Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis Pigmentosa

• Published in: Science (American Association for the Advancement of Science) 2010-07, Vol.329 (5990), p.413-417
• Main Authors: Busskamp, Volker, Duebel, Jens, Balya, David, Fradot, Mathias, Viney, Tim James, Siegert, Sandra, Groner, Anna C, Cabuy, Erik, Forster, Valérie, Seeliger, Mathias, Biel, Martin, Humphries, Peter, Paques, Michel, Mohand-Said, Saddek, Trono, Didier, Deisseroth, Karl, Sahel, José A, Picaud, Serge, Roska, Botond
• Format: Article
• Language: English
• Subjects: Amacrine cells; Animals; Biological and medical sciences; Blindness; Dependovirus; Dependovirus - genetics; Disease Models, Animal; Electric current; Evoked Potentials, Visual; Eye and associated structures. Visual pathways and centers. Vision; Eye diseases; Fundamental and applied biological sciences. Psychology; Ganglia; Gene expression; Gene Therapy; Genetic disorders; Genetic Therapy; Genetic Vectors; Genetics; Grants; Halobacteriaceae; Halobacteriaceae - genetics; Halorhodopsins; Halorhodopsins - genetics; Halorhodopsins - metabolism; Humans; Life Sciences; Light; Mice; Mice, Knockout; Neurons; Photoreceptors; Promoter Regions, Genetic; Retina; Retina - physiology; Retinal Cone Photoreceptor Cells; Retinal Cone Photoreceptor Cells - physiology; Retinal cones; Retinal detachment; Retinal Ganglion Cells; Retinal Ganglion Cells - physiology; Retinitis Pigmentosa; Retinitis Pigmentosa - physiopathology; Retinitis Pigmentosa - therapy; Tissue Culture Techniques; Transfection; Vertebrates: nervous system and sense organs; Vision, Ocular; Visual Pathways; Visual Pathways - physiology
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1190897

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.