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Shanta Sarfare, Seok-Hong Min, Sanford L Boye, Shannon Elizabeth Boye, William W Hauswirth, Christine Nichols Kay; Gene therapy for a mouse model of Achromatopsia. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5469. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Achromatopsia is an autosomal recessive retinal disorder characterized by cone photoreceptor dysfunction with an incidence of 1:30,000. Mutations in the cone cyclic nucleotide gated cation channel beta (CNGB3) account for 50% of the incidence of achromatopsia. Although there is a Cngb3 knockout mouse, it is difficult to investigate cone function in this model, as cones comprise a very small proportion of the mouse retina. Mice lacking the Nrl gene have no rods, increased S-cones and enhanced cone function. In this study, we investigated the results of gene replacement therapy in a Cngb3/Nrl double knockout (DKO) mouse retina to more closely approximate the cone-dominant macula of achromatopsia patients.
One microliter viral vector AAV8 (Y733F)-Cngb3 (1 x1012 vector genomes/ml) where the Cngb3 gene is driven by the photoreceptor-specific IRBP/GNAT2 promoter, was injected in the subretinal space of 15 days old Cngb3/Nrl DKO mice. One eye was injected whereas the contralateral eye was the non-injected control.
The treated eyes show increased photopic ERG and S-opsin mediated ERG b-wave amplitude responses compared to untreated fellow eyes up to 8 months post-injection. Administration of the AAV8-Cngb3 resulted in the preservation of S-opsin and cone transducin in the photoreceptor outer segments up to 3 months post-injection.
AAV-mediated gene delivery of CNGB3 results in long-term restoration of cone function in the Cngb3/Nrl DKO mouse. Ongoing studies include live OCT imaging and immunolocalization of other cone-specific markers in the treated mice. The Cngb3/Nrl DKO mice may serve as a useful model for developing and testing therapeutic strategies for human cone photoreceptor degenerative diseases.
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