Validation of Serum Neurofilament Light Chain as a Prognostic and Monitoring Biomarker in Multiple Sclerosis

血清神经丝轻链作为多发性硬化症预后和监测生物标志物的验证

• 批准号: 10543186
• 负责人: PETER A CALABRESI
• 金额: $ 126.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543186
• 关键词: Age; Atrophic; Biological Assay; Biological Markers; Blood; Blood Tests; Brain; Central Nervous System Diseases; Cerebrospinal Fluid; Characteristics; Clinical; Cytoskeletal Proteins; Data; Decision Making; Demyelinating Diseases; Diabetes Mellitus; Disease; Electronics; Enhancing Lesion; Enrollment; Europe; Health; Healthcare; Hyperlipidemia; Hypertension; Image; Immune; Immunoassay; Immunotherapy; Inflammatory; Injury; Institution; Intervention; Lesion; Light; Magnetic Resonance Imaging; Measures; Mediating; Medical; Monitor; Multicenter Studies; Multiple Sclerosis; Nerve; Neurologic; Neurons; Obesity; Outcome; Pathologic; Patient Care; Patients; Pharmaceutical Preparations; Proteins; Qualifying; Race; Radiology Specialty; Randomized, Controlled Trials; Research; Sampling; Serum; Severity of illness; Site; Smoking; Standardization; Technology; Treatment Efficacy; United States; Validation; Visit; aggressive therapy; biobank; blood-based biomarker; brain tissue; brain volume; cerebral atrophy; clinical practice; cohort; comorbidity; demographics; design; disability; disability risk; disorder subtype; follow-up; gray matter; illness length; interest; kidney dysfunction; multiple sclerosis patient; multiple sclerosis treatment; nervous system disorder; neurofilament; novel; prognostic; prospective; recruit; research clinical testing; sex; tool; treatment response

Multiple sclerosis (MS) is an immune-mediated, inflammatory disorder of the central nervous system. Despite being classically considered a demyelinating disorder, it has been demonstrated that neuro-axonal injury occurs early in the disease course and represents the pathologic substrate for permanent neurological disability in people with MS (PwMS). In clinical practice, disease monitoring in PwMS is performed by clinical evaluation and use of conventional magnetic resonance imaging (MRI) measures, including new T2 lesions and/or presence of T1 post-gadolinium (Gd) enhancing lesions. Notably, these conventional MRI measures assess for the presence of inflammatory disease activity rather than neuro-axonal loss and are only modestly associated with clinical measures of disability in MS, a phenomenon known as the “clinico-radiological paradox”. There is an unmet need in MS for a biomarker that may identify PwMS with ongoing neuro-axonal damage prior to the accrual of permanent clinical disability, in order to allow for timely intervention. Neurofilaments are neuron-specific cytoskeletal proteins that are released following neuro-axonal damage. Increased neurofilament light chain (NfL) levels have been found in the blood and cerebrospinal fluid (CSF) in several neurological disorders, including MS. In MS, there is evidence that serum NfL (sNfL) levels correlate closely with CSF NfL levels, are associated with clinico-radiological measures of disease activity, are modulated by disease modifying therapies (DMTs), and predict disability worsening and brain atrophy. However these data are derived mainly from small, single-center studies, and the influence of factors including demographics, disease subtype, and co-morbid conditions on sNfL levels in MS remains poorly characterized. It is also remains unclear if sNfL levels may be used to monitor response to therapy, guide decision-making regarding potency of immunotherapy, and predict long-term outcomes. While, given this emerging evidence, there is great interest in sNfL for use as a prognostic and monitoring biomarker of neuro-axonal injury in MS, further clinical validation is necessary in larger, demographically diverse, clinically heterogeneous, multi-center cohorts. Furthermore, it is of utmost importance that validation is performed utilizing a robust, scalable assay that may be rapidly implemented in the clinical realm. We plan to measure sNfL utilizing a novel automated immunoassay (Siemens Healthineers; performed on an existing clinically available platform) in serum samples from two large multi-center studies: 1) MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a network of 10 healthcare institutions in the United States and Europe, merging research with ongoing patient care by collecting standardized clinical/imaging data and biospecimens during routine medical visits. As of February 1st, 2019, >15,000 patients have opted to participate in MS PATHS with biospecimens already available for >5,000 patients. 2) TREAT-MS (Traditional versus Early Aggressive Therapy for Multiple Sclerosis) is an ongoing, pragmatic, randomized controlled trial, designed to evaluate in treatment naïve MS patients whether an “early aggressive” therapy approach, versus starting with a traditional, first-line therapy approach, influences the longer-term risk of disability (at 48 months). TREAT-MS is prospectively recruiting 900 subjects across ~45 sites in the US (83 enrolled as of February 1st, 2019) with anticipated enrollment of 700 subjects in the bio-banking sub-study. We anticipate that large-scale clinical validation of sNfL in MS as a prognostic and monitoring tool in this study will lead to submission to the FDA of a full qualification package and will lead to availability of the first blood-based biomarker of MS.

