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)生物标记物的发现和验证，以及特定的挑战主题03-NS-102：神经生物标记物的标准化和验证。虽然许多研究已经确定了肌萎缩侧索硬化症(ALS)可能的基于蛋白质的生物标记物，但所有研究都使用了有限数量的总测试对象。因此，需要大量的验证研究来确认ALS的这些潜在生物标记物。然后，这些经过验证的生物标记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是一种孤儿疾病，需要多中心的临床研究来获得必要数量的患者和对照样本，以便正确地验证ALS的生物标记物。我们在快速推进ALS的多中心生物标记物验证研究方面具有得天独厚的优势。我们已经制定了采集血浆和脑脊液样本的标准操作程序。在过去的一年里，我们已经创建了一个由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ALS社区内的许多领导人。我们假设，选择基于蛋白质和抗体的生物标记物将在一项使用来自全国多个诊所的脑脊液和血液样本的大型前瞻性研究中得到验证。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多中心生物标记物验证研究的关键挑战。第一个具体目标是在全国20家肌萎缩侧索硬化症诊所使用标准操作程序收集生物液样本。第二个目标是进行有针对性的ELISA法和基于质谱仪的多反应监测(MRM)分析，以验证ALS的特定蛋白质生物标记物。最终目标将使用这些相同的生物液样本来验证ALS患者中是否存在针对脊髓蛋白的特异性抗体。这项研究将验证ALS的特异性蛋白质和抗体生物标志物，这将有助于ALS体外诊断方法的发展。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。 公共卫生相关性：拟议研究的总体目标是验证肌萎缩侧索硬化症(ALS)的特定生物标记物。肌萎缩侧索硬化症是一种致命的运动神经元退行性疾病，任何年龄的成年人都可以发病，但我们对其病因知之甚少，无法快速诊断出肌萎缩侧索硬化。我们经过验证的基于蛋白质和抗体的ALS生物标记物将为ALS创建快速诊断测试。

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.