Published Online June 24 2010
< Science Express Index
Science DOI: 10.1126/science.1190897
  • Research Article

Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis pigmentosa

  1. Volker Busskamp1,2,*,
  2. Jens Duebel1,*,
  3. David Balya1,*,
  4. Mathias Fradot3,4,5,
  5. Tim James Viney1,
  6. Sandra Siegert1,
  7. Anna C. Groner2,6,
  8. Erik Cabuy1,
  9. Valérie Forster3,4,5,
  10. Mathias Seeliger7,
  11. Martin Biel8,
  12. Peter Humphries9,
  13. Michel Paques3,4,5,10,11,
  14. Saddek Mohand-Said3,4,5,10,
  15. Didier Trono2,6,
  16. Karl Deisseroth12,
  17. José A. Sahel3,4,5,10,11,
  18. Serge Picaud3,4,5,11 and
  19. Botond Roska1,†
  1. 1Neural Circuit Laboratories, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  2. 2NCCR Frontiers in Genetics Program, Geneva, 1211, Switzerland.
  3. 3Inserm, UMR_S968,Institut de la Vision, Paris, France.
  4. 4UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
  5. 5CNRS, UMR_7210, Paris, F-75012, France.
  6. 6School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  7. 7Diagnostics Research Group, Department of Ophthalmology II, Eberhard-Karls University, Tübingen, Germany.
  8. 8Center for Integrated Protein Science CIPS-M and Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany.
  9. 9Smurfit Institute of Genetics, Trinity College, Dublin, Ireland.
  10. 10Centre d’Investigation Clinique 503, Inserm-Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris, France.
  11. 11Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.
  12. 12Department of Bioengineering, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  1. †To whom correspondence should be addressed. E-mail: botond.roska{at}fmi.ch

  1. ↵* These authors contributed equally to this work.

Abstract

Retinitis pigmentosa refers to a diverse group of hereditary diseases affecting two million people worldwide that lead to incurable blindness. 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. We show that expression of archaebacterial halorhodopsin in light-insensitive cones can substitute for the native phototransduction cascade and restore their 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.

    • Received for publication 14 April 2010.
    • Accepted for publication 11 June 2010.