Biomarker discovery and validation in a Duchenne dystrophy natural history study

杜氏营养不良自然史研究中生物标志物的发现和验证

• 批准号: 8544782
• 负责人: YETRIB HATHOUT
• 金额: $ 35.13万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544782
• 关键词: Adrenal Cortex Hormones; Adult; Affect; Aftercare; Age; Ancillary Study; Biological Markers; Birth; Blood; Cessation of life; Childhood; Clinical; Clinical Trials; Clinical Trials Design; Communities; Correlation Studies; Creatine Kinase; Data; Databases; Department of Defense; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Dose; Duchenne muscular dystrophy; Dystrophin; Education; Emotional; Enrollment; Ethnic group; Face; Funding; Future; Genes; Goals; Industry; Infant; Inherited; International; Knowledge; Laboratory Finding; Life; Link; Measurement; Measures; MicroRNAs; Molecular; Muscle; Muscle Weakness; Muscular Dystrophies; Mutation; Natural History; Neuromuscular Diseases; Newly Diagnosed; Outcome Measure; Outpatients; Parents; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Prevalence; Proteomics; Public Health; Rare Diseases; Recruitment Activity; Rehabilitation therapy; Research; Research Design; Sample Size; Sampling; Serum; Serum Proteins; Severities; Severity of illness; Staging; Stream; Surrogate Endpoint; Therapy Clinical Trials; Time; United States National Institutes of Health; Universities; Validation; authority; base; biobank; biomedical informatics; cohort; cost; cost effective; cytokine; drug development; effective therapy; male; metabolomics; nanoparticle; novel; novel therapeutics; parent project; programs; repository; response; treatment effect; young adult

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by mutation of the dystrophin gene with resultant progressive muscle weakness, leading to death usually by young adulthood. It is the most common childhood neuromuscular disorder affecting about 1 in 3,500 males across all ethnic groups. Although no effective treatment for DMD is available at this time, promising and novel therapeutic treatments have emerged for DMD that will require well-designed clinical trials. Regulatory authorities such as the FDA are often more willing to consider biomarkers as surrogate endpoints or even the primary endpoint in rare disorders such as DMD, particularly in short-duration Phase II dose-ranging studies involving limited numbers of patients. As such, the identification of sensitive and reliable biomarkers becomes a high priority. The goal of this application for an ancillary study to a large clinical trial is to discover and validate sensitive and specific serum biomarkers for DMD. We also propose to develop an integrated molecular/clinical database with associated bio-repository to enable biomarker discovery and validation in DMD on an international scale. The parent study is the 422 subject CINRG Longitudinal Natural History Study in DMD funded by the US Department of Education, NIH and Department of Defense, and Parent Project Muscular Dystrophy until 2015. The specific aims of the project are: Aim 1) Collect sera from 422 DMD subjects ages 4 to adulthood enrolled in the CINRG Longitudinal Natural History Study, with two samples collected per patient at 1 year intervals (844 samples total). For 50 subjects starting corticosteroids, samples will be collected at baseline, 6 months and 1 year post treatment initiation. Aim 2) Carry out a broadly based biomarker discovery on 30 DMD patients, with representative age and disease stage, in comparison to 30 age-matched controls using baseline and 1-year samples from Aim 1. Biomarker discovery will include microRNA profiling, metabolomics profiling, cytokine bead-arrays, and nanoparticle proteomics. Aim 3) Validate selected candidate biomarkers in the entire sample cohort, and identify those biomarkers related to a) disease severity, b) disease progression, and c) responsiveness to corticosteroid treatment effect. Aim 4) Construct an integrated molecular/clinical database and link this to the serum biorepository. We hypothesize that sensitive and specific biomarkers indicative of Duchenne muscular dystrophy disease severity, progression, and corticosteroid drug activity can be identified and validated using measurement of circulating microRNAs, cytokine panels, nanoparticle proteomics, and/or metabolomics. This proposed ancillary study is significant for patients with DMD because it will identify sensitive and disease-specific novel biomarkers. The identification of robust biomarkers will have a substantial impact on Phase II clinical trials using biomarkers as endpoints, and will likely to have significant knowledge transfer to other dystrophies.

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种由肌营养不良蛋白基因突变引起的x连锁神经肌肉疾病，导致进行性肌肉无力，通常在青年期导致死亡。这是最常见的儿童神经肌肉疾病，在所有种族中，每3500名男性中就有1人患有此病。虽然目前还没有有效的治疗DMD的方法，但有希望的和新的治疗方法已经出现，需要精心设计的临床试验。FDA等监管机构通常更愿意将生物标志物作为DMD等罕见疾病的替代终点，甚至是主要终点，特别是在涉及有限数量患者的短时间II期剂量范围研究中。因此，识别敏感可靠的生物标志物成为当务之急。这项大型临床试验的辅助研究申请的目标是发现和验证DMD的敏感和特异性血清生物标志物。我们还建议开发一个集成的分子/临床数据库和相关的生物资源库，以便在国际范围内发现和验证DMD的生物标志物。该研究是由美国教育部、美国国立卫生研究院和国防部资助的422名受试者的纵向自然历史研究，以及截至2015年的肌肉萎缩症家长项目。该项目的具体目标是：目标1)收集参加CINRG纵向自然史研究的422名4至成年DMD受试者的血清，每1年收集2份样本（共844份样本）。对于50名开始使用皮质类固醇的受试者，将在治疗开始后的基线、6个月和1年收集样本。Aim 2)对30名具有代表性年龄和疾病分期的DMD患者进行广泛的生物标志物发现，与30名年龄匹配的对照组相比，使用Aim 1的基线和1年样本。生物标志物的发现将包括microRNA分析、代谢组学分析、细胞因子头部阵列和纳米颗粒蛋白质组学。目的3)在整个样本队列中验证选定的候选生物标志物，并确定与a)疾病严重程度，b)疾病进展和c)对皮质类固醇治疗效果的反应性相关的生物标志物。目标4)建立一个完整的分子/临床数据库，并将其与血清生物库连接起来。我们假设，可以通过循环microrna、细胞因子小组、纳米颗粒蛋白质组学和/或代谢组学的测量来识别和验证指示杜氏肌营养不良疾病严重程度、进展和皮质类固醇药物活性的敏感和特异性生物标志物。这项拟议的辅助研究对DMD患者具有重要意义，因为它将识别敏感和疾病特异性的新型生物标志物。确定强大的生物标志物将对以生物标志物为终点的II期临床试验产生重大影响，并可能对其他营养不良症具有重要的知识转移。