PLACEBO-CONTROLLED STUDY OF X-ALD DIET THERAPY

X-ALD 饮食疗法的安慰剂对照研究

• 批准号: 7604721
• 负责人: HUGO W MOSER
• 金额: $ 0.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7604721
• 关键词: Adolescence; Adrenomyeloneuropathy; Adult; Affect; Cerebrum; Cervical; Chest; Childhood; Clinical Trials; Code; Computer Retrieval of Information on Scientific Projects Database; Corticospinal Tracts; Defect; Diet therapy; Distal; Double-Blind Method; Equilibrium; Esthesia; Evaluation; Fatty Acids; Funding; General Hospitals; Genes; Grant; Image; Inflammatory; Institution; Link; Lorenzo' s oil; Magnetism; Massachusetts; Membrane Proteins; Motor; Multiple Sclerosis; Myelin; Neurologic; Oral Administration; Outcome Measure; Paraparesis; Patients; Phenotype; Placebos; Plasma; Preventive; Research; Research Personnel; Resources; Sensory; Source; Speed; Spinal Cord; Spinal Cord Diseases; Structure; Techniques; Testing; Therapeutic Intervention; Tissues; United States National Institutes of Health; Validation; Week; Woman; axonopathy; boys; dorsal column; men; middle age; novel; older women; placebo controlled study; trierucate; young adult

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. We propose to conduct a double blinded placebo-controlled study of 4:1 Glyceryl Trioleate-Glyceryl Trierucate "Lorenzo's Oil" (LO) therapy in pure adrenomyeloneuropathy (AMN). AMN is one of the major phenotypes of X-linked adrenoleukodystropy (X-ALD). X-ALD is due to a defect in ABCD1, a gene that codes for ALDP, a peroxisomal membrane protein. X-ALD is associated with the abnormal accumulation of saturated very long chair fatty acids (VLCFA) in plasma and tissues. Pure AMN is the form of X-ALD that manifests with slowly progressive paraparesis and sensory deficits. Its principal pathological change is a non-inflammatory distal axonopathy that involves the dorsal columns in the cervical segments and the corticospinal tract in the lower thoracic and lumbar segments. It affects most commonly young adult men, and less severely, middle aged or older women who are heterozygous for X-ALD. Approximately forty percent of all patients with X-ALD have this form of the illness. AMN stands in contrast to the rapidly progressive cerebral forms in which there is a rapidly progressive inflammatory disintegration of myelin. These are most common in childhood (Childhood Cerebral X-ALD, (CCER)), but they may manifest in adolescence or adults in patients who have AMN. Patients who have cerebral involvement in addition to pure AMN are referred to as "AMN cerebral." The oral administration of 4:1 glyceryl trioleate-glyceryl trierucate "Lorenzo's Oil" (LO) normalizes plasma VCLFA levels in X-ALD patients within four weeks. While earlier clinical trials had been disappointing, relatively long duration studies that were completed recently suggest that is beneficial in two types of X-ALD: 1) as a preventive of neurological involvement in asymptomatic boys; and 2) pure AMN where it appears to slow progression. However, neither or these studies were controlled. We now propose a four-year placebo-controlled study to determine the effects of LO on the progression of pure AMN. The study will involve 100 adult men with pure AMN and 100 adult women who are heterozygous for X-ALD and have pure AMN. Half of the patients will be studies at Johns Hopkins, the other half at the Massachusetts General Hospital. We request here CGRC support for the first year of the Hopkins component. Primary outcome measures will include standardized scales that have been validated for multiple sclerosis. An important novel part of the study is the utilization and validation of newly developed markers, namely quantitative tests of balance, sensation and motor function, and magnetic transfer imaging of the dorsal columns in cervical cord. Our preliminary studies suggest they may permit more sensitive and rapid assessment of the changes in spinal cord function and structure than can be achieved with current techniques, and this may facilitate and speed the evaluation of therapeutic intervention. They may also be applicable to the study of other spinal cord disorders.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们建议进行一项4：1三油酸甘油酯-三甘油酸甘油酯“洛伦佐油”(LO)治疗单纯肾上腺髓神经病(AMN)的双盲安慰剂对照研究。AMN是X连锁肾上腺脑白质营养不良(X-ALD)的主要表型之一。X-ALD是由于ABCD1基因的缺陷所致，ABCD1是一种过氧化物体膜蛋白ALDP的编码基因。X-ALD与血浆和组织中饱和的超长椅子脂肪酸(VLCFA)的异常积累有关。单纯AMN是X-ALD的一种形式，表现为缓慢进行性瘫痪和感觉障碍。其主要病理改变是一种非炎症性远端轴索病变，累及颈段的背柱和下胸腰段的皮质脊髓束。它最常见的影响是年轻的成年男性，以及不太严重的X-ALD杂合子的中年或老年女性。大约40%的X-ALD患者患有这种疾病。AMN与快速进展性脑形式形成对比，在快速进展性脑形式中，髓鞘迅速进行性炎症分解。这些症状最常见于儿童期(儿童期大脑X-ALD，(CCER))，但也可能表现在青春期或成年AMN患者。除单纯AMN外，还有脑部受累的患者被称为“AMN脑部”。 口服4：1三油酸甘油酯-三甘油酸甘油酯“洛伦佐油”(LO)可在四周内使X-ALD患者的血浆VCLFA水平恢复正常。虽然早期的临床试验令人失望，但最近完成的相对较长持续时间的研究表明，这对两种类型的X-ALD是有益的：1)作为预防无症状男孩的神经损害；2)在似乎减缓进展的情况下，单纯的AMN。然而，这两项研究或这些研究都没有受到控制。我们现在建议进行一项为期四年的安慰剂对照研究，以确定LO对单纯AMN进展的影响。这项研究将涉及100名患有纯合AMN的成年男性和100名患有X-ALD杂合子并患有纯合AMN的成年女性。一半的患者将在约翰·霍普金斯大学进行研究，另一半将在马萨诸塞州综合医院进行研究。我们在此请求CGRC为霍普金斯组件的第一年提供支持。主要结果衡量标准将包括已被验证用于多发性硬化症的标准化量表。本研究的一个重要创新部分是对新开发的标记物的利用和验证，即平衡、感觉和运动功能的定量测试，以及颈髓背柱的磁转移成像。我们的初步研究表明，它们可能会比目前的技术更敏感和更快速地评估脊髓功能和结构的变化，这可能会促进和加快治疗干预的评估。它们也可能适用于其他脊髓疾病的研究。