Multicenter Therapeutic Trials of X-Linked ALD

X连锁 ALD 的多中心治疗试验

• 批准号: 6545406
• 负责人: HUGO W MOSER
• 金额: $ 64万
• 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/6545406
• 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(申请人提供)：X连锁肾上腺脑白质营养不良症(X-ALD)主要影响神经系统、白质和轴突以及肾上腺皮质。其发病率约为1：17,000。表型表达在同一个家庭中经常不同，在男性中的表现范围从儿童脑型，可能导致10岁时完全残疾和死亡，到肾上腺脊髓神经病(AMN)，它在25岁左右出现，表现为几十年来缓慢进展的偏瘫。X-ALD杂合子的女性在中年或更晚时可能会发展为AMN样综合征。大多数男性有原发性肾上腺皮质功能不全，这是对类固醇替代疗法的反应。超长链脂肪酸堆积(VLCFA)是主要的生化异常。该缺陷基因编码一种过氧化物体膜蛋白(ALDP)。对于这些神经系统症状，尚无一贯有效的治疗方法。骨髓移植有益于早期脑部受累的患者，但风险很高。 研究人员提出了一项纵向队列研究和两个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综合医院、明尼阿波利斯的明尼苏达大学和旧金山的加州大学。该计划将由约翰霍普金斯大学彭博公共卫生学院的临床试验中心协调。具体目标2将建立一个由300名男性X-ALD患者和100名X-ALD杂合子女性组成的队列，以允许对自然历史进行纵向研究。随访将使用客观和有效的神经学和神经心理功能以及生活质量测量方法。神经影像研究已被证明是脑部疾病的有价值的替代标记，并将由两名神经放射科医生使用在国家医学图书馆的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评估AMN的进展。具体目标3将在脑型X-ALD患者中进行4-苯丁酸酯治疗的安全性-有效性研究，并在患有AMN的男性患者和患有AMN样综合征的杂合子女性患者中进行胰岛素样生长因子-1的安慰剂对照试验。