Multi-Center ALS Biomarker Validation Study (CReATe Biomarkers)

为ALS患者开发有效的治疗方法已被证明是非常具有挑战性的。原因很多且复杂，但其中最主要的是ALS患者群体的表型异质性和II期临床试验期间临床结果测量对治疗效果的不敏感性。结果是，在第二阶段结束时，很难就哪些药物进入第三阶段临床试验做出明智的决定。人们普遍认为，特定类型的生物标志物在帮助克服这些障碍方面有很大的希望。预后生物标志物有助于通过增加可从现有临床参数确定的值来预测病程，可用作合格性或分层标准，以确保更同质的研究人群，在这些人群中治疗效果可能更容易得到证实。纵向轨迹（和变异性）明确的生物标志物有可能作为治疗效果的药效学生物标志物。例如，表明实验治疗导致生物标志物水平的正常化，将为实验化合物的治疗效果提供支持性证据，并有助于做出决策，以将特定治疗剂推进到下一阶段的临床开发。在过去的10多年里，密集的发现工作已经产生了大量的生物标志物候选者，但这些候选者都没有以多中心的方式得到验证。在该项目中，我们的目标是通过对主要的基于生物流体的生物标志物候选物-尿p75神经营养因子受体胞外结构域（p75 ECD）、血液和脑脊液（CSF）磷酸化神经丝重链（pNfH）、血液和CSF神经丝轻链（NfL）进行多中心验证研究来缩小这一知识差距，并且在具有C9 orf 72六核苷酸重复扩增的人群中，外周血单个核细胞（PBMC）和CSF中二肽重复蛋白聚（GP）水平。为了实现验证这些生物标志物的拟议目标，我们将利用CReATe联盟正在进行的活动，通过这些活动，将对约500名ALS患者进行纵向深度表型分析，进行全基因组测序，并从他们那里收集和储存一组相关的生物液体。

Developing effective therapies for ALS patients has proven to be extraordinarily challenging. The reasons are many and complex, but dominant amongst these are the phenotypic heterogeneity of the ALS patient population and the insensitivity of clinical outcome measures to therapeutic effect during phase II clinical trials. The result is that it is very difficult to make well informed go/no-go decisions at the end of phase II with respect to which drugs to move forward into phase III clinical trials. Specific types of biomarkers are widely believed to hold great promise in helping to overcome these barriers. Prognostic biomarkers that help to predict the course of disease by adding value to what can be determined from readily available clinical parameters, might be used as eligibility or stratification criteria to ensure more homogeneous study populations within which treatment effect may be more readily demonstrable. Biomarkers whose longitudinal trajectory (and variability) is well defined have the potential to serve as pharmacodynamic biomarkers of treatment effect. Showing for example, that an experimental therapeutic leads to normalization of a biomarker level, would provide supportive evidence for the therapeutic effect of an experimental compound and help to empower decisions to advance the particular therapeutic agent into the next phase of clinical development. Intense discovery efforts over the course of the last 10+ years have yielded a plethora of biomarker candidates, but none of these have yet been validated in a multi-center fashion. In this project we aim do close this knowledge gap by undertaking a multi- center validation study of the lead biological-fluid-based biomarker candidates – urinary p75 neurotrophin receptor extracellular domain (p75ECD), blood and cerebrospinal fluid (CSF) phosphorylated neurofilament heavy (pNfH), blood and CSF neurofilament light (NfL) and, in the population with a C9orf72 hexanucleotide repeat expansion, peripheral blood mononuclear cell (PBMC) and CSF levels of the dipeptide repeat protein poly(GP). To accomplish the proposed aims of validating these biomarkers, we will leverage the ongoing activities of the CReATe Consortium through which ~500 ALS patients will be deeply phenotyped longitudinally, undergo whole genome sequencing, and from whom a relevant set of biological fluids are being collected and stored.