Cutaneous Phosphorylated Alpha-Synuclein for Detection of Prodromal Synucleinopathies

项目摘要 一组毁灭性的疾病，统称为突触核蛋白病，影响超过200万人在美国， 具有显著的发病率、高死亡率和巨大的相关卫生保健费用。突触核蛋白病是 其特征是一种错误折叠的蛋白质，磷酸化的α-突触核蛋白（P-SYN）， 中枢和外周神经系统。突触核蛋白病包括帕金森氏病（PD）、痴呆伴发性帕金森病（PD）、痴呆伴发性帕金森病（PD）、痴呆伴发性帕金森病（PD）、痴呆伴发性帕金森病（PD）和痴呆伴发性帕金森病。 路易体（DLB）、多系统萎缩（MSA）和单纯自主神经功能衰竭（PAF）的临床症状不同 和疾病进展率。目前，对于任何突触核蛋白病都不存在疾病修饰疗法。 突触核蛋白病患者的皮肤神经纤维内P-SYN的沉积提供了诊断 清晰度，并随着疾病进展而增加。重要的是，还观察到P-SYN的皮肤沉积， 大多数诊断为特发性快速眼动睡眠行为障碍（iRBD）的患者， 其中>90%的患者在15天内表型转化为临床上明显的突触核蛋白病 多年的诊断。目前，用于确定临床上明显的突触-突触- iRBD患者中不存在神经病变。诊断工具能够评估和可靠地预测概率 在前驱期阶段的表型转化是一个迫切的和未满足的需求，具有临床重要性和公共卫生 在全球范围内的影响。皮肤神经诊断（CND生命科学），一个CLIA认证的实验室， 已经开发出了其核心技术，可以在小（3 mm）患者的穿刺皮肤活检中检测P-SYN 并推出了第一个商用的突触核蛋白病诊断测试，Syn-One Test™。在这 针对II期研究，CND Life Sciences将通过检测P-SYN来推进Syn-One Test™ 在iRBD患者中预测表型转化风险并加速测试的商业可行性 通过创新的人工智能增强病理解释结果。实现这一 目的，CND生命科学公司进行了可行性研究，以证明皮肤P-SYN沉积 可以在94-100%的突触核蛋白病患者中可靠地检测到，而在疾病对照受试者中没有检测到， 而初步试验研究表明，在64%的iRBD患者中观察到P-SYN。在这份提案中，CND 生命科学将与北美前驱突触核蛋白病（NAPS）联盟（NIH- 资助的项目），以1）定义预测表型的P-SYN沉积和神经纤维变性的指标， iRBD患者的转换（目的1）和2）通过数字定量分析增强病理阅读， 使用AI增强检测系统的Syn-One Test™（Aim 2）。成功完成本研究将 推进Syn-One Test™的临床实用性，改善患者护理，提高商业潜力 产品，并最终加速疾病改善疗法的发展。

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.