多发性硬化症（MS）是一种免疫介导的中枢神经系统炎症性疾病。尽管 被经典地认为是脱髓鞘障碍，已经证明会发生神经轴损伤 在疾病的早期 患有MS（PWM）的人。在临床实践中，PWMS中的疾病监测是通过临床评估和 使用常规磁共振成像（MRI）措施，包括新的T2病变和/或存在 T1后加多丹（GD）增强病变。值得注意的是，这些常规的MRI措施评估 炎症性疾病活动而不是神经轴丧失，仅与临床相关 MS中的残疾度量，一种被称为“临床 - 放射学悖论”的现象。有一个未满足的 在MS中，需要在生物标志物中识别可能在持续的神经轴损伤的PWM的生物标志物 永久性临床残疾的应计，以便及时干预。 神经丝是神经特异性细胞骨架蛋白，在神经轴后释放 损害。在血液和脑脊液中发现了神经丝轻链（NFL）水平的增加 （CSF）在包括MS在内的几种神经系统疾病中。在MS中，有证据表明血清NFL（SNFL）水平 与CSF NFL水平紧密相关，与疾病活动的临床放射学测量相关，是 通过修饰疗法（DMT）的疾病调节，并预测残疾的担心和脑萎缩。然而 这些数据主要来自小型单中心研究，以及包括 MS中SNFL水平的人口统计学，疾病亚型和合并症的特征仍然很差。 还不清楚SNFL水平是否可以用于监测对治疗的反应，指导决策 考虑免疫疗法的效力，并预测长期结局。鉴于这个新兴的证据， SNFL非常兴趣用作神经轴损伤的预后和监测生物标志物 在MS中，需要进一步的临床验证，在较大的人口统计学上，临床上有多样化 异质，多中心队列。此外，验证是至关重要的 使用可在临床领域快速实施的可伸缩测定法进行。 我们计划使用一种新型的自动免疫测定法（西门子卫生员；进行的）测量SNFL 在两个大型多中心研究的血清样品中现有的临床可用平台上）：1）MS路径 （多发性硬化合作伙伴推进技术和健康解决方案）是一个由10个医疗保健组成的网络 美国和欧洲的机构，通过收集持续的患者护理将研究合并 常规医疗就诊期间的标准化临床/成像数据和生物测量。截至2019年2月1日， > 15,000名患者选择参加已有> 5,000的Biospimens的MS路径 患者。 2）治疗 - MS（传统与早期侵略性治疗多发性硬化症）是一种持续的 务实的，随机对照试验，旨在评估治疗的幼稚MS患者 积极的”治疗方法，从传统的一线治疗方法开始，都会影响 长期残疾风险（在48个月时）。 Treat-Ms可能会在〜45个地点招募900名受试者 在美国（截至2019年2月1日，有83次注册），预计将在Bio-Banking中注册700名受试者 子研究。 我们预计MS中SNFL的大规模临床验证是一种预后和监测 本研究中的工具将导致提交完整资格包的FDA，并将导致 MS的第一个基于血液的生物标志物的可用性。