Departments of Ophthalmology and Biochemistry and Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
Research Service, VA Western NY Healthcare System, Buffalo, NY 14260, USA.
Molecules. 2018 Oct 22;23(10):2720. doi: 10.3390/molecules23102720.
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive human disease caused by mutations in the gene encoding 7-dehydrocholesterol (7DHC) reductase (DHCR7), resulting in abnormal 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 features of this disease model and the evidence linking 7DHC-derived oxysterols to the pathobiology of the disease, with particular emphasis on the associated retinal degeneration. A recent study has shown that treating the rat model with cholesterol plus suitable antioxidants completely prevents the retinal degeneration. These findings are discussed with regard to their translational implications for developing an improved therapeutic intervention for SLOS over the current standard of care.
史密斯-莱姆利-奥皮茨综合征（SLOS）是一种常染色体隐性遗传疾病，由编码 7-脱氢胆固醇（7DHC）还原酶（DHCR7）的基因突变引起，导致 7DHC 在体内组织和液体积聚异常，胆固醇水平降低。通过用 DHCR7 抑制剂 AY9944 处理正常大鼠，可建立该疾病的大鼠模型，该抑制剂可导致进行性、不可逆转的视网膜变性。在此，我们综述了该疾病模型的特征以及将 7DHC 衍生的氧化固醇与疾病的病理生物学联系起来的证据，特别强调了相关的视网膜变性。最近的一项研究表明，用胆固醇加适当的抗氧化剂治疗大鼠模型可完全阻止视网膜变性。本文就这些发现及其对开发改善 SLOS 治疗干预措施的转化意义进行了讨论，目前的治疗标准是改善护理。
