) gene transfer vectors offer one strategy to achieve this. The focus on Ad for gene transfer was based on basic research establishing the biology of Ad, and the knowledge that Ad efficiently delivers the viral genome to the target cells. Importantly, Ad are not oncogenic in humans, the genomes of common Ad are completely defined, the Ad genome can be easily modified, and recombinant Ad can be readily produced in large quantities and highly concentrated without modifying the ability of the virus to infect cells.

In retrospect, the original goal of using Ad as simple delivery systems to permanently complement genetic defects seems naive. Whereas Ad gene transfer vectors can achieve robust expression of the transgene in many target organs, expression of the transgene is limited in time, resulting from a complex combination of innate and adaptive immune host defenses against the virus (5,6). In this context, Ad vectors in their present form are most useful in applications where transient (days to weeks) expression is sufficient to have the desired therapeutic effect. For applications where persistent expression is required to achieve a therapeutic goal, there are still many challenges before and if Ad vectors will be successful. In this chapter, we summarize the biology of Ad, the construction and use of first-generation Ad vectors, the current status of advanced forms of Ad vectors, clinical applications of Ad vectors, and the future prospects of using Ad in gene transfer applications.

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