May 2003
Volume 44, Issue 13
ARVO Annual Meeting Abstract  |   May 2003
An Improved Adult Animal Model of Smith-Lemli-Opitz Syndrome
Author Affiliations & Notes
  • S.J. Fliesler
    Ophthalmology, Saint Louis Univ School of Med, St Louis, MO, United States
  • M.J. Richards
    Ophthalmology, Saint Louis Univ School of Med, St Louis, MO, United States
  • B.A. Nagel
    Ophthalmology, Saint Louis Univ School of Med, St Louis, MO, United States
  • G.A. Vogler
    Comparative Med., Saint Louis Univ School of Med, St Louis, MO, United States
  • N.S. Peachey
    Cleveland VAMC and Cole Eye Inst./Cleveland Clinic Foundation, Cleveland, OH, United States
  • D.K. Vaughan
    Biology, Univ. of Wisconsin-Oshkosh, Oshkosh, WI, United States
  • Footnotes
    Commercial Relationships  S.J. Fliesler, None; M.J. Richards, None; B.A. Nagel, None; G.A. Vogler, None; N.S. Peachey, None; D.K. Vaughan, None.
  • Footnotes
    Support  GRANTS: EY07361, March of Dimes, and RPB unrestricted deptl. grant (SJF); Dept. of Veteran Affairs
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 3597. doi:
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      S.J. Fliesler, M.J. Richards, B.A. Nagel, G.A. Vogler, N.S. Peachey, D.K. Vaughan; An Improved Adult Animal Model of Smith-Lemli-Opitz Syndrome . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3597.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract: : Purpose:Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disease caused by a defect in cholesterol (Chol) biosynthesis, at the level of 3ß-hydroxysterol-Δ7-reductase. Prior SLOS animal models have employed either feeding or bolus injection of inhibitors of the reductase (AY9944 or BM15.766). To provide a more controlled pharmacological model of SLOS, we tested the efficacy of continuous systemic AY9944 delivery in adult rats, using implanted osmotic pumps. Methods:Alzet pumps (Model 2ML4, 28-day) containing AY9944 (2 ml, 50 mg/ml water, 2.5 l/h) were implanted into anesthetized adult (3-mo. old, ca. 250 g) female Sprague-Dawley rats (N=10) under the dorsal skin. Over a 3-mo. Period, new pumps were inserted and old pumps removed every 4 wk. Rats were maintained under dim cyclic light (12L:12D, 20-40 lux) and fed Chol-free chow and water ad lib. Serum sterol levels were monitored by HPLC bi-weekly. After dark- and light-adapted ERGs were recorded, one eye from each rat was taken for histological and quantitative morphometric analysis, while contralateral retinas, livers, and brains, were harvested for sterol analysis. The results were compared against those obtained previously from control rats. Results: 7-dehydrocholesterol (7DHC) to Chol mole ratio in all tissues of treated rats was >5:1; by contrast, 7DHC/Chol < 0.01 in control tissues. Dark- and light-adapted ERG amplitudes were markedly reduced, and their implicit times were substantially elevated, relative to controls. Outer nuclear layer (ONL) thickness was reduced by 20-30%, relative to controls. Conclusions: Osmotic pump delivery of AY9944 offers an improved SLOS animal model, obviating the tedium and inherent variability of daily drug administration by diet or injections, while providing reliable, uniform, and continuous drug delivery at pharmacologically effective levels. Retinal degeneration and functional deficits were even greater than those previously obtained by systemic administration of AY9944 during gestational and postnatal development in rats (Fliesler et al., ARVO 2002), and also are consistent with retinal dysfunction observed in SLOS patients (Boisvert et al, ARVO 2002).

Keywords: lipids • retinal degenerations: cell biology • photoreceptors 

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