Development of a Blood-based Test for Identifying Synucleinopathy in Patients with Dementia

项目总结 在这一快速跟踪SBIR应用中，NeuroDex，Inc.计划利用其在细胞外小泡(EV)方面的专业知识 免疫亲和分离开发一种血液测试，以检测高灵敏度的联合核病症，与长期- 帮助临床医生识别抗精神病药物是有害的和禁忌的患者的长期目标。 开发和商业化对共核疾病敏感的血液检测将解决 选择适当的抗精神病药物治疗以避免严重不良反应的主要未得到满足的需求。 这项拟议的工作利用了一种专利程序NeuroDex，该程序是为将电动汽车从血浆中分离出来而开发的 细胞特异性表面标志物的免疫亲和力。使用这种方法，该公司展示了20倍的 提高NDES的信噪比，这是分析SYN所必需的特异度，因为&gt； 血浆中90%的aSYN不是起源于大脑，与疾病无关。以前的努力是衡量 未处理血浆中的aSYN未产生任何诊断价值，但在NDE分离后进行测定 提供强大的分类功能。利用这种方法，NeuroDex开发了测试aSYN的方法 在神经元、小胶质细胞和少突胶质细胞来源的EV表面。这些检测都是成功的 以较高的准确率区分35例健康对照、51例PD患者和30例MSA患者。NeuroDex Now 建议完成发现阶段(第一阶段)并进行分析和临床验证(第二阶段)。 第一阶段-目标1.确定纳入联核病检测小组的最终生物标记物。vbl.使用 195个来自健康个人和有一系列尸检确认的联体核病患者的样本，我们将 评估可能的生物标志物的不同组合的性能，以选择与最佳组合 性能。成功指标：≥80%的PPV用于确定合并核病患者，≥90%的NPV。目标 2.对选定的化验结果进行鉴定。成功指标：精度冠状病毒≤20%，8倍稀释范围内的线性度， 和LLQ与临床标本相容。进入第二阶段的通过/不通过标准：完成 发现阶段，在a)提供≥90%净现值的小组中包括一组定义的生物标志物，b)可以 以稳健的方式测量(精密度和再现性的变异性&20%)。第二阶段--目标1.分析 诊断化验的有效性。里程碑和成功指标：1)成功审核CLIA实验室SOP，2) FDA突破性指定提交的分析数据包。目标2.初步临床验证 在CLIA认证的实验室中进行诊断分析。我们将对来自患者的700个样本进行验证。 患有或不患有联核症的痴呆症患者和年龄匹配的对照组。里程碑和成功指标： 原发：NPV≥90%；次要：PPV≥80%。Impact-开发和严格验证一种新型血液 痴呆与突触核蛋白病理的鉴别诊断试验将产生一种商业上可行的 诊断以提供适当的治疗计划和临床试验分层，以改进药物开发。

PROJECT SUMMARY In this Fast Track SBIR application, NeuroDex, Inc. proposes to use its expertise in extracellular vesicle (EV) immunoaffinity isolation to develop a blood test that detects synucleinopathies with high sensitivity, with the long- term goal of helping clinicians identify patients for whom antipsychotic drugs are harmful and contraindicated. Development and commercialization of a sensitive blood test for synucleinopathies would address a major unmet need for selecting appropriate antipsychotic treatments that avoid severe adverse effect. The proposed work leverages a proprietary procedure NeuroDex developed for isolating EVs from plasma using immunoaffinity for cell-specific surface markers. Using this approach, the company demonstrated a > 20-fold increase in signal to noise ratio of NDEs, a degree of specificity that is essential for analyzing aSYN because > 90% of aSYN in plasma does not originate in the brain and is not disease related. Previous efforts to measure aSYN in unprocessed plasma have not yielded any diagnostic value, but measurement after NDE isolation provides powerful classification. Leveraging this approach, NeuroDex has developed assays to test aSYN within and on the surface of neuron-, microglia-, and oligodendrocyte-derived EVs. These assays successfully distinguished 35 healthy controls, 51 PD patients, and 30 MSA patients with high accuracy. NeuroDex now proposes to complete the discovery phase (Phase I) and conduct analytical and clinical validation (Phase II). PHASE I—Aim 1. Identify final biomarkers to be included in the synucleinopathy detection panel. Using 195 samples from healthy individuals and patients with an array of autopsy-confirmed synucleinopathies, we will assess the performance of different panels of the possible biomarkers to select the combination with the best performance. Success Metric: ≥ 80% PPV for identifying patients with synucleinopathies and ≥ 90% NPV. Aim 2. Qualify the selected assays. Success Metrics: precision CoV ≤ 20%, linearity across 8-fold dilution range, and LLQ compatible with clinical samples. Go/No Go Criterion for Progression to Phase II: Completion of the discovery phase to include a defined set of biomarkers in a panel that a) provides ≥ 90% NPV and b) can be measured in a robust manner (variability in precision and reproducibility <20%). PHASE II—Aim 1. Analytical validation of the diagnostic assay. Milestones & Success Metrics: 1) Successful audits for CLIA lab SOP, 2) analytical data package for FDA breakthrough designation submission. Aim 2. Preliminary clinical validation of the diagnostic assay in a CLIA-certified lab. We will validate the assays with 700 samples from patients with dementia with or without synucleinopathies and age-matched controls. Milestones & Success Metrics: primary: NPV ≥ 90%; secondary: PPV ≥ 80%. Impact—Development and rigorous validation of a novel blood test for differential diagnosis of dementia with synuclein pathology would produce a commercially-viable diagnostic to inform appropriate treatment plans and clinical trial stratification for improved drug development.