PLACEBO-CONTROLLED STUDY OF X-ALD DIET THERAPY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。我们建议对纯肾上腺髓神经病变（AMN）进行4:1三油酸甘油酯-三酸甘油酯“洛伦佐油”（LO）治疗的双盲安慰剂对照研究。AMN是x -连锁肾上腺白质营养不良（X-ALD）的主要表型之一。X-ALD是由于编码ALDP（一种过氧化物酶体膜蛋白）的ABCD1基因缺陷所致。X-ALD与血浆和组织中饱和甚长椅脂肪酸（VLCFA）的异常积累有关。纯AMN是X-ALD的形式，表现为缓慢进行性麻痹和感觉缺陷。其主要病理改变为非炎性远端轴索病变，累及颈节段背柱和下胸椎段和腰椎节段皮质脊髓束。它最常影响年轻成年男性，而不太严重的是X-ALD杂合的中年或老年女性。大约40%的X-ALD患者患有这种疾病。AMN与快速进展的大脑形式相反，其中有髓磷脂的快速进展性炎症解体。这些在儿童时期最为常见（儿童期大脑X-ALD， （CCER）），但也可能在患有AMN的青少年或成人患者中表现出来。除了单纯的AMN外，还累及大脑的患者被称为“脑型AMN”。口服4:1三油酸甘油-三酸甘油“洛伦佐油”（LO）可使X-ALD患者血浆VCLFA水平在四周内恢复正常。虽然早期的临床试验令人失望，但最近完成的相对持续时间较长的研究表明，它对两种类型的X-ALD是有益的：1)预防无症状男孩的神经系统受累；2)纯AMN，它似乎减缓了进展。然而，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对纯AMN进展的影响。该研究将涉及100名纯AMN的成年男性和100名X-ALD杂合且纯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总医院进行研究。我们在此请求CGRC为霍普金斯部分的第一年提供支持。主要结果测量将包括已被证实用于多发性硬化症的标准化量表。本研究的一个重要新颖部分是利用和验证新开发的标志物，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，与目前的技术相比，它们可以更灵敏、更快速地评估脊髓功能和结构的变化，这可能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。

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.