Cutaneous Phosphorylated Alpha-Synuclein for Detection of Prodromal Synucleinopathies

用于检测前驱期突触核蛋白病的皮肤磷酸化 α-突触核蛋白

• 批准号: 10481117
• 负责人: Todd Levine
• 金额: $ 109.26万
• 依托单位: CND LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481117
• 关键词: Academia; Address; Affect; American; Biological Sciences; Biopsy; Blinded; CLIA certified; Clinical; Clinical Trials; Cognitive; Collaborations; Cutaneous; Data; Dementia with Lewy Bodies; Deposition; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Dreams; Enrollment; Feasibility Studies; Funding; Future; Health Care Costs; Industry; Laboratories; Location; Measurement; Measures; Methodology; Methods; Modeling; Morbidity - disease rate; Motor; Movement; Multiple System Atrophy; Nerve Degeneration; Nerve Fibers; Neurodegenerative Disorders; Neurologist; Neurology; Ocular Motility Disorders; Parkinson Disease; Pathologic; Pathologist; Pathology; Patient Care; Patients; Pattern Recognition; Peripheral Nervous System; Persons; Pilot Projects; Probability; Proteins; Public Health; Punch Biopsy; Pure Autonomic Failures; REM Sleep Behavior Disorder; Reading; Reproducibility; Risk; Sensitivity and Specificity; Severity of illness; Stains; Structure; Surrogate Endpoint; Symptoms; Technology; Testing; Time; United States National Institutes of Health; Visual; accurate diagnostics; alpha synuclein; base; circulating biomarkers; companion diagnostics; deep learning algorithm; detection platform; diagnostic tool; diagnostic value; digital; disorder control; effective therapy; follow-up; imaging approach; improved; innovation; laboratory experience; minimally invasive; misfolded protein; mortality; patient population; phase 2 study; public-private partnership; rapid eye movement; relating to nervous system; success; synuclein; synucleinopathy; therapy development; vocalization; whole slide imaging

PROJECT SUMMARY A group of devastating diseases, collectively termed synucleinopathies, affect over 2 million people in the U.S., carry significant morbidity, high mortality and enormous associated health care costs. Synucleinopathies are characterized by the abnormal deposition of a misfolded protein, phosphorylated α−synuclein (P-SYN), within the central and peripheral nervous systems. Synucleinopathies include Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF) differ in clinical symptoms and disease progression rates. Currently, no disease modifying therapies exist for any of the synucleinopathies. Deposition of P-SYN within the cutaneous (skin) nerve fibers of synucleinopathy patients provides diagnostic clarity and increases with disease progression. Importantly, cutaneous deposition of P-SYN is also observed in the majority of patients diagnosed with idiopathic rapid eye movement sleep behavior disorder (iRBD), a prodro- mal synucleinopathy in which >90% of patients phenoconvert to clinically apparent synucleinopathy within 15 years of diagnosis. At present, methods for determining the disease trajectory of clinically apparent synucle- inopathy in patients with iRBD do not exist. Diagnostic tools able to evaluate and reliably predict the probability of phenoconversion at prodromal stages is an urgent and unmet need with clinical importance and public health implications at a global scale. Cutaneous Neurodiagnostics (CND Life Sciences), a CLIA-certified laboratory, has developed its core enabling technology of detecting P-SYN in small (3 mm) patients’ punch skin biopsies and launched the first commercially available diagnostic test for synucleinopathy, the Syn-One Test™. In this Direct to Phase II study, CND Life Sciences will advance the Syn-One Test™ through detection of P-SYN in iRBD patients to predict phenoconversion risk and accelerate the commercial viability of testing through an innovative AI-powered augmented pathological interpretation of the results. To achieve this objective, CND Life Sciences has conducted feasibility studies to demonstrate that cutaneous P-SYN deposition can be reliably detected in 94-100% of synucleinopathy patients and in none of the disease control subjects, while preliminary pilot studies showed that P-SYN is observed in 64% of iRBD patients. In this proposal, CND Life Sciences will collaborate with the North American Prodromal Synucleinopathy (NAPS) consortium (an NIH- funded project) to 1) define the metrics of P-SYN deposition and nerve fiber degeneration that predict pheno- conversion in iRBD patients (Aim 1) and 2) enhance pathological reading through digital quantitative analysis of the Syn-One Test™ using an AI-augmented detection system (Aim 2). Successful completion of this study will advance the clinical utility of the Syn-One Test™, improving patient care, increasing the commercial potential of the product, and ultimately accelerating the development of disease-modifying therapies.

项目摘要 一群毁灭性的疾病，共同称为突触核心病，影响美国超过200万人 具有明显的发病率，高死亡率和巨大相关的医疗保健费用。剧核病是 以异常折叠蛋白的磷酸化α-突触核蛋白（p-syn）的异常沉积为特征 中央和周围神经系统。剧核病包括帕金森氏病（PD），痴呆症 路易尸体（DLB），多系统萎缩（MSA）和纯自主教失败（PAF）在临床症状上有所不同 和疾病进展率。目前，对于任何突触核心病，都没有改变疾病的疗法。 突触核酸患者皮肤（皮肤）神经纤维中P-syn的沉积提供诊断 疾病进展的清晰度和增加。重要的是，在 大多数被诊断为特发性快速眼动睡眠行为障碍（IRBD）的患者，一种 麦芽核炎麦芽核炎，其中90％的患者在15之内的患者表现为临床明显的突触核力疗法 多年诊断。目前，用于确定临床明显突触的疾病轨迹的方法 不存在IRBD患者的无症病患者。诊断工具可以评估并可靠地预测概率 前驱阶段的态转换是一个紧迫而未满足的需求，具有临床重要性和公共卫生 全球范围的含义。皮肤神经诊断（CND Life Sciences），CLIA认证的实验室， 已经开发了其核心启用技术，可以在小（3毫米）患者的Punch皮肤活检中检测P-SYN 并启动了Syn-One Test™Synucleinopathy的首个市售诊断测试。在这个 直接进行II期研究，CND Life Sciences将通过检测P-SYN推进Syn-One Test™ 在IRBD患者中，预测表现风险并加速测试的商业生存能力 通过创新的AI驱动性增强对结果的病理解释。实现这一目标 目的，CND生命科学已经进行了可行性研究，以证明皮肤P-Syn沉积 在94-100％的突触核力病患者中可以可靠地检测到 尽管初步的初步研究表明，在64％的IRBD患者中观察到P-Syn。在此提案中，CND 生命科学将与北美前驱突触核心病（NAPS）联盟合作（NIH- 资助项目）至1）定义P-Syn沉积和神经纤维变性的指标，以预测现象 IRBD患者的转化（目标1）和2）通过数字定量分析来增强病理阅读 使用AI增强检测系统的Syn-One Test™（AIM 2）。这项研究成功完成将 推进Syn-One Test™的临床实用性，改善患者护理，增加商业潜力 该产品，并最终加速了疾病改良疗法的发展。