Authors

Discussion

Wilson’s disease is an autosomal-recessive disorder of hepatocellular copper deposition caused by mutations in the gene encoding for the copper-transporter, ATP7B. Importantly, Wilson’s disease commonly manifests in liver failure and there remains relatively few treatments approved for clinical use. Therefore, there is a need to develop novel therapeutics capable of alleviating the disease phenotype. A major bottleneck in developing new treatment modalities is the lack of a physiologically relevant in vitro model that recapitulates the Wilson’s disease phenotype. hiPSCs-derived hepatocytes have the potential to bridge this gap. To develop an in vitro model of Wilson’s disease, we used a CRISPR/Cas9-based approach to introduce the most common pathogenic ATP7B variants found within European/North American (H1069Q) and Asian (R778L) populations to our hiPSCs. The genetically edited cells were then successfully differentiated into hepatocytes and treated with copper to recapitulate the Wilson’s disease pathophysiology. The diseased cells showed increased copper accumulation and oxidative stress upon copper challenge when compared to isogenic healthy cells. Moreover, the excess copper accumulation could be reversed through the use of a clinically relevant chelator agent, Trientine Hydrochloride. Taken together, we have developed an in vitro model of Wilson’s disease that recapitulates the disease pathophysiology and is responsive to small molecule-based treatments.