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资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。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、精神发育迟滞综合征，由于胆固醇生物合成的先天性错误。具体地，这些患者由于3-β-羟基甾醇δ-7-还原酶基因（DHCR 7）的突变而具有3-β-羟基甾醇δ-7还原酶活性的缺陷。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）转化为胆固醇。SLOS的临床表现非常多变，表型谱很广。在严重的极端，SLOS是一种致命的疾病，具有多种主要的先天性异常，在轻度病例中，SLOS结合了轻微的身体伤痕与行为和学习障碍。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，在北美人群中，最常见的SLOS突变等位基因的携带者频率约为1%。目前，治疗是基于膳食胆固醇补充剂。虽然临床症状有所改善，但血清胆固醇水平很少正常化，血清7-DHC水平持续升高。由于升高的7-DHC水平可能具有毒性作用，因此已提出用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。因为它在早期阶段阻断胆固醇合成，所以它也阻断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）在低水平下起作用。我们怀疑辛伐他汀可能会增加这种酶的量。如果发生这种情况，虽然酶没有更好地工作，但有更多的酶存在，更多的7-DHC可能转化为胆固醇。虽然饮食胆固醇补充剂已注意到临床改善，但血清胆固醇水平很少正常化，血清7-DHC水平持续升高。本临床研究方案的目的是采用双盲、安慰剂对照交叉设计，在轻度至典型SLOS患者中检测辛伐他汀治疗作为胆固醇补充剂的补充的临床疗效和安全性。