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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

基本信息

批准号：
8735609
负责人：
YETRIB HATHOUT
金额：
$ 36.39万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-09 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8735609
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

项目摘要

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X连锁神经肌肉疾病，由肌营养不良蛋白基因突变引起，导致进行性肌无力，通常在年轻时死亡。它是最常见的儿童神经肌肉疾病，影响所有种族群体中约1/3，500的男性。虽然目前尚无有效的DMD治疗方法，但DMD的有前途的新型治疗方法已经出现，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视为DMD等罕见疾病的替代终点甚至主要终点，特别是在涉及有限患者数量的短期II期剂量范围研究中。因此，鉴定敏感和可靠的生物标志物成为高度优先事项。本申请作为大型临床试验的辅助研究的目的是发现和验证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/临床数据库与相关的生物知识库，使生物标志物的发现和验证DMD在国际范围内。母研究是由美国教育部、NIH和国防部资助的DMD中422名受试者的CINRG纵向自然史研究，以及2015年之前的肌营养不良母项目。该项目的具体目标是：目标1）从参加CINRG纵向自然史研究的422名4岁至成年期DMD受试者收集血清，每名患者每隔1年收集两份样本（共844份样本）。对于开始皮质类固醇治疗的50例受试者，将在基线、治疗开始后6个月和1年采集样本。目的2）使用来自目的1的基线和1年样本，对30名具有代表性年龄和疾病阶段的DMD患者与30名年龄匹配的对照进行广泛基础的生物标志物发现。生物标志物的发现将包括microRNA分析，代谢组学分析，细胞因子珠阵列和纳米颗粒蛋白质组学。目的3）在整个样品组群中筛选所选的候选生物标志物，并鉴定与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那些生物标志物。目的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，可以使用循环microRNA、细胞因子组、纳米颗粒蛋白质组学和/或代谢组学的测量来鉴定和验证指示杜氏肌营养不良症疾病严重程度、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，因为它将确定敏感和疾病特异性的新生物标志物。确定稳健的生物标志物将对使用生物标志物作为终点的II期临床试验产生重大影响，并可能对其他营养不良产生重要的知识转移。