Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa Journal Article

Author(s): Busskamp, Volker; Duebel, Jens; Bálya, Dávid; Fradot, Mathias; Viney, Tim J; Siegert, Sandra; Groner, Anna C; Cabuy, Erik; Forster, Valérie; Seeliger, Mathias W; Biel, Martin; Humphries, Peter; Pâques, Michel; Mohand-Saïd, Saddek; Trono, Didier; Deisseroth, Karl A; Sähel, José A; Picaud, Serge A; Roska, Botond M
Article Title: Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa
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.
Keywords: nonhuman; priority journal; protein expression; review; animal experiment; mouse; Light; animal model; adenovirus vector; halorhodopsin; genetic engineering; light effect; morphology; pathology; rodent; evoked visual response; ex vivo study; gene activation; gene targeting; gene therapy; phototransduction; retina cone; retinitis pigmentosa
Journal Title: Science
Volume: 329
Issue 5990
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2010-07-23
Start Page: 413
End Page: 417
DOI: 10.1126/science.1190897
Notes: This study was supported by Friedrich Miescher Institute funds; a U.S. Office of Naval Research Naval International Cooperative Opportunities in Science and Technology Program grant; a Marie Curie Excellence grant and a European Union (EU) HEALTH-F2-223156 grant to B.R.; a grant from the EU (RETICIRC) to B.R. and S.P.; grants from the Agence nationale de la recherche (MEDINAS, RETINE) to S.P.; a Center Grant from Foundation Fighting Blindness (U.S.) to S.M.-S. and J.A.S.; grants from the Swiss National Science Foundation and the EU to D.T.; a grant from the EU (TREATRUSH) to J.A.S., S.P., and B.R.; a Marie Curie Postdoctoral Fellowship to D.B.; and a National Centers of Competence in Research Frontiers in Genetics fellowship to V.B. and A.C.G. The Ocular Genetics Unit at Trinity College Dublin is supported by Science Foundation Ireland
Open access: no