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J.-J. Pang, B. Lei, W. Deng, Y. Umino, D. Everhart, Q. Li, B. Chang, M. Biel, R. Barlow, W. W. Hauswirth; AAV-Mediated Gene Therapy Restores Cone System Functions in cpfl5 Mouse, a Model of Human Achromatopsia With CNGA3 Mutation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5355.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in the gene encoding the alpha-subunit of the cone cyclic nucleotide-gated (CNGA3) channels cause cone function loss in mammals including humans. We tested if AAV-mediated Cnga3 gene therapy can restore cone system function in cpfl5 (Cone Photoreceptor Function Loss 5) mice, a natural model of human Achromatopsia 2 with Cnga3 mutation.
At postnatal day 14, 1 µl of AAV5-CBA-Cnga3 vector (1 x 1013 viral particles /ml) was injected subretinally into one eye of 30 cpfl5 mice. The untreated contralateral eye was used as a control. Dark- and light-adapted ERGs were recorded periodically from 3 to 20 weeks after injections. 20 weeks after treatment, visual function was assessed with routine ERGs and dark-adapted flicker ERGs. Visual acuity and contrast sensitivity were also measured 20 weeks after treatment. Then both treated and control eyes were harvested for histochemical studies.
In treated eyes, restored light-adapted ERG waveforms were recorded 3 weeks after injections and remained stable for at least 20 weeks. The ERG amplitudes were about 60-70% of those of normal C57BL/6J mice. Cone-driven ERGs were not recordable from contralateral untreated eyes. Dark-adapted flicker ERGs indicate that the treatment significantly improved the cone-driven responses but had no effect on rod-driven responses. Behavioral tests showed near normal cone-driven visual acuity and contrast sensitivity in the treated but not in untreated eyes of cpfl5 mice. Immunohistochemistry showed CNGA3 staining in the outer segments of most cones in the treated eyes but not in cones from partner untreated eyes.
AAV mediated gene therapy corrects a cone CNGA3 deficiency in a naturally occurring mouse model of human Achromatopsia 2. The genetic intervention restores the cone system function as demonstrated by ERG and behavioral tests.
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