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周围神经元，导致它们放电 小纤维神经病（SFN）是一种非常常见的类型。 许多神经病，包括糖尿病或有毒物质暴露引起的神经病，通常最早或最早影响较小纤维的末端。 最严重的是感觉、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，然而，由于大多数自主神经轴突支配和 调节身体系统的也是小直径纤维，SFN也会引起内部症状——不耐受 正常的劳累程度、严重疲劳、头晕、心率加快和胃肠道症状。 大纤维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），END（表皮神经突密度）测量是通过微小的冲孔进行的。 与临床指标一起，验证该生物标记物以识别可疑的患者。 皮肤活检测试是第一个原因不明的 SFN 正式病例定义的组成部分。 由 FDA、NIH 和行业支持的全球专家行动委员会会议发起。 包括 P.I.，建议将 END 测量作为临床试验纳入的强制性要求（Freeman，R. 等，2017） 因此，越来越多地使用诊断测试的生物标志物资格要求。 包括临床和治疗研究，尽管有时方法细节和分析有所不同 经认可的大学和美国商业实验室之间的任何不一致都会增加相同活检的风险。 使用 END 可能会产生不同的 END 数字和/或不同的解释。 包容性或结果的测量可能会略有不同或产生不同的结果 2022 年，Oaklander 博士和其他人将 SFN 与长期新冠病毒联系起来。 因此，包括 NIH 的 RECOVER 在内的长期新冠肺炎研究正在考虑增加 END 测量。 拟议研究的目的是确定并验证获得和 分析 END 生物标记物，目的是响应申请人的 DDTBMQ000079 LOI 批准以生成。 完整的生物标志物预选计划的目标是结合匿名的 END 测量值和来自大型的其他数据。 美国诊断皮肤活检实验室的健康对照和患者数据集，以确定知识差距，然后进行比较 并验证潜在的解决方案。目标 III 在需要时添加了前瞻性活检。 利益相关者，包括外部认可的交叉验证实验室和神经病学学会，以生成 标准操作程序和 END 的统计模型将得到改进。 分布，包括变量和算法的选择，将得到优化和验证。