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R. Malhotra, D. A. White, J. J. Fritz, R. D. Young, M. E. Boulton, A. S. Lewin, W. W. Hauswirth, M. P. Krebs, S. Kaushal; Treatment of Retinal Degeneration by mTOR Inhibition in Mouse Model of Rhodopsin Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4923.
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To study the effect of mTOR inhibition in mitigating retinal degeneration in a new P23H opsin mouse model.
hP23Hrho+/- mice were treated with rapamycin or placebo once a week intraperitoneally. Electroretinogram (ERG) b-wave amplitude measurements were performed monthly. Outer nuclear layer (ONL) thickness was determined histologically on DAPI stained frozen sections. In addition, immunofluorescence staining was done for opsin, Atg7 and Atg8. Electron microscopy studies were performed to determine rod ultrastructure. The effect of rapamycin in the retina was monitored by immunoblotting retinal lysates for the levels of phosphorylated S6 and opsin.
Intraperitoneally injected rapamycin inhibits mTOR and consequently led to the reduction of phosphorylated S6 levels in the retina. In the treated mice, there was a 2- fold preservation of the scotopic b-wave amplitudes at 3 months. Histological analysis also showed a 3.5-fold preservation in ONL thickness of the rapamycin treated mice compared to the placebo injected animals. At the ultrastructural level, rod outer segments were longer and better organized in treated mice. Also, there was increased staining of the autophagosome markers Atg7 and Atg8- suggesting the activation of autophagy in the rod cells. Rapamycin treatment also cleared mislocalized opsin in the outer nuclear layer and rod inner segments.
Rapamycin mitigates the loss of electrophysiological function associated with P23H opsin retinal degeneration and also preserves ONL thickness. The drug also induced autophagy, which correlated with a reduction in the amount of mislocalized opsin, suggesting its role in the clearance of opsin.
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