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

基本信息

批准号：
10703452
负责人：
Todd Levine
金额：
$ 95.25万
依托单位：
CND LIFE SCIENCES, INC.
依托单位国家：
美国
项目类别：
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/10703452
关键词：
Academia Acceleration Address Affect American Biological Sciences Biopsy Blinded CLIA certified Central Nervous System Clinical Clinical Trials Cognitive Collaborations Cutaneous Data Dementia with Lewy Bodies Deposition Detection Development Diagnosis Diagnostic Diagnostic tests Disease Disease Progression Dreams 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 Phosphorylation 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 behavior disorder diagnosis 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 neural participant enrollment patient population phase 2 study public-private partnership rapid eye movement success synuclein synucleinopathy therapy development vocalization whole slide imaging

项目摘要

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.

项目概要一组统称为突触核蛋白病的毁灭性疾病影响着美国超过 200 万人，突触核蛋白病具有显着的发病率、高死亡率和巨大的相关医疗费用。其特征是错误折叠蛋白磷酸化 α-突触核蛋白 (P-SYN) 的异常沉积，中枢和周围神经系统疾病包括帕金森病 (PD)、痴呆症。路易体 (DLB)、多系统萎缩 (MSA) 和纯自主神经衰竭 (PAF) 的临床症状有所不同目前，尚无针对任何突触核蛋白病的疾病修饰疗法。 P-SYN 在突触核蛋白病患者皮肤神经纤维内的沉积提供了诊断依据重要的是，在皮肤中也观察到 P-SYN 的沉积。大多数患者被诊断患有特发性快速动眼睡眠行为障碍 (iRBD)，这是一种前驱症状。 mal 突触核蛋白病，其中 >90% 的患者在 15 年内表型转变为临床明显的突触核蛋白病目前，确定临床明显症状的疾病轨迹的方法。 iRBD 患者的疾病不存在能够评估和可靠预测概率的诊断工具。前驱阶段的表型转化是一项具有临床重要性和公共卫生意义的紧迫且未得到满足的需求皮肤神经诊断（CND 生命科学）是一家经过 CLIA 认证的实验室，已开发出在小型（3 毫米）患者穿孔皮肤活检中检测 P-SYN 的核心支持技术并推出了第一个市售的突触核蛋白病诊断测试 Syn-One Test™。 CND Life Sciences 将直接进入 II 期研究，通过检测 P-SYN 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驱动的增强病理结果解释来实现这一目标。为了达到这一目的，CND Life Sciences 进行了可行性研究，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，而在任何疾病对照受试者中均未检测到，而初步试点研究表明，在 64% 的 iRBD 患者中观察到 P-SYN。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）1）定义预测表型的 P-SYN 沉积和神经纤维变性的指标 iRBD 患者的转化（目标 1）和 2）通过数字定量分析增强病理学读数使用人工智能增强检测系统的 Syn-One Test™（目标 2）将成功完成本研究。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，并最终加速疾病缓解疗法的开发。