The adenovirus (Ad) has been extensively exploited as a gene therapy vector because of its ability to efficiently transduce a wide variety of cell types from many different species independent of the cell cycle to direct high-level transgene expression. First-generation Ad vectors (FGAd) typically have the viral early region 1 (E1) replaced by the therapeutic transgene. First-generation Ad vectors are replication deficient and require E1 complementing cells for propagation. However, the majority of the Ad genome remains intact leading to low-level expression of viral genes in the transduced cells. This is directly cytotoxic and also leads to an adaptive cellular immune response against the transduced cells consequently resulting in transient transgene expression and long-term toxicity, thus rendering these vectors unsuitable for many gene therapy applications where long-term transgene expression is desired. In an attempt to further attenuate Ad, vectors have been engineered with deletions or mutations in the viral E2 and E4 genes in addition to deletion of E1. Despite the potential offered by these multiply deleted Ad vectors (also called second- or third-generation Ad vectors), the majority of the viral coding sequences still remain and therefore so does the potential for their expression. The advantages of multiply deleted Ad over FGAd remain controversial as some studies show them to be superior in terms of reduced toxicity and enhanced longevity of transgene expression whereas others do not. Significant improvement in the safety and efficacy of Ad-based vectors came with the development of helper-dependent adenoviral vectors (HDAds, also referred to as gutless, gutted, mini, fully deleted, high-capacity, A, pseudo) which are deleted of all viral coding sequences. Helper-dependent adenoviral vectors retain the advantages of FGAd including high efficiency in vivo transduction and high-level transgene expression. However, owing to the absence of viral gene expression in transduced cells, these HDAds are able to mediate highlevel, long-term transgene expression in the absence of chronic toxicity. In addition, because the vector genomes exist episomally in transduced cells, the risks of germline transmission and insertional mutagenesis leading to oncogenic transformation are negligible. Moreover, the deletion of the viral sequences permits a tremendous cloning capacity of ~ 37 kb allowing for the delivery of whole genomic loci, multiple transgenes, and large cis-acting elements. A summary of the current state of HDAd is presented here and a more comprehensive discussion can be found elsewhere.[1] Discussions regarding Ad and early-generation Ad vectors can be found elsewhere in this volume.

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