Letter to the Editor: Liver Cell Models for Premature Termination Codon Readthrough Analyses

Amzal and colleagues (1) reported about the prospect of pharmacological premature termination codon (PMT) readthrough of ABCB11 mRNA in bile salt export pump deficiency, the latter causing progressive familial intrahepatic cholestasis (PFIC)-type 2. The authors demonstrate that aminoglycoside antibiotics can stimulate readthrough of nonsense mutation-induced PMT in the ABCB11 mRNA, thereby rescuing full-length ABCB11 protein synthesis. The study provides proof-of-principle for a potential new therapy for nonsense mutation-associated PFIC2. The authors acknowledge that their cell line-based model does not take nonsense-mediated mRNA decay (NMD) into account, which however determines whether PFIC2 patients may actually benefit from PMT readthrough therapy. Importantly, other cell models exist that do take NMD into account and we believe these should be discussed as part of the path to bring their exciting findings closer to the clinic.