title: Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy.
abstract: Mutations in the CNGB3 gene account for >50% of all known cases of achromatopsia. Although of early onset, its stationary character and the potential for rapid assessment of restoration of retinal function following therapy renders achromatopsia a very attractive candidate for gene therapy. Here we tested the efficacy of an rAAV2/8 vector containing a human cone arrestin promoter and a human CNGB3 cDNA in CNGB3 deficient mice. Following subretinal delivery of the vector, CNGB3 was detected in both M- and S-cones and resulted in increased levels of CNGA3, increased cone density and survival, improved cone outer segment structure and normal subcellular compartmentalization of cone opsins. Therapy also resulted in long-term improvement of retinal function, with restoration of cone ERG amplitudes of up to 90% of wild-type and a significant improvement in visual acuity. Remarkably, successful restoration of cone function was observed even when treatment was initiated at 6 months of age; however, restoration of normal visual acuity was only possible in younger animals (e.g. 2-4 weeks old). This study represents achievement of the most substantial restoration of visual function reported to date in an animal model of achromatopsia using a human gene construct, which has the potential to be utilized in clinical trials.
authors.affiliation: The Department of Genetics, UCL Institute of Ophthalmology, London, UK.
authors.forename: Livia S
authors.initials: LS
authors.lastname: Carvalho
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xu
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Pearson
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Smith
authors.forename: James W
authors.initials: JW
authors.lastname: Bainbridge
authors.forename: Lynsie M
authors.initials: LM
authors.lastname: Morris
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fliesler
authors.forename: Xi-Qin
authors.initials: XQ
authors.lastname: Ding
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D019390:Arrestins / Q000235:genetics; D002470:Cell Survival; D003117:Color Vision Defects / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007267:Injections; D051379:Mice; D008822:Mice, Transgenic; D055355:Opsins / Q000378:metabolism; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D012160:Retina / Q000378:metabolism / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology / Q000648:ultrastructure; D013997:Time Factors; D014785:Vision, Ocular / Q000502:physiology*; D014792:Visual Acuity / Q000502:physiology
chemical_list: D019390:Arrestins; C415904:CNGB3 protein, human; C532622:CNGB3 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; D055355:Opsins