Multi-Center ALS Biomarker Validation Study (CReATe Biomarkers)

事实证明，为ALS患者开发有效的治疗方法非常具有挑战性。原因有很多，也很复杂，但其中最主要的原因是ALS患者群体的表型异质性，以及II期临床试验中临床结局指标对治疗效果的不敏感。结果是，在II期结束时，就哪些药物可以进入III期临床试验而言，很难做出明智的决定。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具有很大的希望。预后生物标志物通过增加可从现成的临床参数确定的价值来帮助预测疾病的进程，可以用作资格或分层标准，以确保更均匀的研究人群，其中治疗效果可能更容易证明。纵向轨迹（和可变性）明确的生物标志物有潜力作为治疗效果的药效学生物标志物。例如，表明实验性治疗导致生物标志物水平正常化，将为实验性化合物的治疗效果提供支持性证据，并有助于决定将特定治疗剂推进到临床开发的下一阶段。在过去的10多年里，人们进行了大量的发现工作，已经产生了大量的生物标志物候选物，但这些候选物都没有以多中心的方式得到验证。在这个项目中，我们的目标是通过对主要的基于生物液体的生物标志物候选物进行多中心验证研究来缩小这一知识差距-尿p75神经营养因子受体细胞外结构域（p75ECD），血液和脑脊液（CSF）磷酸化神经丝重（pNfH），血液和CSF神经丝轻（NfL），以及在具有C9orf72六核苷酸重复扩增的人群中，外周血单核细胞（PBMC）和脑脊液中二肽重复蛋白（GP）的水平。为了实现验证这些生物标志物的目标，我们将利用CReATe联盟正在进行的活动，通过该联盟将对约500名ALS患者进行纵向深度表型分型，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.