Carvalho, LS; Xu, JH; Pearson, RA; Smith, AJ; Bainbridge, JW; Morris, LM; Fliesler, SJ; ... Ali, RR; + view all Carvalho, LS; Xu, JH; Pearson, RA; Smith, AJ; Bainbridge, JW; Morris, LM; Fliesler, SJ; Ding, XQ; Ali, RR; - view fewer (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.

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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.

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