1. ¹INSERM UMR U649, CHU-Hotel Dieu, Nantes, France
2. ²Etablissement Français du Sang, Pays de la Loire, Nantes, France
3. ³CHU-Hotel Dieu, Service d'Ophtalmologie, Nantes, France
4. ⁴Ecole Nationale Vétérinaire de Nantes, Services d'Urgences, Nantes, France
5. ⁵Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA

Correspondence: Dr F Rolling, Laboratoire de Thérapie Génique, INSERM U649, CHU-Hotel Dieu, Bât J Monnet, 30 Avenue J Monnet, 44035 Nantes Cedex 01, France. E-mail: fabienne.rolling@univ-nantes.fr

Received 26 July 2007; Revised 30 August 2007; Accepted 30 August 2007; Published online 4 October 2007.

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.