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S.J. Fliesler, N.S. Peachey, B.G. Jeffrey, M.J. Richards, B.A. Nagel, D.K. Vaughan; Dose–Response Effects of AY9944 on Retinal Structure, Function, and Sterol Composition in an Adult Rat Model of Smith–Lemli–Opitz Syndrome. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2500.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We previously described an adult rat model of Smith–Lemli–Opitz Syndrome (SLOS) with progressive retinal degeneration, using Alzet pump delivery of AY9944 (an inhibitor of the defective enzyme in SLOS). SLOS is a recessive disease caused by defective cholesterol biosynthesis, resulting in abnormally low levels of cholesterol (Chol) and excessive levels of 7–dehydrocholesterol (7DHC) in all bodily tissues. Here, we evaluated dose–dependent effects of AY9944 on visual function, retinal histology and sterol composition in this animal model. Methods: Adult Sprague–Dawley rats (ca. 250 g) were fed 0% Chol chow and implanted every 4 wk with Alzet pumps containing AY9944 in PBS, so as to deliver either 0.37 mg/kg/day ("low dose") or 2.5 mg/kg/day ("high dose"), N=6 each. Serum sterol analysis was performed biweekly to monitor drug efficacy. At 12 wk, maximum rod ERG amplitude (RmP3) and phototransduction sensitivity (S) were derived from the ensemble fit of a P3 model to ERG a–waves recorded to 5 flash intensities (–0.7 to 1.5 log cd–s/m2). One eye from each rat was taken for quantitative morphometric analysis; contralateral retina, serum, liver, and brain were harvested for sterol analysis. Control adult female rats were analyzed similarly, for comparison. Results: Retina 7DHC/Chol mole ratios were 0.51±0.10 (low dose), 1.00±0.18 (high dose), and 0 (control). RmP3 and S values for the low–dose group were comparable to controls; however, the high–dose group exhibited an 82% reduction in RmP3 and a 45% reduction in S, relative to controls. Mean outer nuclear layer (ONL) thickness and ROS length were moderately (low dose) to markedly (high dose) reduced after 12 wk of treatment. Conclusions: AY9944 treatment causes dose–dependent effects on retinal structure and function, which are nonlinearly dependent upon the changes in sterol composition.
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