Silencing of MYH7 ameliorates disease phenotypes in human IPSC cardiomyocytes

Alexandra Dainis, Kathia Zaleta-Rivera, Alexandre Ribeiro, Andrew Chia Hao Chang, Ching Shang, Feng Lan, Paul W. Burridge, W. Robert Liu, Joseph C. Wu, Alex Chia Yu Chang, Beth L. Pruitt, X. Matthew Wheeler, Euan Ashley*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

RNA silencing has been shown to be an effective therapeutic treatment in a number of diseases, including neurodegenerative disorders. Studies of allele-specific silencing in hypertrophic cardiomyopathy (HCM) to date have focused on mouse models of disease. We here examine allele-specific silencing in a human-cell model of HCM. We investigate two methods of silencing, short hairpin RNA (shRNA) and antisense oligonucleotide (ASO) silencing, using a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model. We used cellular micropatterning devices with traction force microscopy and automated video analysis to examine each strategy’s effects on contractile defects underlying disease. We find that shRNA silencing ameliorates contractile phenotypes of disease, reducing disease-associated increases in cardiomyocyte velocity, force, and power. We find that ASO silencing, while better able to target and knockdown a specific disease-associated allele, showed more modest improvements in contractile phenotypes. These findings are the first exploration of allele-specific silencing in a human HCM model and provide a foundation for further exploration of silencing as a therapeutic treatment for MYH7-mutation-associated cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)293-303
Number of pages11
JournalPhysiological genomics
Volume52
Issue number7
DOIs
StatePublished - 2020

Keywords

  • Allele-specific
  • Hypertrophic cardiomyopathy
  • RNA silencing

ASJC Scopus subject areas

  • Physiology
  • Genetics

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    Dainis, A., Zaleta-Rivera, K., Ribeiro, A., Chang, A. C. H., Shang, C., Lan, F., Burridge, P. W., Liu, W. R., Wu, J. C., Chang, A. C. Y., Pruitt, B. L., Wheeler, X. M., & Ashley, E. (2020). Silencing of MYH7 ameliorates disease phenotypes in human IPSC cardiomyocytes. Physiological genomics, 52(7), 293-303. https://doi.org/10.1152/physiolgenomics.00021.2020