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Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

Gene Therapy volume 16, pages 862–873 (2009)Cite this article

A Corrigendum to this article was published on 13 August 2009

Abstract

Intraocular inflammation has been recognized as a major factor leading to blindness. Because tumor necrosis factor-α (TNF-α) enhances intraocular cytotoxic events, systemic anti-TNF therapies have been introduced in the treatment of severe intraocular inflammation, but frequent re-injections are needed and are associated with severe side effects. We have devised a local intraocular nonviral gene therapy to deliver effective and sustained anti-TNF therapy in inflamed eyes. In this study, we show that transfection of the ciliary muscle by plasmids encoding for three different variants of the p55 TNF-α soluble receptor, using electrotransfer, resulted in sustained intraocular secretion of the encoded proteins, without any detection in the serum. In the eye, even the shorter monomeric variant resulted in efficient neutralization of TNF-α in a rat experimental model of endotoxin-induced uveitis, as long as 3 months after transfection. A subsequent downregulation of interleukin (IL)-6 and iNOS and upregulation of IL-10 expression was observed together with a decreased rolling of inflammatory cells in anterior segment vessels and reduced infiltration within the ocular tissues. Our results indicate that using a nonviral gene therapy strategy, the local self-production of monomeric TNF-α soluble receptors induces a local immunomodulation enabling the control of intraocular inflammation.

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Acknowledgements

We thank Dr Jean-Louis Bourges for his help to perform the acquisition of confocal microscopy videos. We also thank Christophe Klein for his precious technical skills regarding videos retouching and Dr Serge Camelo for helpful discussions and critical reading of the paper. 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, C Bloquel, L Kowalczuc, L Jonet, B Thillaye-Goldenberg, M-C Naud, Y de Kozak, D BenEzra & F Behar-Cohen

  2. Centre de Recherche des Cordeliers, Université Pierre et Marie Curie—Paris6, UMR S 872, Paris, France

    E Touchard, C Bloquel, L Kowalczuc, L Jonet, B Thillaye-Goldenberg, M-C Naud, Y de Kozak, D BenEzra & F Behar-Cohen

  3. Université Paris Descartes, UMR S 872, Paris, France

    E Touchard, C Bloquel, L Kowalczuc, L Jonet, B Thillaye-Goldenberg, M-C Naud, Y de Kozak, D BenEzra & F Behar-Cohen

  4. INSERM, U640, Paris, France

    P Bigey & D Scherman

  5. CNRS, UMR8151, Paris, France

    P Bigey & D Scherman

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

    P Bigey & D Scherman

  7. Department of Chemical and Genetic Pharmacology, Ecole Nationale Supérieure de Chimie de Paris, Université Paris Descartes, Paris, France

    P Bigey & D Scherman

  8. The BenEzra Eye Institute, Assouta-Rishon, Israel

    D BenEzra

  9. Department of Ophthalmology, Assistance Publique—Hôpitaux de Paris, Hôtel-Dieu of Paris, Université Paris Descartes, Paris, France

    F Behar-Cohen

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  1. E Touchard
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Correspondence to F Behar-Cohen.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Touchard, E., Bloquel, C., Bigey, P. et al. Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis. Gene Ther 16, 862–873 (2009). https://doi.org/10.1038/gt.2009.43

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  • DOI: https://doi.org/10.1038/gt.2009.43

Keywords

  • nonviral gene therapy
  • eye
  • inflammation
  • p55 TNFR
  • electroporation
  • drug delivery

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