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.

中文翻译：

---

预防 Smith-Lemli-Opitz 综合征大鼠模型的视网膜变性。


Smith-Lemli-Opitz 综合征 (SLOS) 是一种隐性人类疾病，由 DHCR7（7-脱氢胆固醇还原酶）水平的胆固醇 (CHOL) 合成缺陷引起，DHCR7（7-脱氢胆固醇还原酶）通常催化 7-脱氢胆固醇 (7DHC) 转化为 CHOL。 SLOS 患者和接受 DHCR7 抑制剂 AY9944 治疗的大鼠中会出现 7DHC 和 7DHC 衍生的氧甾醇的形成和异常积累。大鼠 SLOS 模型表现出进行性和不可逆的视网膜功能障碍和变性，通过饮食补充 CHOL 只能部分改善这种情况。我们假设 7DHC 衍生的氧甾醇与这种视网膜变性有因果关系，并且阻断或减少它们的形成应该可以最大限度地减少表型。在这里，使用 SLOS 大鼠模型，我们证明，在保护视网膜结构和功能以及降低 7DHC 衍生方面，联合膳食补充 CHOL 加抗氧化剂（维生素 E 和 C，加亚硒酸钠）比单独膳食补充 CHOL 提供更好的结果氧甾醇的形成。这些原理验证研究结果为设计临床试验提供了一个转化性的临床前框架，使用 CHOL-抗氧化剂联合疗法作为当前 SLOS 治疗标准的改进治疗干预措施。