Development of a predictive biomarker for Parkinson's disease

帕金森病（PD）影响全球约700万人，预计到2040年病例将翻一番。目前，NHS的年度费用为每位患者2，118英镑，每个PD家庭的年度经济负担为20，123英镑。目前还没有疾病修饰疗法，但这些疗法正在临床试验中。开展临床试验的一个主要瓶颈是在发病的最早阶段确定患者并排除疾病模拟物。PD在临床表现前几年开始。识别出处于前驱期的个体对于临床试验和最终的疾病改善疗法是最佳的。我们已经开发了一种血液测试，其基于神经源性α-突触核蛋白的血清测量来预测PD病理，α-突触核蛋白是>95%病例中的关键致病蛋白。具体而言，我们免疫捕获表达神经元抗原L1 CAM（L1 EV）的细胞外囊泡，并开发了30分钟内高效芯片上L1 EV分离的微流体原型。我们发现，使用多个队列中的> 1，000个样本，总L1 EV相关α-突触核蛋白水平在PD的前驱期和临床期增加。我们现在寻求支持，将该平台开发为标准化临床测试。我们将完善检测参数，并将我们的微流体原型转化为适合临床实践的设备，与高灵敏度的下游标记物定量结合使用。将在具有发生PD风险的个体或具有不同疾病进展速率的患者的深度表型纵向队列中测试最终测定形式。

Parkinson's disease (PD) affects ~7 million people globally with a projected doubling in cases by 2040. Currently, the annual cost to the NHS is £2,118 per patient with an annual economic burden of £20,123 per PD household. There is no disease-modifying therapy currently, but such therapeutics are in clinical trials. A major bottleneck in the conduction of clinical trials is the identification of patients at the earliest stages of the pathogenesis and the exclusion of disease-mimics. PD starts several years before clinical presentation. Identifying individuals in this prodromal phase would be optimal for clinical trials and eventual instigation of disease-modifying therapies. We have developed a blood test that predicts PD pathology based on serum measurements of neuronally-derived alpha-synuclein, the key pathogenic protein in >95% of cases. Specifically, we immunocapture extracellular vesicles expressing the neuronal antigen L1CAM (L1EV) and have developed microfluidic prototypes for highly effective on-chip L1EV isolation within 30min. We discovered that total L1EV associated alpha-synuclein levels are increased in the prodromal and clinical phase of PD using >1,000 samples across multiple cohorts. We now seek support to develop this platform as a standardised clinical test. We will refine the assay parameters and translate our microfluidic prototype into a device suitable for clinical practice, to be used in conjunction with highly sensitive downstream marker quantification. The final assay format will be tested in a deeply phenotyped longitudinal cohort of individuals at risk of developing PD or patients with different rates of disease progression.