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Robin Roberts, Bruce A. Berkowitz, David P. Bissig, Deepank Utkhede, Anthony Pepio; Oral Synthetic cis retinoid (QLT091001) treatment improves visual performance in an Leber Congenital Amaurosis (LCA) mouse model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3350. doi: https://doi.org/.
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Experimental mouse models are useful for evaluating the efficacy of new pharmaceutical treatments for abnormal visual cycle activity and associated retinal degeneration. We used a combination of two non-invasive
OKT, which evaluates visual performance, and MRI, which measures central retinal thickness, in an Rpe65 mutant mouse model of LCA to investigate the effectiveness of orally administered QLT091001, a synthetic retinoid replacement for 11-cis retinal.Methods: A total of 40 rd12 mutant mice with defective Rpe65 isomerase activity (6-7 weeks of age, Jackson Labs) were treated in a masked fashion with vehicle or QLT091001 (oral gavage) and then light (n=20) or dark (n=20) adapted. A control group of 30 age-matched C57Bl/6 mice (C) was similarly treated with vehicle or QLT091001 (oral gavage), then light (n=9) or dark (n=19) adapted. Each mouse was studied with OKT (spatial frequency threshold [SF] and contrast sensitivity [CS]) and MRI.
The SF and CS data showed no differences between light and dark control groups, and were in agreement with previously published values. In rd12 mice, the following SF and CS patterns were found, and were mostly independent of light or dark adaption: Cvehc = Cdrug = rd12drug > rd12vehc; note "="means not significantly different and ">" or "<" means statistical significance on a 2-tailed test (at the 0.05 level). One exception to this pattern was CS in the light adapted groups: Cvehc and Cdrug less than or equal to rd12drug. Whole retinal thickness patterns, regardless of light and dark, were: Cvehc = Cdrug which were greater than rd12drug which was greater than rd12vehc. The relatively smaller retinal thickness of the rd12vehc group likely reflects a higher number of somewhat older (7 week) mice (and thus more retinal degeneration) relative to that in the other groups (~6 week).
In this single time point study, QLT091001 clearly improved reduced visual performance in a mouse model of inherited retinal degeneration in a manner independent of retinal thickness. The combination of OKT and MRI provides a useful and informative approach for evaluating efficacy of pharmacological treatment in mouse models with visual cycle deficits.
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