Development of a predictive biomarker for Parkinson's disease

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.

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 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 >10 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 clinical test. We will convert our microfluidic prototype into an automated device for rapid and robust L1EV isolation with a modular design to be used in cojunction with highly sensitive downstream marker quantification. We will refine our electrochemical alpha-synuclein quantification assay to improve sensitivity and minimise variability vis-à-vis to electrochemiluminescence. We will then test the final assay format in a deeply phenotyped longitudinal cohort of individuals at risk of developing PD or patients with different rates of disease progression. In this way we will confirm that the test identifies people at risk of phenoconvertion and define parameters for objective monitoring of the disease.