Multi-Center ALS Biomarker Validation Study (CReATe Biomarkers)

为肌萎缩侧索硬化症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，以及在II期临床试验期间临床结果指标对治疗效果不敏感。其结果是，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知情的通过/不通过决定。人们普遍认为，特定类型的生物标记物在帮助克服这些障碍方面大有可为。预后生物标记物可以通过增加从现成的临床参数中可以确定的值来帮助预测疾病的进程，可以用作资格或分层标准，以确保在更同质的研究人群中可能更容易证明治疗效果。其纵向轨迹(和变异性)定义良好的生物标记物有可能作为治疗效果的药效学生物标记物。例如，表明实验性治疗导致生物标记物水平正常化，将为实验化合物的治疗效果提供支持性证据，并有助于制定决策，将特定治疗剂推进到临床开发的下一阶段。在过去的10年里，紧张的发现努力已经产生了过多的生物标志物候选，但这些都还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铅生物-流体生物标志物候选进行多中心验证研究-尿液p75神经营养素受体胞外区(P75ECD)、血液和脑脊液(CSF)磷酸化神经丝重(PNfH)、血液和脑脊液神经丝轻(NFL)，以及在C9orf72六核苷酸重复扩增的人群中，外周血单个核细胞(PBMC)和脑脊液二肽重复蛋白聚(GP)水平。为了实现提出的验证这些生物标志物的目标，我们将利用Create Consortium正在进行的活动，通过该联盟，将对大约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存储一套相关的生物液。

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.