Cutaneous Phosphorylated Alpha-Synuclein for Detection of Prodromal Synucleinopathies

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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.