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E.C. Jenewein, S.J. Fliesler, M.J. Richards, D.K. Vaughan; Effect of AY9944 on the Cone–Dominant Ground Squirrel Retina . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1663.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We previously described an adult rat (rod–dominant) 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 aberrant cholesterol (Chol) biosynthesis, resulting in abnormally low levels of Chol and excessive levels of 7–dehydrocholesterol (7DHC) in all bodily tissues. Here, we evaluated effects of AY9944 on retinal histology and sterol composition in the cone–dominant ground squirrel. Methods: Adult ground squirrels (190–250 g, N=8) were fed 0% Chol chow and implanted every 4 wk with Alzet pumps containing AY9944 in PBS, so as to deliver 2.5 mg/kg/day. After 12 wk, one eye from each ground squirrel was taken for morphological analysis (light and electron microscopy); contralateral retina, serum, and liver were harvested for sterol analysis. A control animal was implanted with pumps containing sterile saline. Results: 7DHC/Chol mole ratios after 12 wk of AY9944 treatment were as follows: outer segments, 0.60 ±0.11; residual retina, 0.64±0.05; liver, 0.52±0.26; and serum, 0.18±0.07 (vs. 0 for all control tissues). Histology of AY9944–treated retinas after 12 wk revealed membrane and lipid inclusions in the RPE, vacuolation of RPE, and edematous cone pedicles. Electron microscopy revealed membrane abnormalities in cone outer and inner segments, as well as the RPE abnormalities obvious by light microscopy. Conclusions:AY9944 treatment of the pigmented, cone–dominant ground squirrel causes the expected accumulation of 7DHC in retina and other tissues, with concomitant histological abnormalities consistent with (but less severe than) the retinal degeneration observed in the rod–dominant SLOS rat model.
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