The PREMEDiCARE project has demonstrated that it is possible to reproduce in vitro the differences observed in patients affected by the same disease-causing mutation who show different clinical phenotypes (i.e. symptoms).
In our study (Lee & Sala & Mura et al. Cardiovascular Research, 2021, doi: 10.1093/cvr/cvaa019) two relatives were affected by the KCNQ1-p.Y111C variant, which causes a severe loss-of-function in a cardiac potassium channel (KV7.1 IKs). Surprisingly, one of the patients had a prolonged QT interval and was severely symptomatic while the other was completely asymptomatic, and we have investigated whether it was possible to recreate this discrepancy in vitro with hiPSC-CMs.
We have characterized the electrophysiology of hiPSC-CMs from these two subjects and compared to that from a control, and we have found that hiPSC-CMs are capable of discriminate the different clinical severity of LQTS despite the presence of an identical disease-causing variant. We have further investigated the mechanism underlying this discrepancy demonstrating that in this family the phenotypic differences were caused by two common single nucleotide polymorphisms (SNPs) in a gene (MTMR4) involved in the ubiquitination-mediated degradation of ion channels. These “protective” SNPs reduced the efficacy by which potassium channels are degraded and prevented the collateral degradation of another key cardiac potassium channel (KV11.1 hERG), compensating for the loss-of-function induced by the LQTS variant.
In a second study (Sala et al., bioRxiv, 2021, doi: 10.1101/2021.06.25.449913) we further verified whether the different disease severity among carriers of LQTS variant was also inducing a differential drug response to proarrhythmic drugs. In other words, we investigated whether hiPSC-CMs from symptomatic patients with LQTS were more prone to develop drug-induced arrhythmias compared to those from asymptomatic patients or from controls. By testing the effect of the QT-prolonging drug hydroxychloroquine, recently repurposed in the attempt to prevent or treat of COVID-19, we have demonstrated that disease-specific hiPSC-CMs do show a differential sensitivity to QT prolonging drugs that agrees with the underlying genotype. This demonstrates that safety pharmacology may indeed benefit from disease-specific cohorts of hiPSC-CMs in addition to drug testing in hiPSC-CMs from commercial sources or healthy donors.
The results of the PREMEDiCARE project were published in peer-reviewed journals (Cardiovascular Research, European Heart Journal, Stem Cell Reports) and presented in virtual meetings, with the most recent findings also uploaded on preprint servers (bioRxiv) to facilitate the dissemination of the results while the manuscript is undergoing peer review. At the time of writing this report, the PREMEDiCARE project has led to 3 peer-reviewed articles, 2 peer-reviewed reviews, 1 editorial, 1 peer-reviewed book chapter, 1 preprint publication (currently under peer-review), 1 podcast (European Society of Cardiology Cardiotalk).
