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Zawartość zarchiwizowana w dniu 2024-06-18

Human pluripotent stem cells for modeling and correcting long-QT syndrome

Final Report Summary - HPSCLQT (Human pluripotent stem cells for modeling and correcting long-QT syndrome)

Introduction and project objectives

The long QT syndrome (LQTS) is an inherited or acquired disorder characterized by delayed ventricular repolarization predisposing affected individuals to fatal cardiac arrhythmias. In ~90% of the familial cases, LQTS is associated with mutation in one of two potassium voltage-gated channel genes: KCNQ1, causing LQT1, and KCNH2, causing LQT2. LQT1- and LQT2- human induced pluripotent stem cells (hiPSCs) recapitulate the disease phenotype and have been used to understand the underlying molecular mechanisms of the condition. The aims of this project are 1) to correct LQT1- and LQT2-causing mutations in patient-specific hiPSCs; 2) to target the same nucleotide changes in human embryonic stem cells (hESCs); 3) to characterize the electrophysiological phenotype of cardiomyocytes derived from “genetically corrected” patient-specific iPSCs and from mutated hESCs; and 4) to compare the pharmacological response of derivative cardiomyocytes.

Work performed since the beginning of the project

Using a conventional gene targeting approach based on homologous recombination, we have successfully corrected the LQT1- and LQT2-causing mutations in patient derived hiPSCs and introduced the LQT2-genetic lesion in hESCs. We have studied the electrophysiological properties of cardiomyocytes derived from all the isogenic pairs. In particular, using the two LQT2 isogenic lines, we have also investigated the molecular mechanism of action of the mutation. Finally, we tested the pharmacological response of these cardiomyocytes to specific molecules.

Achieved results

Correcting the mutation in hiPSCs allowed us to demonstrate that the mutation is causally linked to the electrophysiological phenotype observed in the derivative cardiomyocytes. By targeting the same mutations in hESCs, causality of that specific genetic defect was also confirmed. Furthermore, we discovered that the pathological mechanism underlying the disease entails a trafficking defect of the mutated channel and that proteasomes might be implicated in the clearance of the defective protein. Finally, we showed that the LQT2-causing mutation increases drug sensitivity thereby possibly enhancing arrhythmogenic risk in affected patients.

Expected final results and their potential impact and use

We expect that our approach will influence the field of disease modeling using hPSCs. In particular, our system (Fig. 1) represents an elegant strategy to prove a specific genotype-phenotype correlation.
Because our results provide the first evidence that isogenic pairs are essential for meaningful interpretation of a genetic cardiac condition, they have already been well received by the international scientific community at international meetings and through citations. We believe that our work has set a high bar for publishing hPSC cardiac disease models in the future.
Furthermore, we can provide the wider scientific community with new human LQTS cell models, offering invaluable in vitro systems that can be more extensively applied for drug discovery and drug safety pharmacology, most particularly enhanced drug sensitivities.

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