DDT-BMQ-000079 Establishing Performance Characteristics of the Epidermal Neurite Density (END) Biomarker to Assist Diagnosis of Small Fiber Neuropathy

DDT-BMQ-000079 建立表皮神经突密度 (END) 生物标志物的性能特征以辅助诊断小纤维神经病

• 批准号: 10619324
• 负责人: Anne Louise Oaklander
• 金额: $ 24.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10619324
• 关键词: DDT; BMQ; 000079; Establishing; Performance

In the polyneuropathies, adverse conditions damage the body’s peripheral neurons, causing them to fire dysfunctionally and sometimes begin to degenerate. Small-fiber neuropathy (SFN) is a very common type. Many neuropathies, including from diabetes or toxic exposures, often affect the ends of smaller fibers earliest or most severely. Sensory, chronic tingling, itch, and numbness, typically starting in the feet and lower legs then spreading upwards are external symptoms of SFN. However, as most of the autonomic axons that innervate and regulate the body systems are also small-diameter fibers, SFN also causes internal symptoms–intolerance of usual level of exertion, profound fatigue, lightheadedness, rapid heart rate, and gastrointestinal symptoms. SFN is not detected by the standard diagnostic biomarker for large-fiber neuropathies (electromyography and nerve conduction study). Instead, END (epidermal neurite density) measurements are made from tiny punch biopsies from the lower leg. Along with clinical indicators, this biomarker is validated to identify suspected cases. Skin biopsy testing is integral to the first formal case definition of SFN from uncertain cause, formulated by a global expert ACTTION Committee meeting supported by FDA, NIH, and industry. This group, that included the P.I., recommended END measurement as mandatory for clinical trial inclusion (Freeman, R. et al. Neurology, 2020). Hence this request for biomarker qualification for a diagnostic test increasingly used including for clinical and treatment research, despite sometimes varying methodological details and analyses between accredited university and commercial U.S. labs. Any inconsistencies increase risk that the same biopsy could generate different END numbers and/or divergent interpretations. Clinical research studies using END measurements for inclusion or outcomes might enroll slightly different participants or generate different efficacy data that could influence FDA approval. In 2022, Dr. Oaklander and others linked SFN to long-COVID illnesses, so long-COVID studies including NIH’s RECOVER are considering adding END measurement. The objective of the proposed studies is to identify and then validate best methods of obtaining and analyzing the END biomarker. The Aims respond to the applicants’ DDTBMQ000079 LOI approval to generate a full Biomarker Qualifier Plan. Aim I analyzes anonymized END measurements and other data from a large US diagnostic skin biopsy lab dataset of healthy controls and patients to identify knowledge gaps, then compare and validate potential solutions. Aim II adds prospective biopsies where needed. Aim III includes other stakeholders including outside accredited labs for cross-validation and neurological societies to generate Guidelines. Standard operating procedures would be improved throughout, and statistical modeling for END distribution, including selection of variables and algorithms, would be optimized and validated.

在多发性神经病中，不良情况会损害人体的周围神经元，导致它们发射 功能障碍，有时开始退化。小型纤维神经病（SFN）是一种非常普遍的类型。 许多神经病，包括来自糖尿病和有毒暴露的神经病，通常会影响较小纤维的末端或 最严重。感觉，慢性刺痛，瘙痒和麻木，通常从脚和小腿开始 向上扩散是SFN的外部症状。但是，作为支配和支配的大多数自主轴突 调节身体系统也是小直径纤维，SFN还会引起内部症状 - 通常的劳累水平，深刻的疲劳，头晕，快速心率和胃肠道症状。 大型神经病的标准诊断生物标志物（肌电图）未检测到SFN 和神经传导研究）。相反，结束（表皮神经元密度）测量是由微小的打孔器进行的 下腿的活检。除临床指标外，该生物标志物被验证以识别可疑 案例。皮肤活检测试是不确定原因的第一个正式案例定义的组成部分， 由FDA，NIH和行业支持的全球专家行为委员会会议。这个小组，那 包括P.I.，建议的末端测量是临床试验纳入的强制性测量（Freeman，R。等。 神经病学，2020年）。因此，该诊断测试的生物标志物资格越来越多地使用 包括临床和治疗研究，有时会改变方法论细节和分析 在认可的大学和美国商业实验室之间。任何不一致会增加同一活检的风险 可以产生不同的终端数字和/或不同的解释。临床研究使用END 纳入或结果的测量可能会略有不同或产生不同的参与者 可能影响FDA批准的效率数据。 2022年，奥克兰德博士和其他人将SFN与长期持续联系在一起 疾病，包括NIH康复在内的长期研究的研究正在考虑增加最终测量。 拟议研究的目的是识别并验证获得最佳方法和 分析最终生物标志物。目的对申请人的DDTBMQ000079 LOI批准做出回应以生成 完整的生物标志物预选赛计划。目的我分析了大型的匿名最终测量和其他数据 美国诊断性皮肤活检实验室的健康对照和患者的数据集，以识别知识差距，然后比较 并验证潜在的解决方案。 AIM II在需要时增加了潜在的活检。 AIM III包括其他 利益相关者在内，包括外部认可的实验室，用于交叉验证和神经社会产生 指南。标准操作程序将在整个过程中得到改进，并为结束进行统计建模 分布（包括变量和算法的选择）将得到优化和验证。