PLACEBO-CONTROLLED STUDY OF X-ALD DIET THERAPY

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来源获得了主要资金，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。我们建议进行一项双盲安慰剂对照研究，研究4：1甘油三油酸酯-甘油三芥酸酯“洛伦佐油”（LO）治疗单纯肾上腺脊髓神经病（AMN）。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ABCD 1基因缺陷引起的，ABCD 1基因编码ALDP，一种过氧化物酶体膜蛋白。X-ALD与血浆和组织中饱和极长链脂肪酸（VLCFA）的异常积累有关。纯AMN是X-ALD的形式，表现为缓慢进行性下肢轻瘫和感觉缺陷。其主要病理变化是一种非炎症性远端轴突病变，涉及颈段的背柱和下胸段和腰段的皮质脊髓束。它最常影响年轻的成年男性，不太严重，中年或老年妇女谁是杂合子的X-ALD。大约40%的X-ALD患者患有这种疾病。AMN与快速进展的脑型形成对比，在脑型中存在髓鞘的快速进展的炎性崩解。这些在儿童时期最常见（儿童脑X-ALD，（CCER）），但它们可能在青少年或成人AMN患者中表现出来。除了单纯AMN之外还累及大脑的患者被称为“大脑AMN”。口服4：1的甘油三油酸酯-甘油三芥酸酯“洛伦佐油”（LO）在四周内使X-ALD患者的血浆VCLFA水平正常化。虽然早期的临床试验令人失望，但最近完成的相对较长时间的研究表明，它在两种类型的X-ALD中是有益的：1）作为无症状男孩神经系统受累的预防剂; 2）纯AMN，它似乎减缓了进展。然而，这两项研究都没有对照。我们现在提出一项为期四年的安慰剂对照研究，以确定LO对纯AMN进展的影响。这项研究将涉及100名纯AMN成年男性和100名X-ALD杂合子纯AMN成年女性。一半的患者将在约翰霍普金斯医院接受研究，另一半将在马萨诸塞州总医院接受研究。我们在此请求全球区域中心为霍普金斯部分的第一年提供支助。主要结果测量将包括已被验证为多发性硬化症的标准化量表。这项研究的一个重要的新部分是利用和验证新开发的标记物，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，它们可能允许更敏感和快速的评估脊髓功能和结构的变化比可以实现与当前的技术，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。本研究于2005年3月5日启动。45名患者（28名女性和17名男性）完成了2天的基线评估，并参加了

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 adrenoleukodystrophy (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 chain 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 it 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 of these studies were controlled. We now propose a four-year placebo-controlled study to determine the effect 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 studied at Johns Hopkins, the other half at the Massachusetts General Hospital. We request here GCRC 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. This study was initiated on Marcy 5, 2005. Forty-five patients (28 women and 17 men) have completed their 2-day baseline evaluation and are participating in the pro