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

TO THE EDITOR:

Amzal et al.^{( 1 )} reported about the prospect of pharmacological premature termination codon (PMT) readthrough of ATP‐binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11) mRNA in bile salt export pump deficiency, the latter causing progressive familial intrahepatic cholestasis (PFIC)‐type 2. The investigators demonstrate that aminoglycoside antibiotics can stimulate readthrough of nonsense mutation‐induced PMT in ABCB11 mRNA, thereby rescuing full‐length ABCB11 protein synthesis. The study provides proof of principle for a potential therapy for nonsense mutation‐associated PFIC2. The investigators 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.

NMD is a cellular surveillance pathway that safeguards the quality of mRNA transcripts and eliminates most PMT‐containing mRNA. NMD efficiency is variable and depends, among others, on the precise nonsense mutation. Because a sufficient amount of target mRNA is a prerequisite for effective PMT readthrough and the synthesis of a sufficient amount of the encoded protein, NMD poses a significant hurdle in the application of PMT readthrough‐stimulating drugs in the clinic.^{( 2 )}

Measurements of patients’ baseline ABCB11 mRNA may provide a prognostic indicator of response to PMT readthrough‐stimulating drugs, but because ABCB11 is exclusively expressed in hepatocytes, this would require a liver biopsy. Patient‐derived somatic cells from blood, skin, or urine are easier to obtain. These can be reprogrammed to induced pluripotent stem cells (iPSCs) and subsequently differentiated to hepatocytes. Human iPSC‐derived hepatocytes that form bile canaliculi and express ABCB11 were recently reported,^{( 3 )} as well as a PFIC2 patient iPSC‐derived hepatocyte model for ABCB11 deficiency.^{( 4 )} The big advantage of patient iPSC‐derived hepatocytes is that these express the endogenously expressed—and NMD‐responsive—gene variant(s) and reflect individual NMD levels.

With the exciting results from Amzal et al. at hand, confirmatory studies using iPSC‐derived hepatocytes promise a better and patient‐tailored prediction of PMT readthrough‐stimulating drug efficacy, as such or in combination with NMD inhibitors, for the treatment of nonsense mutation‐associated PFIC and other hereditary liver diseases.

Author Contributions

Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: L.M., Q.L., S.C.D.v.I.; drafting the article or revising it critically for important intellectual content: L.M., Q.L., S.C.D.v.I.; final approval of the version to be published: L.M., Q.L., S.C.D.v.I.