High-Throughput Screening for Novel Drug Discovery Using Patient-Specific Induced Pluripotent Stem Cells for Familial Hypertrophic Cardiomyopathy
Abstract
The aim of this proposal is to discover a new medication for hypertrophic cardiomyopathy (HCM) using cardiomyocytes (CMs) generated from human induced pluripotent stem cells (hiPSCs). HCM is a prevalent hereditary heart disease affecting approximately 1 in 500 people worldwide, including military families. It is characterized by the thickening of heart tissue, which reduces the size of the heart chambers, impairs relaxation time, causes arrhythmias, and can ultimately result in sudden cardiac death (SCD). To identify potential treatments for HCM, a high-throughput screening approach can be used with patient-specific iPSC-derived CMs representing various HCM genotypes. In this study, we demonstrate the validation of hypertrophic defects using CMs derived from HCM patients with R723C/MLP-W4R mutations. We also show that declining MLP levels play a crucial role in stabilizing sarcomeres in cardiac cells, leading to remodeling sarcomeres and HCM disease progression. Additionally, we employed multiple HCM iPSC-CM lines to confirm our findings, including an enlarged cell area, elevated expression of BNP, prolonged twitch event with delayed relaxation, and increased peak force compared to the control. Subsequently, we have validated two drug candidates that can inhibit calcineurin/NFAT or mitigate enhanced actomyosin crossbridge formation in patient-derived hiPSC-CMs. Furthermore, we conducted transcriptome analysis using RNA sequencing (RNAseq) on control cells, isogenic MYH7-corrected cells, isogenic MLP-corrected cells, and proband MLPW4R;MYH7-R723C iPSC-CMs to gain insight into the mechanisms underlying pathological hypertrophy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2022
- Accession Number
- AD1205005
Entities
People
- Jin‐Kyu Park
Organizations
- Yale University