title: Targeting channelrhodopsin-2 to ON-bipolar cells with vitreally administered AAV Restores ON and OFF visual responses in blind mice.
abstract: Most inherited retinal dystrophies display progressive photoreceptor cell degeneration leading to severe visual impairment. Optogenetic reactivation of retinal neurons mediated by adeno-associated virus (AAV) gene therapy has the potential to restore vision regardless of patient-specific mutations. The challenge for clinical translatability is to restore a vision as close to natural vision as possible, while using a surgically safe delivery route for the fragile degenerated retina. To preserve the visual processing of the inner retina, we targeted ON bipolar cells, which are still present at late stages of disease. For safe gene delivery, we used a recently engineered AAV variant that can transduce the bipolar cells after injection into the eye's easily accessible vitreous humor. We show that AAV encoding channelrhodopsin under the ON bipolar cell-specific promoter mediates long-term gene delivery restricted to ON-bipolar cells after intravitreal administration. Channelrhodopsin expression in ON bipolar cells leads to restoration of ON and OFF responses at the retinal and cortical levels. Moreover, light-induced locomotory behavior is restored in treated blind mice. Our results support the clinical relevance of a minimally invasive AAV-mediated optogenetic therapy for visual restoration.
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Macé
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Caplette
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Marre
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris, France.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Sengupta
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Chaffiol
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris, France.
authors.forename: Peggy
authors.initials: P
authors.lastname: Barbe
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris, France.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Desrosiers
authors.affiliation: Department of Biophysical Chemistry, Max Planck Institute of Biophysics, Frankfurt am Main, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Bamberg
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris, France [4] Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France [5] Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.
authors.forename: Jose-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Picaud
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris, France.
authors.forename: Jens
authors.initials: J
authors.lastname: Duebel
authors.affiliation: 1] INSERM, U968, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France [3] CNRS, UMR_7210, Paris, France.
authors.forename: Deniz
authors.initials: D
authors.lastname: Dalkara
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001766:Blindness / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000075402:Channelrhodopsins; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D058449:Intravitreal Injections; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051245:Retinal Bipolar Cells / Q000378:metabolism* / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D014796:Visual Perception / Q000235:genetics; D014822:Vitreous Body
chemical_list: D000075402:Channelrhodopsins
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