SBIR-STTR Award

In this Fast Track SBIR application, NeuroDex, Inc. proposes to use its expertise in extracellular vesicle (EV)immunoaffinity isolation to develop a blood test that detects synucleinopathies with high sensitivity, with the long-term goal of helping clinicians identify patients for whom antipsychotic drugs are harmful and contraindicated.Development and commercialization of a sensitive blood test for synucleinopathies would address amajor unmet need for selecting appropriate antipsychotic treatments that avoid severe adverse effect.The proposed work leverages a proprietary procedure NeuroDex developed for isolating EVs from plasma usingimmunoaffinity for cell-specific surface markers. Using this approach, the company demonstrated a > 20-foldincrease in signal to noise ratio of NDEs, a degree of specificity that is essential for analyzing aSYN because >90% of aSYN in plasma does not originate in the brain and is not disease related. Previous efforts to measureaSYN in unprocessed plasma have not yielded any diagnostic value, but measurement after NDE isolationprovides powerful classification. Leveraging this approach, NeuroDex has developed assays to test aSYN withinand on the surface of neuron-, microglia-, and oligodendrocyte-derived EVs. These assays successfullydistinguished 35 healthy controls, 51 PD patients, and 30 MSA patients with high accuracy. NeuroDex nowproposes to complete the discovery phase (Phase I) and conduct analytical and clinical validation (Phase II).PHASE I-Aim 1. Identify final biomarkers to be included in the synucleinopathy detection panel. Using195 samples from healthy individuals and patients with an array of autopsy-confirmed synucleinopathies, we willassess the performance of different panels of the possible biomarkers to select the combination with the bestperformance. Success Metric: ≥ 80% PPV for identifying patients with synucleinopathies and ≥ 90% NPV. Aim2. Qualify the selected assays. Success Metrics: precision CoV ≤ 20%, linearity across 8-fold dilution range,and LLQ compatible with clinical samples. Go/No Go Criterion for Progression to Phase II: Completion of thediscovery phase to include a defined set of biomarkers in a panel that a) provides ≥ 90% NPV and b) can bemeasured in a robust manner (variability in precision and reproducibility <20%). PHASE II-Aim 1. Analyticalvalidation of the diagnostic assay. Milestones & Success Metrics: 1) Successful audits for CLIA lab SOP, 2)analytical data package for FDA breakthrough designation submission. Aim 2. Preliminary clinical validationof the diagnostic assay in a CLIA-certified lab. We will validate the assays with 700 samples from patientswith dementia with or without synucleinopathies and age-matched controls. Milestones & Success Metrics:primary: NPV ≥ 90%; secondary: PPV ≥ 80%. Impact-Development and rigorous validation of a novel bloodtest for differential diagnosis of dementia with synuclein pathology would produce a commercially-viablediagnostic to inform appropriate treatment plans and clinical trial stratification for improved drug development.

Public Health Relevance Statement:
PROJECT NARRATIVE Up to 30% of patients with dementia have aggregates of alpha-synuclein called Lewy bodies in the brain, and when these are present, patients should not receive antipsychotic drugs to treat common symptoms because these drugs can cause rapid worsening of the disease and early death. Current methods to determine which patients have these aggregates are difficult, expensive, and rarely used in patients without clear evidence of specific diseases, resulting in more than two-thirds of these patients going undiagnosed. This project is designed to develop and validate a new blood-based test to determine whether patients with dementia have these aggregates, with the goal of informing patient care to prevent inappropriate prescription of antipsychotic drugs.

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