2. Academic Validation
  3. Myosin inhibitor reverses hypertrophic cardiomyopathy in genotypically diverse pediatric iPSC-cardiomyocytes to mirror variant correction

Myosin inhibitor reverses hypertrophic cardiomyopathy in genotypically diverse pediatric iPSC-cardiomyocytes to mirror variant correction

  • Cell Rep Med. 2024 Apr 16:101520. doi: 10.1016/j.xcrm.2024.101520.
Caroline Kinnear 1,  Abdelrahman Said 1,  Guoliang Meng 2,  Yimu Zhao 3,  Erika Y Wang 4,  Naimeh Rafatian 5,  Neha Parmar 1,  Wei Wei 2,  Filio Billia 6,  Craig A Simmons 7,  Milica Radisic 8,  James Ellis 9,  Seema Mital 10
Affiliations

Affiliations

  • 1 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
  • 2 Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
  • 3 Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
  • 4 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 5 Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
  • 6 Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada; Ted Rogers Centre for Heart Research, Toronto, ON M5G 1M1, Canada.
  • 7 Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3G8, Canada; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON M5G 1M1, Canada.
  • 8 Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada; Terrence Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
  • 9 Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jellis@sickkids.ca.
  • 10 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Ted Rogers Centre for Heart Research, Toronto, ON M5G 1M1, Canada; Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: seema.mital@sickkids.ca.
PMID: 38642550 DOI: 10.1016/j.xcrm.2024.101520
Abstract

Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like Myosin ATPase inhibitors have not been evaluated in children. We generate patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 (V606M; R453C), MYBPC3 (G148R) or digenic variants (MYBPC3 P955fs, TNNI3 A157V). We also generate CMs harboring MYBPC3 mono- and biallelic variants using CRISPR editing of a healthy control. Compared with isogenic and healthy controls, variant-positive CMs show sarcomere disorganization, higher contractility, calcium transients, and ATPase activity. However, only MYH7 and biallelic MYBPC3 variant-positive CMs show stronger myosin-actin binding. Targeted Myosin ATPase inhibitors show complete rescue of the phenotype in variant-positive CMs and in cardiac Biowires to mirror isogenic controls. The response is superior to verapamil or metoprolol. Myosin inhibitors can be effective in genotypically diverse HCM highlighting the need for Myosin inhibitor drug trials in pediatric HCM.

Keywords

CRISPR gene editing; MYBPC3; MYH7; cardiomyocytes; hypertrophic cardiomyopathy; induced pluripotent stem cells; metoprolol; myosin ATPase inhibitor; pediatric; verapamil.

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