Discussion

Despite intensive pre-marketing toxicity testing of newly developed drugs, severe drug-induced toxicity may go undetected, only surfacing when drugs are being used by the general population. Drug-induced toxicity has an idiosyncratic component associated with the presence of particular mutations or single nucleotide polymorphisms (SNPs) in genes essential for the functioning of vital organs such as heart and liver. An in vitro cellular model harbouring these mutations/SNPs would increase pre-clinical detection of organ-specific drug-induced toxicity. The CRISPR/Cas9 genome editing tool allows for controlled gene targeting and subtle genetic modification in a broad range of organisms. Using this tool, we have generated human pluripotent stem cell lines harbouring mutations/SNPs associated with drug-induced toxicity, such as the G1681A mutation in the I(Kr) potassium channel encoded by KCNH2, which is associated with drug-induced cardiotoxicity. Directed differentiation of these cells allows for drug toxicity screening which has the potential to complement, or even partially replace, animal experiments during drug development.