Biomarker discovery and validation in a Duchenne dystrophy natural history study

描述(申请人提供)：Duchenne肌营养不良症(DMD)是一种X连锁的神经肌肉疾病，由dystrophin基因突变引起，导致进行性肌肉无力，通常导致青壮年死亡。这是最常见的儿童神经肌肉疾病，在所有种族中，每3500名男性中就有一人受到影响。虽然目前还没有治疗DMD的有效方法，但有希望的、新的治疗方法已经出现，这需要精心设计的临床试验。FDA等监管机构往往更愿意考虑将生物标记物作为替代终点，甚至是DMD等罕见疾病的主要终点，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，识别敏感和可靠的生物标志物成为一个高度优先的问题。该应用程序用于大型临床试验的辅助研究的目的是发现和验证DMD的敏感和特异的血清生物标记物。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信息库，以便在国际范围内发现和验证DMD的生物标记物。家长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DMD的CINRG纵向自然历史研究，以及2015年前的家长项目肌营养不良症。该项目的具体目标是：1)收集422名4岁至成年的DMD患者的血清，每名患者每隔一年收集两份样本(共844份)。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。目的2)在30名具有代表性年龄和疾病分期的DMD患者身上进行广泛的生物标志物发现，与使用AIM 1的基线样本和1年样本的30名年龄匹配的对照组进行比较。生物标志物的发现将包括microRNA图谱、代谢组学图谱、细胞因子微珠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记物，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相关的生物标记物。目的4)构建一个完整的分子/临床数据库，并将其与血清生物信息库相连接。我们假设，指示Duchenne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生物标记物可以通过循环microRNA、细胞因子面板、纳米颗粒蛋白质组学和/或代谢组学的测量来识别和验证。这项拟议的辅助研究对DMD患者具有重要意义，因为它将识别敏感的和疾病特异性的新生物标记物。稳健生物标记物的识别将对使用生物标记物作为终点的第二阶段临床试验产生重大影响，并可能对其他营养不良症产生重大的知识转移。

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.