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。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。 Smith-Lemli-Opitz综合征（SLO，RSH综合征，OMIM＃270400）是一种常染色体隐性，多重畸形，精神迟缓综合征，这是由于天生的胆固醇生物合成误差。具体而言，这些患者由于3β-羟基甲醇7-脱氧酶基因（DHCR7）突变而导致的3β-羟基肽delta-7还原酶活性缺乏。这种酶促缺乏会损害7-脱氢胆固醇（7-DHC）在胆固醇生物合成的最后一步中转化为胆固醇。 SLO的临床表现非常可变，表型光谱很广。在严重的频谱末端，SLOS是一种致命疾病，具有多个主要先天性异常，在温和的情况下，SLO将较小的物理污名与行为和学习障碍结合在一起。根据临床研究，SLO的发病率为1/10,000至1/60,000。分子研究表明，北美人群中最常见的SLOS突变等位基因的载体频率约为1％。目前，治疗是基于饮食中补充胆固醇的。尽管已经注意到临床改善，但血清胆固醇水平很少被标准化，血清7-DHC水平持续存在。由于升高的7-DHC水平可能具有毒性作用，因此已经提出了对HMG-COA还原酶抑制剂的SLOS患者的治疗。辛伐他汀是一种抑制人体合成胆固醇的能力的药物。因为IS是胆固醇在早期的胆固醇合成，所以它也可以阻止7-DHC合成。在轻度至典型的SLOS儿童中，将7-DHC转换为胆固醇的蛋白质（酶）在低水平上起作用。我们怀疑辛伐他汀可能会增加该酶的量。如果发生这种情况，尽管酶确实可以更好地工作，但还有更多。由于存在更多的酶，可以将更多的7-DHC转换为胆固醇。尽管补充饮食胆固醇已经注意到临床改善，但血清胆固醇水平很少被标准化，血清7-DHC水平持续升高。该诊所研究方案的目的是测试辛伐他汀治疗的临床功效和安全性，作为使用双盲，安慰剂控制的跨界设计中轻度至古典SLOS患者补充胆固醇的补充。