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Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy

Carvalho, LS; Xu, JH; Pearson, RA; Smith, AJ; Bainbridge, JW; Morris, LM; Fliesler, SJ; ... Ali, RR; + view all (2011) Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy. Human Molecular Genetics , 20 (16) 3161 - 3175. 10.1093/hmg/ddr218. Green open access

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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.

Type: Article
Title: Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddr218
Publisher version: http://dx.doi.org/10.1093/hmg/ddr218
Language: English
Additional information: This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: nucleotide-gated channel, leber congenital amaurosis, cone photoreceptor, adenoassociated-virus, retinitis-pigmentosa, CNGA3 mutations, color-blindness, transgenic mice, restores vision, alpha-subunit
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1307698
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