Cutaneous Phosphorylated Alpha-Synuclein for Detection of Prodromal Synucleinopathies

项目总结 一组毁灭性的疾病，统称为联体核病，影响着美国200多万人， 导致严重的发病率、高死亡率和巨大的相关医疗费用。并核病是 特征是错误折叠的蛋白质磷酸化α−突触核蛋白(P-SYN)在 中枢和外周神经系统。联核病包括帕金森氏病(PD)、痴呆和 路易小体(DLB)、多系统萎缩(MSA)和单纯自主神经衰竭(PAF)在临床症状上有所不同 和疾病进展率。目前，还没有针对任何一种共核病的疾病修饰疗法。 突触核病患者皮肤(皮肤)神经纤维中P-SYN的沉积为诊断提供依据 清晰度，并随着疾病进展而增加。重要的是，在皮肤中也观察到P-SYN的沉积 大多数被诊断为特发性快速眼动睡眠行为障碍(IRBD)的患者，是一种前驱疾病。 90%的患者在15岁内表型转化为临床明显的突触核病症 多年的诊断。目前，确定临床显性突触疾病轨迹的方法主要有： IRBD患者中不存在心肌病。能够评估和可靠预测概率的诊断工具 前驱症状阶段的表型转化是一个具有临床重要性和公共卫生意义的迫切而未得到满足的需求。 在全球范围内的影响。皮肤神经诊断(CND生命科学)，CLIA认证的实验室， 已经开发了其核心使能技术，即在小(3 Mm)患者的穿孔皮肤活检中检测P-SYN 并推出了第一个商业化的联核症诊断测试--Synn-One测试™。在这 针对第二阶段研究，CND生命科学公司将通过检测P-SYN来推进Synn-One测试™ 在iRBD患者中预测表型转换风险并加快测试的商业可行性 通过对结果进行创新的人工智能增强病理解释。要做到这一点 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 可在94%-100%的突触核病患者中可靠地检测到，而在所有疾病对照对象中均未检测到， 而初步的初步研究表明，P-SYN存在于%的iRBD患者中。在本提案中，CND 生命科学公司将与北美前驱综合征(NAP)联盟(NIH- 资助项目)1)定义P-SYN沉积和神经纤维变性的指标，以预测表型- IRBD患者的转化(目标1)和2)通过数字定量分析 使用人工智能增强检测系统的Syn-One测试™(目标2)。成功完成这项研究将 提高Synn-One测试™的临床实用价值，改善患者护理，增加 该产品，并最终加快了疾病修正疗法的开发。

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.