EFFECT OF GLYCERYL TRIERUCATE THERAPY OF ALD

三芥酸甘油酯治疗酒精性肝病的效果

• 批准号: 7378950
• 负责人: HUGO W MOSER
• 金额: $ 0.04万
• 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/7378950
• 关键词: EFFECT; GLYCERYL; TRIERUCATE; THERAPY; ALD

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. X-linked adrenoleukodystrophy (X-ALD) affects mainly the nervous system white matter and the adrenal gland. It shows a wide range of phenotypic expression. The childhood cerebral form manifests most commonly at 6-8 years of age, and is rapidly progressive, often leading to severe neurological disability before age 10 years. Other forms such as adrenomyloneuropathy (AMN) manifest in adulthood and progress more slowly. The principal biochemical abnormality is the accumulation of saturated very long chain fatty acids (VLCFA), due to a defect in the peroxisomal oxidation of these substances. It is likely, but not proven, that the VLCFA excess contributes to pathogenesis. In 1989 it was shown that the oral administration of a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, also referred to as Lorenzo Oil, can normalize the levels of VLCFA in plasma within 4 weeks. This observation led to the hope administration of this substance to asymptomatic patients could reduce the frequency and severity of subsequent neurologic damage. The present study is designed to assess whether this is the case. Because of the severe nature of the disease, and the striking biochemical effect of Lorenzo Oil on plasma VLCFA levels, a non-randomized study design was adopted. Evaluation of clinical efficacy will be based upon the comparison of clinical course of patients who were placed on oil therapy while they were asymptomatic, with that in a historical control group. Analysis of the age of onset in a large series of historical controls in the US and in Europe, indicate that 31 to 39% of patients with the biochemical defect develop neurologic symptoms by eleven years of age. The present study focuses on the clinical outcome of 125 neurologically X-ALD patients in the US who have been placed on Lorenzo Oil therapy, and is coordinated closely with a similar study in Europe that involves a similar number of patients. The main focus of the study will be on patients who began this therapy before 6 years of age and who have been followed to and beyond their eleventh birthday. We anticipate that between 50 and 60 patients will meet these criteria. The end point will be the proportion of these patients who devleop neurologic symptoms prior to their eleventh birthday. A positive result would be a proportion which is significantly less than 31 to 39%. Power calculations indicate that this sample size will permit detection of a 50% reduction in neurologic involvement by eleven years of age at the 0.05 significance level with 80% power.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。X-连锁肾上腺脑白质营养不良(X-ALD)主要累及神经系统、脑白质和肾上腺。它表现出广泛的表型表达。儿童期脑型最常见于6-8岁，进展迅速，通常在10岁之前导致严重的神经功能障碍。其他形式，如肾上腺髓神经病(AMN)，在成年时表现出来，进展较慢。主要的生化异常是饱和超长链脂肪酸(VLCFA)的积累，这是由于这些物质的过氧化体氧化缺陷所致。VLCFA过量可能是发病机制之一，但尚未得到证实。1989年的研究表明，口服4：1的三油酸甘油酯和三甘油酸甘油酯(又称洛伦佐油)可在4周内使血浆中VLCFA水平恢复正常。这一观察结果使人们希望，给没有症状的患者服用这种物质可以降低随后神经损伤的频率和严重程度。本研究旨在评估这种情况是否属实。由于疾病的严重性，以及洛伦佐油对血浆VLCFA水平的显著生化影响，采用了非随机研究设计。临床疗效的评估将基于对无症状时接受石油治疗的患者与历史对照组的临床病程进行比较。对美国和欧洲一系列历史对照的发病年龄的分析表明，31%至39%的生化缺陷患者在11岁时出现神经症状。目前的研究重点是美国125名接受洛伦佐石油疗法的神经性X-ALD患者的临床结果，并与欧洲的一项涉及类似数量的患者的类似研究密切协调。这项研究的主要焦点将是那些在6岁之前开始这种疗法的患者，以及那些一直被跟踪到11岁生日或11岁以后的患者。我们预计将有50到60名患者符合这些标准。终点将是这些患者在11岁生日之前出现神经症状的比例。一个积极的结果将是一个明显低于31%到39%的比例。功率计算表明，这个样本量将允许在0.05%的显着性水平上，在80%的功率下，在11岁之前检测到神经受累减少50%。