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Gene delivery from the E3 region of replicating human adenovirus: evaluation of the ADP region

Gene Therapy volume 8, pages 1132–1141 (2001)Cite this article

Abstract

Genetically modified replication-selective human adenoviruses are currently undergoing testing in the clinical setting as anticancer agents. Coupling the lytic function of these viruses with virus-mediated transgene delivery represents a powerful extension of this treatment. We have designed a unique system for gene delivery from the replicating virus. It takes advantage of the endogenous gene expression control sequences (promoter, splicing, polyadenylation signals) to efficiently and predictably deliver transgenes from the non-essential E3 transcription unit while still maintaining the expression of the remaining E3 genes in the multi-gene transcription unit. In this article, we engineered restriction enzyme sites into the virus genome selectively to delete the ADP gene and replace it with the therapeutic transgenes CD and TNFα. We demonstrate that: (1) transgene expression from this region mirrors the substituted ADP gene; (2) the loss of ADP in these viruses results in infected cells with extended viability and protein synthesis when compared with a wild-type Ad5 infected cell; and (3) expression of surrounding E3 genes can be maintained in such a system. The potential advantages of delivering transgenes from the ADP region of the replicating adenovirus are discussed.

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Acknowledgements

Thank you to Dr Jerry Shen for critical reading of the manuscript, Dr William SM Wold for E3 antibodies and Ynez Dugan for manuscript preparation and Maxine Bauzon for excellent technical assistance.

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Author notes

  1. LK Hawkins

    Present address: ICRF, Molecular Oncology Unit, Hammersmith Hospital, DuCane Rd, London, W12 0HS, UK

Authors and Affiliations

  1. Onyx Pharmaceuticals, 3031 Research Drive, Richmond, 94806, CA, USA

    LK Hawkins & TW Hermiston

  2. Berlex Biosciences, 15049 San Pablo Avenue, PO Box 4099, Richmond, 94804-0099, CA, USA

    TW Hermiston

Authors
  1. LK Hawkins
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  2. TW Hermiston
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Hawkins, L., Hermiston, T. Gene delivery from the E3 region of replicating human adenovirus: evaluation of the ADP region. Gene Ther 8, 1132–1141 (2001). https://doi.org/10.1038/sj.gt.3301508

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