Towards Precision Medicine With Human iPSCs for Cardiac Channelopathies

Abstract

Long-QT syndrome, a frequently fatal inherited arrhythmia syndrome caused by genetic variants (congenital) or drugs (acquired), affects 1 in 2000 people worldwide. Its sentinel event is often sudden cardiac death, which makes preclinical diagnosis by genetic testing potentially life-saving. Unfortunately, clinical experience with genetic testing has shown that it is difficult to correctly identify genetic variants as disease causing. These current deficiencies in accurately assigning pathogenicity led to the discovery of increasing numbers of rare variants classified as variant of uncertain significance. To overcome these challenges, new technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) genome editing can be combined with human induced pluripotent stem cell-derived cardiomyocytes to provide a new approach to decipher pathogenicity of variants of uncertain significance and to better predict arrhythmia risk. To that end, the overarching goal of our network is to establish the utility of induced pluripotent stem cell-based platforms to solve major clinical problems associated with long-QT syndrome by determining how to (1) differentiate pathogenic mutations from background genetic noise, (2) assess existing and novel variants associated with congenital and acquired long-QT syndrome, and (3) provide genotype- and phenotype- guided risk stratification and pharmacological management of long-QT syndrome. To achieve these goals and to further advance the use of induced pluripotent stem cells in disease modeling and drug discovery, our team of investigators for this Leducq Foundation Transatlantic Networks of Excellence proposal will work together to (1) improve differentiation efficiency, cellular maturation, and lineage specificity, (2) develop new assays for high throughput cellular phenotyping, and (3) train young investigators to clinically implement patient-specific genetic modeling.

Keywords: genetic testing; induced pluripotent stem cells; long-QT syndrome; mutations; phenotype.

Figure 1.. An overview of our Leducq consortium grant.

Network members include Wu, Schwartz, Yamanaka, Yoshida, Gepstein, Hulot and Knollmann. Our network will recruit patients internationally from cardiology clinics in USA, France, Italy, Israel and Japan to generate their iPSC-CMs, all of which will undergo complete molecular and functional characterization. Patient-specific iPSC-CMs will then be used to assign functional significance of rare genetic variants, model diLQTS and arrhythmia, and repurpose drugs for treating LQTS patients. These studies will help identify novel pathological mechanisms that will improve drug therapy and advance personalized medicine for LQTS.