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Oral administration of doxycycline allows tight control of transgene expression: a key step towards gene therapy of retinal diseases

Gene Therapy volume 14, pages 1668–1673 (2007)Cite this article

Abstract

Gene transfer of neurotrophic or antiangiogenic factors has been shown to improve photoreceptor survival in retinal degenerative disorders (that is retinitis pigmentosa) and to prevent neovascularization in retinal vascular diseases (that is age-related macular degeneration, diabetic retinopathy). Expression of such neurotrophic or antiangiogenic factors after gene transfer requires the use of a regulatory system to control transgene expression to avoid unwanted side effects in cases of overexpression. In a previous study, we demonstrated that rAAV-mediated gene transfer of the tetracycline-regulatable (tetR) system allows transgene regulation in the retina of nonhuman primates after intravenous administration of doxycycline (Dox). The purpose of this study was to evaluate oral administration of Dox to control transgene expression in the retina, since the pharmacokinetics after oral administration of the inducer drug represent a key factor when considering advancing to clinical trials. We report on the outcome of this evaluation and demonstrate that oral administration of Dox at a dose that is clinically used in humans (5 mg kg−1 per day) is capable to continuously induce transgene expression in all macaques tested for 6 months. Moreover, control of transgene expression persists up to 4 years post-subretinal injection, with maximal induced levels of transgene product remaining stable over time.

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Acknowledgements

We thank Matthew Ellinwood for critical reading and editing. We also thank the Vector Core (www.vectors.nantes.inserm.fr) at the University Hospital of Nantes, supported by the Association Française contre les Myopathies (AFM), the INSERM, and the Fondation pour la Thérapie Génique en Pays de la Loire. This work was also supported by the French Lions Club and the Lions Clubs International Foundation (LCIF).

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Authors and Affiliations

  1. INSERM UMR U649, CHU-Hotel Dieu, Nantes, France

    K Stieger, A Mendes-Madeira, D Nivard, N Provost, P Moullier & F Rolling

  2. Etablissement Fran,

    A Mendes-Madeira, D Nivard & P Moullier

  3. ç,

    A Mendes-Madeira, D Nivard & P Moullier

  4. ais du Sang, Pays de la Loire, Nantes, France

    A Mendes-Madeira, D Nivard & P Moullier

  5. CHU-Hotel Dieu, Service d'Ophtalmologie, Nantes, France

    G L Meur & M Weber

  6. Ecole Nationale Vétérinaire de Nantes, Services d'Urgences, Nantes, France

    J-Y Deschamps

  7. Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA,

    P Moullier

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  1. K Stieger
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Correspondence to F Rolling.

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Stieger, K., Mendes-Madeira, A., Meur, G. et al. Oral administration of doxycycline allows tight control of transgene expression: a key step towards gene therapy of retinal diseases. Gene Ther 14, 1668–1673 (2007). https://doi.org/10.1038/sj.gt.3303034

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  • DOI: https://doi.org/10.1038/sj.gt.3303034

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