Multi-Center Validation of Biomarkers for Motor Neuron Disease

描述（由申请人提供）：本申请涉及广泛的挑战领域（03）生物标志物的发现和验证，以及特定的挑战主题03- ns -102：神经生物标志物的标准化和验证。虽然许多研究已经确定了肌萎缩性侧索硬化症（ALS）的推定蛋白质生物标志物，但所有研究都使用了有限数量的测试对象。因此，需要大规模的验证研究来确认这些潜在的ALS生物标志物。然后，这些经过验证的生物标志物可以在诊断测试和分析中向临床推进，以监测临床试验中的药物疗效。由于ALS是一种孤儿病，为了正确验证ALS的生物标志物，需要进行多中心临床研究，以获得必要数量的患者和对照样本。我们在快速推进ALS多中心生物标志物验证研究方面具有独特的优势。我们制定了收集血浆和脑脊液样本的标准操作程序。在过去的一年里，我们创建了一个由20个医疗中心和ALS诊所组成的联盟，并获得了IRB的批准，以利用这些标准化的样本收集程序。这个由诊所和临床研究人员组成的联盟包括许多ALS社区的领导者。我们假设，选择蛋白质和抗体为基础的生物标志物将在一个大型的前瞻性研究中得到验证，该研究使用CSF和来自全国多个诊所的血液样本。为了验证这一假设，我们提出了三个具体目标，以解决启动和快速推进ALS多中心生物标志物验证研究的关键挑战。第一个具体目标是在全国20个渐冻症诊所使用标准操作程序收集生物体液样本。第二个目标是执行靶向ELISA和基于多反应监测（MRM）的质谱分析，以验证ALS的特定蛋白质生物标志物。最终目的是利用这些生物体液样本来验证ALS患者脊髓蛋白特异性抗体的存在。该研究将验证ALS的特异性蛋白质和抗体生物标志物，这将有助于ALS的体外诊断分析的发展。鉴于我们合作团队的经验，我们有信心在挑战奖的两年时间框架内完成拟议的研究。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation, and specific Challenge Topic 03-NS-102: Standardization and validation of neurologic biomarkers. While many studies have identified putative protein based biomarkers for amyotrophic lateral sclerosis (ALS), all have used a limited number of total test subjects. Therefore large validation studies are required to confirm these potential biomarkers for ALS. Such validated biomarkers can then be advanced towards the clinic within diagnostic tests and assays to monitor drug efficacy in clinical trials. Since ALS is an orphan disease, multi-center clinical research studies are required to obtain the necessary number of patient and control samples in order to properly validate biomarkers for ALS. We are uniquely positioned to rapidly advance multi-center biomarker validation studies for ALS. We have established standard operating procedures for the collection of blood plasma and cerebrospinal fluid (CSF) samples. During the past year we have created a consortium of 20 medical centers and ALS clinics with IRB approval to utilize these standardized sample collection procedures. This consortium of clinics and clinical investigators includes many of the leaders within the ALS community. We hypothesize that select protein and antibody based biomarkers will be validated in a large, prospective study using CSF and blood samples from multiple clinics throughout the country. To test this hypothesis, we propose three specific aims that address a key challenge to initiate and rapidly advance a multi-center biomarker validation study for ALS. The first specific aim will collect biofluid samples using standard operating procedures at 20 ALS clinics throughout the country. The second aim is to perform a targeted ELISA and mass spectrometry based multiple reaction monitoring (MRM) assays to validate specific protein biomarkers for ALS. The final aim will use these same biofluid samples to validate the presence of specific antibodies to spinal cord proteins in ALS patients. This study will validate specific protein and antibody based biomarkers for ALS that will assist in the development of in vitro diagnostic assays for ALS. Given the experience of our collaborative team, we are confident in our ability to complete the proposed studies within the 2-year time frame of the Challenge Award. PUBLIC HEALTH RELEVANCE: The overall goal of the proposed study is to validate specific biomarkers for amyotrophic lateral sclerosis (ALS). ALS is a fatal motor neuron degenerative disease that can strike adults of any age, yet we know little about its causes and cannot rapidly diagnose ALS. Our validated protein and antibody based biomarkers for ALS will create quick diagnostic tests for ALS.