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Science 329 (5990): 413-417

Copyright © 2010 by the American Association for the Advancement of Science

Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis Pigmentosa

Volker Busskamp,1,2,* Jens Duebel,1,* David Balya,1,* Mathias Fradot,3,4,5 Tim James Viney,1 Sandra Siegert,1 Anna C. Groner,2,6 Erik Cabuy,1 Valérie Forster,3,4,5 Mathias Seeliger,7 Martin Biel,8 Peter Humphries,9 Michel Paques,3,4,5,10,11 Saddek Mohand-Said,3,4,5,10 Didier Trono,2,6 Karl Deisseroth,12 José A. Sahel,3,4,5,10,11 Serge Picaud,3,4,5,11 Botond Roska1,{dagger}

Abstract: Retinitis pigmentosa refers to a diverse group of hereditary diseases that lead to incurable blindness, affecting two million people worldwide. As a common pathology, rod photoreceptors die early, whereas light-insensitive, morphologically altered cone photoreceptors persist longer. It is unknown if these cones are accessible for therapeutic intervention. Here, we show that expression of archaebacterial halorhodopsin in light-insensitive cones can substitute for the native phototransduction cascade and restore light sensitivity in mouse models of retinitis pigmentosa. Resensitized photoreceptors activate all retinal cone pathways, drive sophisticated retinal circuit functions (including directional selectivity), activate cortical circuits, and mediate visually guided behaviors. Using human ex vivo retinas, we show that halorhodopsin can reactivate light-insensitive human photoreceptors. Finally, we identified blind patients with persisting, light-insensitive cones for potential halorhodopsin-based therapy.

1 Neural Circuit Laboratories, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
2 National Centre of Competence in Research Frontiers in Genetics Program, Geneva 1211, Switzerland.
3 Inserm, UMR_S968, Institut de la Vision, Paris, France.
4 Université Pierre et Marie Curie Paris 06, UMR_S968, Institut de la Vision, Paris F-75012, France.
5 CNRS, UMR_7210, Paris F-75012, France.
6 School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
7 Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Department of Ophthalmology II, Eberhard-Karls University, Tübingen, Germany.
8 Center for Integrated Protein Science Munich and Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany.
9 Smurfit Institute of Genetics, Trinity College, Dublin, Ireland.
10 Centre d’Investigation Clinique 503, Inserm-Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris, France.
11 Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.
12 Department of Bioengineering and Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: botond.roska{at}fmi.ch

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