title: Plasticity of the human visual system after retinal gene therapy in patients with Leber's congenital amaurosis.
abstract: Much of our knowledge of the mechanisms underlying plasticity in the visual cortex in response to visual impairment, vision restoration, and environmental interactions comes from animal studies. We evaluated human brain plasticity in a group of patients with Leber's congenital amaurosis (LCA), who regained vision through gene therapy. Using non-invasive multimodal neuroimaging methods, we demonstrated that reversing blindness with gene therapy promoted long-term structural plasticity in the visual pathways emanating from the treated retina of LCA patients. The data revealed improvements and normalization along the visual fibers corresponding to the site of retinal injection of the gene therapy vector carrying the therapeutic gene in the treated eye compared to the visual pathway for the untreated eye of LCA patients. After gene therapy, the primary visual pathways (for example, geniculostriate fibers) in the treated retina were similar to those of sighted control subjects, whereas the primary visual pathways of the untreated retina continued to deteriorate. Our results suggest that visual experience, enhanced by gene therapy, may be responsible for the reorganization and maturation of synaptic connectivity in the visual pathways of the treated eye in LCA patients. The interactions between the eye and the brain enabled improved and sustained long-term visual function in patients with LCA after gene therapy.
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, University of Pennsylvania Perelman School of Medicine, 309 Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104, USA. F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19014, USA. ashtari@mail.med.upenn.edu.
authors.forename: Manzar
authors.initials: M
authors.lastname: Ashtari
authors.affiliation: Department of Computer Science and Centre for Medical Image Computing, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Penn Image Computing and Science Laboratory, Department of Radiology, University of Pennsylvania, 3600 Market Street, Philadelphia, PA 19104, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cook
authors.affiliation: Department of Radiology, The Children's Hospital of Philadelphia, Philadelphia, PA 19014, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Cyckowski
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, University of Pennsylvania Perelman School of Medicine, 309 Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104, USA. F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19014, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Shindler
authors.affiliation: Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19014, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Marshall
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, University of Pennsylvania Perelman School of Medicine, 309 Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104, USA. F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19014, USA.
authors.forename: Puya
authors.initials: P
authors.lastname: Aravand
authors.affiliation: Department of Radiology, The Children's Hospital of Philadelphia, Philadelphia, PA 19014, USA.
authors.forename: Arastoo
authors.initials: A
authors.lastname: Vossough
authors.affiliation: Penn Image Computing and Science Laboratory, Department of Radiology, University of Pennsylvania, 3600 Market Street, Philadelphia, PA 19104, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Gee
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, University of Pennsylvania Perelman School of Medicine, 309 Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104, USA. F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19014, USA. Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19014, USA.
authors.forename: Albert M
authors.initials: AM
authors.lastname: Maguire
authors.affiliation: Laboratory of Brain and Cognition, National Institutes of Health, 10 Center Drive, MSC 1240, Bethesda, MD 20892, USA.
authors.forename: Chris I
authors.initials: CI
authors.lastname: Baker
authors.affiliation: Center for Advanced Retinal and Ocular Therapeutics, University of Pennsylvania Perelman School of Medicine, 309 Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104, USA. F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19014, USA. Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19014, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
mesh_terms: D000293:Adolescent; D000328:Adult; D016880:Anisotropy; D016022:Case-Control Studies; D002648:Child; D056324:Diffusion Tensor Imaging; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D009473:Neuronal Plasticity; D012160:Retina / Q000502:physiology; D014785:Vision, Ocular; D014793:Visual Cortex / Q000473:pathology; D055815:Young Adult