Multi-Center ALS Biomarker Validation Study (CReATe Biomarkers)

多中心 ALS 生物标志物验证研究 (CReATe Biomarkers)

• 批准号: 10612967
• 负责人: Michael Benatar
• 金额: $ 63.09万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10612967
• 关键词: ALS patients; Amyotrophic Lateral Sclerosis; Animal Model; Axon; Biological; Biological Assay; Biological Markers; Blood; C9ORF72; Categories; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Data; Clinical Trials; Complex; Coupled; Data; Decision Making; Development; Dipeptides; Disease; Disease Progression; Dose; Electrophysiology (science); Eligibility Determination; Enrollment; Ensure; Extracellular Domain; FDA approved; Foundations; Future; Goals; Heterogeneity; Individual; Infrastructure; Investigational Therapies; Knowledge; Laboratories; Lead; Light; Liquid substance; Literature; Mutation; NGFR Protein; Nerve Growth Factor Receptors; Neurodegenerative Disorders; Noise; Outcome Measure; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Phenotype; Phosphorylation; Population; Process; Prognosis; Prognostic Marker; Proteins; Publishing; Resources; Riluzole; Sampling; Signal Transduction; Source; Standardization; Stratification; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Time; Validation; biobank; biomarker validation; candidate marker; clinical development; clinical outcome measures; cohort; comparison control; disease heterogeneity; disease natural history; drug development; effective therapy; empowerment; follow-up; genome sequencing; inclusion criteria; individual patient; neurofilament; neuroimaging; patient population; patient stratification; pharmacodynamic biomarker; phase II trial; phase III trial; phenylmethylpyrazolone; post-market; pre-clinical; prognostic value; repository; response; study population; success; therapeutically effective; tool; tool development; treatment effect; urinary; validation studies; whole genome

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.

事实证明，针对ALS患者开发有效的疗法是巨大的挑战。原因很复杂，但在其中主导的是ALS患者人群的表型异质性以及在II期临床试验期间对治疗效应的临床结果指标的不敏感性。结果是，在II阶段结束时，很难就这些药物前进进入III期临床试验，这是非常困难的。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拥有巨大的希望。通过增加可用的临床参数确定的价值来帮助预测疾病的预后生物标志物，可以用作资格或分层标准，以确保更多均质的研究人群，其中可以更容易地证明治疗效果。纵向轨迹（和变异性）的生物标志物具有很好的定义，具有作为治疗效果的药物模仿生物标志物的潜力。例如，表明实验理论会导致生物标志物水平的正常化，这将为实验化合物的治疗作用提供支持证据，并有助于赋予决策，以将特定的治疗剂推向临床发展的下一个阶段。在过去的十多年中，强烈的发现工作产生了许多生物标志物候选人，但这些都没有以多中心的方式得到验证。 In this project we aim do close this knowledge gap by undertaking a multi-center validation study of the lead biologic-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,在具有C9ORF72六核苷酸重复膨胀的人群中，二肽重复蛋白聚（GP）的CSF水平（GP）。为了实现验证这些生物标志物的拟议目的，我们将利用创建财团正在进行的活动，通过该活动，将对约500名ALS患者进行纵向纵向表型，进行整个基因组测序，并从中收集和存储一组相关的生物学流体。

项目成果

Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations.

• DOI: 10.1093/braincomms/fcad287
• 发表时间: 2023
• 期刊: Brain communications
• 影响因子: 4.8

Biomarker Qualification for Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: Theory and Practice.

肌萎缩侧索硬化症神经丝轻链的生物标志物鉴定：理论与实践。

• DOI: 10.1002/ana.26860
• 发表时间: 2024
• 期刊: Annals of neurology
• 影响因子: 11.2
• 作者: Benatar,Michael;Ostrow,LyleW;Lewcock,JosephW;Bennett,Frank;Shefner,Jeremy;Bowser,Robert;Larkin,Paul;Bruijn,Lucie;Wuu,Joanne
• 通讯作者: Wuu,Joanne