Title: Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome.
Authors: Fliesler, Steven J; Peachey, Neal S; Herron, Josi; Hines, Kelly M; Weinstock, Nadav I; Ramachandra Rao, Sriganesh; Xu, Libin
Published In Sci Rep, (2018 01 19)
Abstract: Smith-Lemli-Opitz Syndrome (SLOS) is a recessive human disease caused by defective cholesterol (CHOL) synthesis at the level of DHCR7 (7-dehydrocholesterol reductase), which normally catalyzes the conversion of 7-dehydrocholesterol (7DHC) to CHOL. Formation and abnormal accumulation of 7DHC and 7DHC-derived oxysterols occur in SLOS patients and in rats treated with the DHCR7 inhibitor AY9944. The rat SLOS model exhibits progressive and irreversible retinal dysfunction and degeneration, which is only partially ameliorated by dietary CHOL supplementation. We hypothesized that 7DHC-derived oxysterols are causally involved in this retinal degeneration, and that blocking or reducing their formation should minimize the phenotype. Here, using the SLOS rat model, we demonstrate that combined dietary supplementation with CHOL plus antioxidants (vitamins E and C, plus sodium selenite) provides better outcomes than dietary CHOL supplementation alone with regard to preservation of retinal structure and function and lowering 7DHC-derived oxysterol formation. These proof-of-principle findings provide a translational, pre-clinical framework for designing clinical trials using CHOL-antioxidant combination therapy as an improved therapeutic intervention over the current standard of care for the treatment of SLOS.
PubMed ID: 29352199
MeSH Terms: Animals; Antioxidants/administration & dosage; Antioxidants/therapeutic use; Cholesterol/administration & dosage; Cholesterol/therapeutic use*; Dietary Supplements; Female; Rats; Rats, Sprague-Dawley; Retina/metabolism; Retinal Degeneration/drug therapy; Retinal Degeneration/prevention & control*; Selenious Acid/administration & dosage; Selenious Acid/therapeutic use; Smith-Lemli-Opitz Syndrome/drug therapy; Smith-Lemli-Opitz Syndrome/prevention & control*; Vitamins/administration & dosage; Vitamins/therapeutic use