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侧索硬化症（ALS）的假定蛋白质为基础的生物标志物，所有使用的总测试对象的数量有限。因此，需要进行大型验证研究来确认ALS的这些潜在生物标志物。然后，这种经验证的生物标志物可以在诊断测试和测定中向临床推进，以监测临床试验中的药物功效。由于ALS是一种孤儿病，因此需要多中心临床研究来获得必要数量的患者和对照样本，以便正确验证ALS的生物标志物。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。我们已经建立了血浆和脑脊液（CSF）样本采集的标准操作规程。在过去的一年中，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，以使用这些标准化的样本采集程序。这个由诊所和临床研究人员组成的联盟包括ALS社区的许多领导者。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的，前瞻性研究中使用来自全国多个诊所的CSF和血液样本进行验证。为了验证这一假设，我们提出了三个具体的目标，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ALS诊所使用标准操作程序收集生物流体样本。第二个目的是进行靶向ELISA和基于质谱的多反应监测（MRM）测定，以验证ALS的特异性蛋白质生物标志物。最终的目标将使用这些相同的生物流体样本来验证ALS患者中脊髓蛋白的特异性抗体的存在。这项研究将验证特定的蛋白质和抗体为基础的生物标志物为ALS，这将有助于在体外诊断检测ALS的发展。鉴于我们的合作团队的经验，我们有信心在挑战奖的2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）的特定生物标志物。ALS是一种致命的运动神经元退行性疾病，可以袭击任何年龄的成年人，但我们对其原因知之甚少，无法快速诊断ALS。我们经过验证的基于蛋白质和抗体的ALS生物标志物将为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.