Multicenter Therapeutic Trials of X-Linked ALD

X连锁 ALD 的多中心治疗试验

• 批准号: 6897486
• 负责人: HUGO W MOSER
• 金额: $ 80万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-18 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897486
• 关键词: adrenoleukodystrophy; adult human (21+); antineoplastics; children; clinical research; genetic disorder; human subject; human therapy evaluation; insulinlike growth factor; longitudinal human study; magnetic resonance imaging; nervous system disorder chemotherapy; neuroimaging; neurologic manifestations; neuropsychological tests; neuropsychology; nuclear magnetic resonance spectroscopy; pathologic process; patient /disease registry; patient oriented research; phenotype; phenylbutyrates; psychomotor function; quality of life; sensorimotor system

DESCRIPTION (provided by applicant): X-linked adrenoleukodystrophy (X-ALD) affects mainly the nervous system white matter and axons and the adrenal cortex. Its incidence is approximately 1:17,000. Phenotypic expression varies often within the same family and in males ranges from the childhood cerebral form, which may lead to total disability and death by 10 years of age, to adrenomyeloneuropathy (AMN), which presents in the middle or late twenties as a paraparesis that is slowly progressive over decades. Women heterozygous for X-ALD may develop an AMN-like syndrome in middle age or later. Most males have primary adrenocortical insufficiency which responds to steroid replacement therapy. Accumulation of very long chain fatty acids (VLCFA) is the principal biochemical abnormality. The defective gene codes for a peroxisomal membrane protein (ALDP). There is no consistently effective therapy for the neurologic manifestations. Bone marrow transplantation benefits patients with early cerebral involvement but carries a high risk. The investigators propose a longitudinal cohort study and two Phase II therapeutic trials. Specific Aim 1 will establish a network of five clinical centers: The Kennedy Krieger Institute in Baltimore, the Texas Children's Hospital in Houston, the Massachusetts General Hospital in Boston, the University of Minnesota in Minneapolis, and the University of California at San Francisco. The Program will be coordinated by the Center for Clinical Trials at the Johns Hopkins Bloomberg School of Public Health. Specific Aim 2 will establish a cohort of 300 male X-ALD patients and 100 women heterozygous for X-ALD to permit a longitudinal study of natural history. Follow-up will utilize objective and validated measures of neurologic and neuropsychologic function, and quality of life. Neuroimaging studies have been shown to be valuable surrogate markers of the cerebral disease and will be scored independently by two neuroradiologists using an electronic transmission system developed for this purpose with the support from the National Library of Medicine. Newly developed quantitative tests will be used to aid assessment progression of AMN. Specific Aim 3 will conduct safety-efficacy studies of 4-phenylbutyrate therapy in patients with the cerebral forms of X-ALD, and a placebo controlled trial of insulin-like growth factor-1 in male patients with AMN and heterozygous women with an AMN like syndrome.

描述（由申请人提供）：X连锁肾上腺脑白质营养不良（X-ALD）主要影响神经系统白色物质和轴突以及肾上腺皮质。 其发病率约为1：17，000。 表型表达通常在同一家族内变化，并且在男性中的范围从儿童期脑型（其可能导致10岁时的完全残疾和死亡）到肾上腺脊髓神经病（AMN）（其在二十多岁中或晚些时候表现为在数十年内缓慢进行的轻瘫）。 X-ALD杂合子的女性可能在中年或更晚时发展为AMN样综合征。 大多数男性有原发性肾上腺皮质功能不全，对类固醇替代疗法有反应。 极长链脂肪酸（VLCFA）的积累是主要的生化异常。 有缺陷的基因编码过氧化物酶体膜蛋白（ALDP）。 对于神经系统表现没有持续有效的治疗方法。 骨髓移植对早期脑受累患者有益，但风险较高。 研究人员提出了一项纵向队列研究和两项II期治疗试验。 具体目标1将建立一个由五个临床中心组成的网络：巴尔的摩的肯尼迪克里格研究所、休斯顿的德克萨斯儿童医院、波士顿的马萨诸塞州总医院、明尼阿波利斯的明尼苏达大学和位于旧金山弗朗西斯科的加州大学。 该计划将由约翰霍普金斯彭博公共卫生学院的临床试验中心协调。 具体目标2将建立一个300名男性X-ALD患者和100名女性X-ALD杂合子的队列，以允许自然史的纵向研究。 随访将采用客观和有效的神经和神经心理功能以及生活质量指标。 神经影像学研究已被证明是脑疾病的有价值的替代标志物，将由两名神经放射科医生使用在国家医学图书馆支持下为此目的开发的电子传输系统独立评分。 新开发的定量测试将用于辅助AMN的评估进展。 具体目标3将在大脑型X-ALD患者中进行4-苯丁酸酯治疗的安全性-有效性研究，并在AMN男性患者和AMN样综合征杂合子女性患者中进行胰岛素样生长因子-1安慰剂对照试验。