Novel and less invasive biomarker assays to measure liver ATP7B in Wilson disease patients

Novel therapies for Wilson disease (WD) will require appropriate biomarkers and clinically relevant endpoints to demonstrate therapeutic efficacy. We aimed to develop robust, minimally invasive biomarker assays to assess target engagement in future clinical trials for WD therapeutics. We conducted a single-center, sample collection biomarker study in 21 patients with WD and 6 control participants. Serum, liver fine needle aspiration biopsy (FNA), and liver core needle biopsy (CNB) samples were collected from participants. RNA and protein were isolated from serum exosome and biopsy samples. Samples were analyzed for mRNA expression by quantitative PCR and for protein expression by a novel electrochemiluminescence (ECL) immunoassay. ATP7B mRNA was detectable in FNA, CNB, and serum exosome samples. However, serum exosomes are not yet a viable method for ATP7B quantification. ATP7B protein was only detectable in CNB samples. We compared the FNA and CNB results for five WD patients and found mRNA expression levels to be comparable with an R² of 0.64 with statistical significance. The methods we developed may be useful in clinical settings to quantify hepatocyte-specific expression of ATP7B for the development of novel therapeutics for Wilson disease.