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

开发一种基于血液的测试来识别痴呆症患者的突触核蛋白病

• 批准号: 10602294
• 负责人: Erez Eitan
• 金额: $ 45万
• 依托单位: NEURODEX INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602294
• 关键词: Address; Adverse effects; Age; Alzheimer' s Disease; American; Amyloid beta-Protein; Antipsychotic Agents; Autopsy; Biological Assay; Biological Markers; Blood; Blood Tests; Blood Vessels; Blood specimen; Brain; Brain region; CLIA certified; Cells; Cessation of life; Classification; Clinical; Clinical Trials; Data Analytics; Dementia; Dementia with Lewy Bodies; Detection; Development; Diagnosis; Diagnostic; Differential Diagnosis; Disease; Drowsiness; Goals; Impaired cognition; Lewy Bodies; Lewy body pathology; Life; Measurement; Measures; Medical; Methods; Microglia; Multiple System Atrophy; Nerve Degeneration; Neurodegenerative Disorders; Neuroleptic Malignant Syndrome; Neurons; Noise; Oligodendroglia; Parkinson Disease; Parkinsonian Disorders; Pathology; Patient Care; Patients; Performance; Pharmaceutical Preparations; Phase; Physicians; Plasma; Procedures; Prognosis; Reproducibility; Sampling; Signal Transduction; Small Business Innovation Research Grant; Specificity; Stratification; Surface; Symptoms; Testing; Validation; Vascular Dementia; Work; alpha synuclein; base; biomarker discovery; brain cell; cell type; commercialization; common symptom; design; diagnostic assay; diagnostic value; drug development; extracellular vesicles; high risk; improved; individual patient; novel; patient stratification; prevent; protein TDP-43; success; synuclein; synucleinopathy; tau Proteins; treatment planning

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.

项目摘要 在这个快速轨道SBIR应用程序中 免疫亲和力隔离以开发血液检查，该血液检测具有高灵敏度的突触核苷病，长期 帮助临床医生确定抗精神病药有害且禁忌症的患者。 敏感血液检查的敏感血液测试的开发和商业化将解决 选择适当的抗精神病药物治疗，以避免严重不良反应。 提出的工作利用了一种专有程序神经deake开发的，用于使用血浆隔离EV 针对细胞特异性表面标记的免疫亲和力。使用这种方法，该公司证明了一个> 20倍 NDE的信号与噪声比的增加，这是分析ASYN至关重要的程度特异性，因为> 血浆中90％的ASYN不起源于大脑，与疾病无关。以前的衡量努力 未加工的血浆中的Asyn尚未产生任何诊断值，而是在NDE隔离后测量 提供强大的分类。利用这种方法，NeuroDex开发了测定以测试ASYN 以及神经元，小胶质细胞和少突胶质细胞衍生的EV的表面。这些测定成功 具有高精度的35例健康对照，51例PD患者和30名MSA患者。 NeuroDex现在 完成发现阶段（I阶段）并进行分析和临床验证的建议（II期）。 第一阶段 - aim 1。确定最终生物标志物包含在突触核管检测板中。使用 195个来自健康个体和患者的样本，有一系列尸检确认的突触性核酸疾病，我们将 评估可能的生物标志物不同面板的性能，以选择最佳的组合 表现。成功度量：鉴定突触核苷患者和≥90％NPV的患者≥80％PPV。目的 2。符合选定的测定。成功指标：精度COV≤20％，在8倍稀释范围内线性性， 和LLQ与临床样品兼容。 Go/no GO标准进入第二阶段：完成 在一个面板中包括一组定义的生物标志物的发现阶段a）提供≥90％的NPV，b）可以是 以健壮的方式测量（精确性的可变性，可重复性<20％）。第二阶段-AIM 1。分析 验证诊断测定法。里程碑与成功指标：1）Clia Lab SOP的成功审核，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认证实验室中的诊断测定法。我们将用患者的700个样品验证测定法 痴呆症患有或没有突触核心病的痴呆症和年龄匹配的对照。里程碑与成功指标： 主要：NPV≥90％；次要：PPV≥80％。影响 - 新血液的开发和严格验证 测试伴突触蛋白病理学痴呆症的鉴别诊断将产生商业上的可行性 诊断以告知适当的治疗计划和临床试验分层，以改善药物开发。