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.
authors.affiliation: Neural Circuit Laboratories, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Volker
authors.initials: V
authors.lastname: Busskamp
authors.forename: Jens
authors.initials: J
authors.lastname: Duebel
authors.forename: David
authors.initials: D
authors.lastname: Balya
authors.forename: Mathias
authors.initials: M
authors.lastname: Fradot
authors.forename: Tim James
authors.initials: TJ
authors.lastname: Viney
authors.forename: Sandra
authors.initials: S
authors.lastname: Siegert
authors.forename: Anna C
authors.initials: AC
authors.lastname: Groner
authors.forename: Erik
authors.initials: E
authors.lastname: Cabuy
authors.forename: Valérie
authors.initials: V
authors.lastname: Forster
authors.forename: Mathias
authors.initials: M
authors.lastname: Seeliger
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.forename: Peter
authors.initials: P
authors.lastname: Humphries
authors.forename: Michel
authors.initials: M
authors.lastname: Paques
authors.forename: Saddek
authors.initials: S
authors.lastname: Mohand-Said
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.forename: José A
authors.initials: JA
authors.lastname: Sahel
authors.forename: Serge
authors.initials: S
authors.lastname: Picaud
authors.forename: Botond
authors.initials: B
authors.lastname: Roska
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005074:Evoked Potentials, Visual; D015316:Genetic Therapy; D005822:Genetic Vectors; D006216:Halobacteriaceae / Q000235:genetics; D025602:Halorhodopsins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008027:Light; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D012160:Retina / Q000502:physiology; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000502:physiology; D012174:Retinitis Pigmentosa / Q000503:physiopathology / Q000628:therapy*; D046509:Tissue Culture Techniques; D014162:Transfection; D014785:Vision, Ocular; D014795:Visual Pathways / Q000502:physiology
chemical_list: D025602:Halorhodopsins