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A novel tetracycline-controlled transactivator–transrepressor system enables external control of oncolytic adenovirus replication

Gene Therapy volume 10, pages 1680–1690 (2003)Cite this article

Abstract

The use of restricted replication-competent adenoviruses (RRCAs) inducing tumor cell-specific lysis is a promising approach in cancer gene therapy. However, the use of RRCAs in humans carries considerable risk, since after injection into the patient, further regulation or inhibition of virus replication from the outside is impossible. Therefore, we have developed a novel system allowing external pharmacological control of RRCA replication. We show here that a tumor-selective E1B-deleted RRCA can be tightly regulated by use of doxycycline (dox)-controlled adenoviral E1A gene expression, which in turn determines vector replication. RRCA replication is switched on by addition and switched off by withdrawal of dox. The system results in efficient tumor cell killing after induction by dox, whereas cells are unaffected by the uninduced system. It was also employed for efficient external control of transgene expression from cotransfected replication-deficient adenovectors. Furthermore, the use of a liver cell-specific human α1-antitrypsin (hAAT)-promoter driving a tetracycline-controlled transcriptional silencer allowed specific protection of cells with hAAT-promoter activity in the absence of dox in vitro and in vivo, delineating a new principle of ‘tissue protective’ gene therapy. The concept of external control of RRCAs may help to improve the safety of cancer gene therapy.

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Acknowledgements

This work was supported by a grant from the Wilhelm Sander-Stiftung to HF (2002.007.1), by the Deutsche Forschungsgemeinschaft through a Heisenberg Fellowship to WP (WP378/2-1 and 378/2-2), by a grant from the Centeon Pharmaceutical Company, by a grant of the Bundesinstitut für gesundheitlichen Verbraucherschutz und Veterinärmedizin to CCZ (BgVV Z 5.1-1328-156), and by the Cardiovascular Research Center and the Research Committee of the University Medical Center Benjamin Franklin, Freie Universität Berlin.

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Authors and Affiliations

  1. Department of Cardiology and Pneumology, University Medical Center Benjamin Franklin, Freie Universität, Berlin, Germany

    H Fechner, X Wang, U Siemetzki, H-P Schultheiss & W Poller

  2. Institute for Experimental Haematology & Transfusion Medicine, University of Bonn Medical Center, Bonn, Germany

    M Srour & R Schwaab

  3. Department of Dermatology, University Medical Center Benjamin Franklin, Freie Universität, Berlin, Germany

    H Seltmann & C C Zouboulis

  4. Dept. of Gastroenterology, University Medical Center Benjamin Franklin, Freie Universität, Berlin, Hindenburgdamm 30, Berlin, 12200

    A P Sutter & H Scherübl

  5. Inst. of Microbiology, University of Erlangen, Erlangen, Germany

    W Hillen

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Fechner, H., Wang, X., Srour, M. et al. A novel tetracycline-controlled transactivator–transrepressor system enables external control of oncolytic adenovirus replication. Gene Ther 10, 1680–1690 (2003). https://doi.org/10.1038/sj.gt.3302051

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