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

在多发性神经病中，不利的条件会损害身体的外周神经元，导致它们开火 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。 许多神经疾病，包括糖尿病或中毒，通常最早或最早影响较小纤维的末端或 最严重的。感觉、慢性刺痛、瘙痒和麻木，通常从脚和小腿开始，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 调节身体系统的纤维也是小直径的，三叉神经痛也会引起内部症状--不耐受 通常劳累程度、极度疲劳、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记物(肌电图法)未检测到SFN 和神经传导研究)。取而代之的是，END(表皮轴突密度)测量是从微小的冲头进行的 小腿的活组织检查。与临床指标一起，这个生物标记物被验证为识别可疑的 案子。皮肤活检测试是第一个由不明原因引起的SFN正式病例定义不可或缺的部分， 由FDA、NIH和业界支持的全球专家行动委员会会议。这个团体，那个团体 将P.I.、推荐的末端测量作为纳入临床试验的强制性指标(Freeman，R.等人)。 神经学，2020)。因此，越来越多地使用对诊断测试的生物标记物资格的请求 包括临床和治疗研究，尽管有时方法细节和分析有所不同 在经过认证的大学和商业美国实验室之间。任何不一致都会增加相同活检的风险 可能会产生不同的结尾数字和/或不同的解释。使用END的临床研究 对纳入或结果的衡量可能会招收略有不同的参与者或产生不同的结果 可能影响FDA批准的疗效数据。2022年，Oaklander博士和其他人将SFN与Long-CoVID联系起来 疾病，所以长久以来-COVID的研究包括NIH的RECOVER正在考虑增加末端测量。 拟议研究的目标是确定并验证获得和 分析末端生物标记物。AIMS响应申请者的DDTBMQ000079意向书批准生成 一份完整的生物标志限定者计划。AIM I分析了匿名终端测量和来自大型 美国诊断皮肤活检实验室数据集的健康对照和患者，以确定知识差距，然后比较 并验证潜在的解决方案。AIM II在需要的地方增加了预期的活组织检查。AIM III包括其他 利益相关者，包括外部认可的实验室，用于交叉验证和神经学协会 指导方针。标准操作程序将在整个过程中得到改进，并建立统计模型 分布，包括变量和算法的选择，将得到优化和验证。

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.