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Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose

Gene Therapy volume 19, pages 886–898 (2012)Cite this article

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Abstract

Glial cell line-derived neurotrophic factor (GDNF) is one of the candidate molecules among neurotrophic factors proposed for a potential treatment of retinitis pigmentosa (RP). It must be administered repeatedly or through sustained releasing systems to exert prolonged neuroprotective effects. In the dystrophic Royal College of Surgeon's (RCS) rat model of RP, we found that endogenous GDNF levels dropped during retinal degeneration time course, opening a therapeutic window for GDNF supplementation. We showed that after a single electrotransfer of 30 μg of GDNF-encoding plasmid in the rat ciliary muscle, GDNF was produced for at least 7 months. Morphometric, electroretinographic and optokinetic analyses highlighted that this continuous release of GDNF delayed photoreceptors (PRs) as well as retinal functions loss until at least 70 days of age in RCS rats. Unexpectedly, increasing the GDNF secretion level accelerated PR degeneration and the loss of electrophysiological responses. This is the first report: (i) demonstrating the efficacy of GDNF delivery through non-viral gene therapy in RP; (ii) establishing the efficacy of intravitreal administration of GDNF in RP associated with a mutation in the retinal pigment epithelium; and (iii) warning against potential toxic effects of GDNF within the eye/retina.

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Acknowledgements

This work was funded in part by the ANR EMERGENCE project ANR-05-EMPB-001-02 and the European project EVI-GENORET LSHG-CT-2005-512036.

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Authors and Affiliations

  1. INSERM, U872 Physiopathology of Ocular Diseases: Therapeutic innovations, Paris, France

    E Touchard, M Berdugo, L Kowalczuk, J-C Jeanny & F Behar-Cohen

  2. Centre de Recherche des Cordeliers, Université Pierre et Marie Curie—Paris6, Paris, France

    E Touchard, M Berdugo, L Kowalczuk, J-C Jeanny & F Behar-Cohen

  3. Université Paris Descartes, Paris, France

    E Touchard, M Berdugo, L Kowalczuk, J-C Jeanny & F Behar-Cohen

  4. Section for Experimental Vitreoretinal Surgery, University Eye Hospital, Tübingen, Germany

    P Heiduschka

  5. University Eye Hospital Münster, Münster, Germany

    P Heiduschka

  6. INSERM, U640, Paris, France

    P Bigey & C Gandolphe

  7. CNRS, UMR8151, Paris, France

    P Bigey

  8. Chemical and Genetic Pharmacology Laboratory, Faculté de Pharmacie, Université Paris Descartes, Paris, France

    P Bigey

  9. ENSCP Chimie ParisTech, Paris, France

    P Bigey

  10. Ecole Nationale Vétérinaire d’Alfort, Maisons-Alfort, France

    S Chahory

  11. Department of Ophthalmology, Hôtel-Dieu de Paris, Paris, France

    F Behar-Cohen

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  1. E Touchard
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Touchard, E., Heiduschka, P., Berdugo, M. et al. Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose. Gene Ther 19, 886–898 (2012). https://doi.org/10.1038/gt.2011.154

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