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，不利的条件会损害身体的外周神经元，导致它们放电 功能失调，有时开始退化。小纤维神经病（SFN）是一种非常常见的类型。 许多神经病变，包括糖尿病或中毒暴露，往往影响较小的纤维末端最早或 最严厉的。感觉，慢性刺痛，瘙痒和麻木，通常始于脚和小腿，然后 向上扩散是SFN的外部症状。然而，由于大多数自主神经轴突支配和 调节身体各系统的纤维直径也都很小，SFN也会引起内部的纤维不耐受 通常的劳累程度、深度疲劳、头晕、心率加快和胃肠道症状。 SFN不能被大纤维神经病的标准诊断生物标志物（肌电图）检测到 和神经传导研究）。相反，END（表皮神经突密度）测量是从微小的打孔器中进行的。 小腿的活组织检查沿着临床指标，该生物标志物经验证可识别疑似 例皮肤活检测试是不可或缺的SFN的第一个正式的情况下定义从不确定的原因，制定 由FDA、NIH和行业支持的全球专家ACTTION委员会会议。这个团体， 包括私家侦探推荐END测量作为临床试验纳入的强制性（Freeman，R.等人 神经病学，2020）。因此，越来越多地使用对诊断测试的生物标志物资格的要求 包括临床和治疗研究，尽管有时方法细节和分析不同 和美国商业实验室之间的联系任何不一致都会增加相同活检的风险 可能会产生不同的END数字和/或不同的解释。使用END的临床研究 纳入或结果的测量可能会招募稍微不同的参与者或产生不同的结果。 可能影响FDA批准的有效性数据。2022年，Oaklander博士和其他人将SFN与长期COVID联系起来 因此，包括NIH的RECOVER在内的COVID研究正在考虑增加END测量。 拟议研究的目的是确定并验证获取和使用最佳方法， 分析END生物标志物。目标响应申请人的DDTBMQ 000079 LOI批准，以生成 一个完整的生物标记物净化器计划目的我分析匿名的结束测量和其他数据，从一个大的 美国诊断皮肤活检实验室健康对照组和患者数据集，以确定知识差距，然后比较 并验证潜在的解决方案。Aim II在需要时增加了前瞻性活检。目标三包括其他 利益相关者，包括外部认可的交叉验证实验室和神经学会， 指南标准作业程序将得到全面改进， 将优化和验证数据分配，包括变量和算法的选择。