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，为 ALS 患者开发有效的疗法极具挑战性。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以及 II 期临床试验中临床结果测量对治疗效果的不敏感性。结果是，在 II 期结束时很难就哪些药物进入 III 期临床试验做出明智的通过/不通过决定。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巨大的前景。预后生物标志物通过增加从现成的临床参数中可以确定的值来帮助预测病程，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得到证明。纵向轨迹（和变异性）明确的生物标志物有潜力作为治疗效果的药效生物标志物。例如，表明实验治疗导致生物标志物水平正常化，将为实验化合物的治疗效果提供支持证据，并有助于做出决策，将特定治疗剂推进到临床开发的下一阶段。在过去十多年的时间里，大量的发现工作已经产生了大量的候选生物标志物，但这些都尚未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神经营养蛋白受体胞外结构域（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）以及人群 具有 C9orf72 六核苷酸重复扩增、外周血单核细胞 (PBMC) 和脑脊液中二肽重复蛋白聚 (GP) 的水平。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，通过该联盟，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，并收集和存储一组相关的生物体液。

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