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: 7604581
• 负责人: Gerald V. Raymond
• 金额: $ 0.92万
• 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/7604581
• 关键词: Adolescence; Adrenoleukodystrophy; 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; Funding; General Hospitals; Genes; Grant; Image; Inflammatory; Institution; Lorenzo' s oil; Magnetism; Massachusetts; Membrane Proteins; Motor; Multiple Sclerosis; Myelin; Neurologic; Oral Administration; Outcome Measure; Paraparesis; Patients; Phenotype; Placebos; Plasma; Preventive; Protocols documentation; 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; Very Long Chain Fatty Acid; Week; Woman; axonopathy; boys; day; 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 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 protocol.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。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。列出的机构是 对于中心，这不一定是调查员的机构。 我们建议对纯肾上腺瘤性肌病（AMN）进行4：1糖糖三分之一的糖基酸三酸酯三级疗法（LO）疗法的双眼安慰剂对照研究。 AMN是X连锁性肾上腺肿瘤（X-ald）的主要表型之一。 X-ald是由于ABCD1的缺陷，ABCD1是一个代码ALDP的基因，ALDP是过氧化物酶体膜蛋白。 X-Ald与血浆和组织中饱和非常长的链脂肪酸（VLCFA）的异常积累有关。纯AMN是X-ald的形式，表现出缓慢的渐进性模拟和感觉缺陷。它的主要病理变化是一种非炎性远端轴突病，涉及宫颈段中的背侧柱以及下胸腔和腰部段中的皮质脊髓段。它会影响最常见的年轻成年男性，并且不太严重，中年或年长的女性是X-ald的杂合子。所有X-ALD患者中约有40％患有这种疾病。 AMN与快速进行性的脑形式形成鲜明对比，髓鞘会迅速进行性炎症性分解。这些在童年时期最常见（儿童脑X-ald，（CCER）），但在患有AMN的患者中可能在青春期或成年人中表现出来。除纯AMN外，具有脑受累的患者被称为“ Amn大脑”。 4：1的口服给药在四周内X-ALD患者的血浆VCLFA水平标准化了4：1糖酸三酸酯三级剂量“ Lorenzo's Oil”（LO）。尽管较早的临床试验令人失望，但最近完成的持续时间相对较长的研究表明，在两种类型的X-ALD中，它是有益的：1）作为预防神经系统参与无症状男孩的预防性； 2）纯AMN似乎会减慢进展。但是，这两项研究都无法控制。现在，我们提出了一项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名具有纯AMN的成年男性，以及100名成年女性，这些女性是X-Ald且具有纯AMN的成年女性。一半的患者将在马萨诸塞州综合医院的另一半的约翰·霍普金斯（Johns Hopkins）进行研究。我们在这里要求GCRC支持霍普金斯组件的第一年。主要结局指标将包括已验证多发性硬化症的标准化量表。该研究的一个重要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，以及颈椎背柱的磁转移成像。我们的初步研究表明，它们可能允许对脊髓功能和结构的变化更加敏感，更快地评估与当前技术所能实现的，这可能有助于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。 这项研究是在2005年5月5日开始的。四十五名患者（28名女性和17名男性）已经完成了为期2天的基线评估，并正在参与该方案。