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Yuxin Zhang, Wei Du, Ping Zhu, Jie Li, Wen-Tao Deng, Chen Zhao, William Hauswirth, Ji-Jing Pang; Long term restoration of cone function following AAV-mediated gene therapy in CNGA3-/-Nrl-/- Mice. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1175.
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© ARVO (1962-2015); The Authors (2016-present)
The cone photoreceptor cyclic nucleotide-gated (CNG) channel is essential for high acuity central vision and color vision. Mutations in gene encoding the alpha-subunit of the cone cyclic nucleotide-gated channel (CNGA3) have been linked to achromatopsia and progressive cone dystrophy in humans. The CNGA3−/−/Nrl−/− mouse is a cone-dominant model of Cnga3 channel deficiency and was bred to mimic the all cone central foveal structure of human achromatopsia 2 with CNGA3 mutations. Here, we tested whether AAV-mediated CNGA3 expression can persistently restore cone function and rescue cone structure at twelve months following subretinal vector injection.
At postnatal day 14, one μl of AAV8 (Y447, 733F)-IRBP/GNAT2-mCnga3 vector (1013 particles/ml) was injected subretinally into one eye of each CNGA3-/-Nrl-/- mouse. The other eye was uninjected to serve as a control. Dark- and light-adapted ERGs were recorded at twelve months after vector treatment. Then treated and control eyes were harvested for immunohistochemical studies.
At twelve months following subretinal injection, rod-mediated scotopic ERG waveforms were unrecordable in either treated or untreated CNGA3−/−/Nrl−/− eyes. At a flash intensity of 1.4 log cd.s/m2, the average b-wave amplitudes of cone-related photopic ERGs in treated CNGA3-/-Nrl-/- eyes (51.8 μV average) was significantly larger than that of untreated eyes (16.05 μV average). Eyes with the best light-adapted ERG restoration showed similar cone opsin distribution as Nrl-/- control eyes with abundant M- and S-opsins observed in their cone outer segments. Both M- and S-cone opsins and cone outer segments were absent in untreated eyes.
AAV-mediated gene therapy restores cone function and halts cone degeneration for at least twelve months in CNGA3-/-Nrl-/- mice. These results serve to support developing a gene therapy clinical trial for human achromatopsia 2 with CNGA3 mutations.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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