TY - JOUR JF - Human Molecular Genetics UR - http://dx.doi.org/10.1093/hmg/ddr218 EP - 3175 TI - Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy SP - 3161 KW - nucleotide-gated channel KW - leber congenital amaurosis KW - cone photoreceptor KW - adenoassociated-virus KW - retinitis-pigmentosa KW - CNGA3 mutations KW - color-blindness KW - transgenic mice KW - restores vision KW - alpha-subunit AV - public VL - 20 N2 - 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. Y1 - 2011/08/15/ ID - discovery1307698 SN - 0964-6906 A1 - Carvalho, LS A1 - Xu, JH A1 - Pearson, RA A1 - Smith, AJ A1 - Bainbridge, JW A1 - Morris, LM A1 - Fliesler, SJ A1 - Ding, XQ A1 - Ali, RR PB - OXFORD UNIV PRESS N1 - 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. IS - 16 ER -