INVESTIGATION OF SIMVASTATIN THERAPY IN SMITH-LEMI-OPITZ SYNDROME

辛伐他汀治疗史密斯-莱米-奥皮兹综合征的研究

• 批准号: 7378968
• 负责人: ELAINE TIERNEY
• 金额: $ 0.48万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378968
• 关键词: INVESTIGATION; SIMVASTATIN; THERAPY; SMITH; LEMI

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Smith-Lemli-Opitz Syndrome (SLOS, RSH syndrome, OMIM #270400) is an autosomal recessive, multiple malformation, mental retardation syndrome due to an inborn error of cholesterol biosynthesis. Specifically, these patients have a deficiency of 3-beta-hydroxysterol delta-7 reductase activity due to mutation of the 3-beta-hydroxysterol 7-reuctase gene (DHCR7). This enzymatic deficiency impairs the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol in the last step of cholesterol biosynthesis. The clinical manifestations of SLOS are extremely variable and the phenotypic spectrum is broad. At the severe end of the spectrum SLOS is a lethal disorder with multiple major congenital anomalies, and in mild cases SLOS combines minor physical stigmata with behavioral and learning disabilities. Based on clinical studies, the incidence rate of SLOS is 1/10,000 to 1/60,000. Molecular studies have shown a carrier frequency of about 1% for the most common SLOS mutant allele in North American populations. Currently, therapy is based on dietary cholesterol supplementation. Although clinical improvement has been noted, serumcholesterol levels are rarely normalized and elevated serum 7-DHC levels persist. Because elevated 7-DHC levels may have toxic effects, treatment of SLOS patients with an HMG-CoA reductase inhibitor has been proposed. Simvastatin is a medication which inhibits the body's ability to synthesize cholesterol. Because is blocks cholesterol synthesis at an early step, it also blocks 7-DHC synthesis. In mild to typical SLOS children, the protein (enzyme) that converts 7-DHC to cholesterol works at a low level. We suspect that simvastatin may increase the amount of this enzyme. If this occurs, although the enzyme does ot work any better, there is more of it. With more enzyme present, more 7-DHC may be converted to cholesterol. Although clinical improvement has been noted with dietary cholesterol supplementation, serum cholesterol levels are rarely normalized and elevated serum 7-DHC levels persist. The goal of this clinicsl research protocol will be to test the clinical efficacy and safety of simvastatin therapy as an addition to cholesterol supplementation in mild to classical SLOS patients using a double-blind, placebo-controlled crossover design.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。 Smith-Lemli-Opitz 综合征（SLOS、RSH 综合征、OMIM #270400）是一种常染色体隐性遗传、多发性畸形、智力低下综合征，由胆固醇生物合成的先天性错误所致。具体来说，这些患者由于 3-β-羟基甾醇 7-还原酶基因 (DHCR7) 突变而缺乏 3-β-羟基甾醇 δ-7 还原酶活性。这种酶缺乏会损害胆固醇生物合成最后一步中 7-脱氢胆固醇 (7-DHC) 向胆固醇的转化。 SLOS 的临床表现极其多样，表型谱广泛。在严重的情况下，SLOS 是一种致命的疾病，具有多种主要的先天异常，而在轻微的情况下，SLOS 结合了轻微的身体耻辱和行为和学习障碍。根据临床研究，SLOS的发生率为1/10,000至1/60,000。分子研究表明，北美人群中最常见的 SLOS 突变等位基因的携带频率约为 1%。目前，治疗基于膳食胆固醇补充剂。尽管已经注意到临床改善，但血清胆固醇水平很少恢复正常，并且血清 7-DHC 水平持续升高。由于 7-DHC 水平升高可能产生毒性作用，因此建议使用 HMG-CoA 还原酶抑制剂治疗 SLOS 患者。辛伐他汀是一种抑制人体合成胆固醇能力的药物。因为它会在早期阻止胆固醇合成，所以它也会阻止 7-DHC 合成。在轻度至典型 SLOS 儿童中，将 7-DHC 转化为胆固醇的蛋白质（酶）水平较低。我们怀疑辛伐他汀可能会增加这种酶的含量。如果发生这种情况，虽然酶的作用并没有更好，但酶的数量却更多了。随着酶的存在，更多的 7-DHC 可能会转化为胆固醇。尽管膳食胆固醇补充剂的临床效果已得到改善，但血清胆固醇水平很少恢复正常，并且血清 7-DHC 水平持续升高。该临床研究方案的目标是使用双盲、安慰剂对照交叉设计，测试辛伐他汀疗法作为胆固醇补充剂的补充对轻度至典型 SLOS 患者的临床疗效和安全性。