Oxysterols and Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome: Implications for an Improved Therapeutic Intervention

摘要

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive human disease causedby mutations in the gene encoding 7-dehydrocholesterol (7DHC) reductase (DHCR7), resulting inabnormal accumulation of 7DHC and reduced levels of cholesterol in bodily tissues and fluids.A rat model of the disease has been created by treating normal rats with the DHCR7 inhibitor,AY9944, which causes progressive, irreversible retinal degeneration. Herein, we review the featuresof this disease model and the evidence linking 7DHC-derived oxysterols to the pathobiology ofthe disease, with particular emphasis on the associated retinal degeneration. A recent study hasshown that treating the rat model with cholesterol plus suitable antioxidants completely prevents theretinal degeneration. These findings are discussed with regard to their translational implications fordeveloping an improved therapeutic intervention for SLOS over the current standard of care.