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Xufeng Dai, Juanjuan Han, Zi-Bing Jin, Yan Qi, Jie Li, Wen-Tao Deng, Bo Chang, William Hauswirth, Ji-Jing Pang; AAV-mediated Lpcat1 gene replacement therapy rescues retinal degeneration in rd11 mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2715. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal degeneration 11 (rd11) mice are a newly discovered naturally occurring animal model with early and rapid photoreceptor dysfunction/degeneration caused by a spontaneous mutation in the Lpcat1 gene encoding lysophosphatidylcholine acyltransferase. This study is to test whether highly efficient tyrosine mutant AAV-mediated gene replacement therapy can restore the retinal function/structure in rd11 mice.
At postnatal day 14, 1 μl of AAV8 (Y733F)-smCBA-Lpcat1 vector (1013 viral genome containing particles/ml) was injected subretinally into one eye of 20 rd11 mice. Uninjected contralateral eyes were used as controls. Ten weeks after injection, dark- and light-adapted ERGs were recorded. Then both treated and control eyes were harvested for immunohistochemical and morphological studies.
In treated eyes, ERG signals were recorded 10 weeks after treatment; both dark- and light-adapted ERG amplitudes were about 70% of the normal level seen in wild type C57 mice. Dark- and light-adapted ERGs were unrecordable in untreated rd11 eyes. More than half of the outer nuclear layer (ONL) was preserved in treated eyes, while only one row of ONL nuclei remained in untreated eyes. Lpcat1 expression was observed in the outer retina, particularly in photoreceptor outer segments in treated eyes by immunohistochemistry, but not in untreated eyes. Both M- and S-cone opsin were observed extensively in treated eyes; in contrast, cone opsin was nearly undetectable in untreated eyes.
Tyrosine-capsid mutant AAV mediated Lpcat1 expression restores/maintains rod and cone function/structure for at least 10 weeks in the rd11 mice, a retinal degeneration model with early and rapid photoreceptor degeneration.
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