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Phenotypic Screening of iPSC-Derived Cardiomyocytes for Cardiotoxicity Testing and Therapeutic Target Discovery

  • Arne A. N. Bruyneel
  • Tyler Muser
  • Vaidya Parthasarathy
  • Dries Feyen
  • Mark MercolaEmail author
Chapter

Abstract

The remarkable ability to generate unlimited numbers of cardiomyocytes and other differentiated cell types, from any person, and to edit the genome to introduce or correct disease-causing mutations, creates unprecedented opportunities for drug discovery. The new technologies have the potential to revolutionize the drug development pipeline, from delineating disease mechanisms and discovery of therapeutic targets to library screening and validation of therapeutic strategies. Moreover, since in vitro phenotypes reflect patient genetics and might predict outcomes, patient induced pluripotent stem cell (iPSCs) might eventually contribute to patient selection for clinical trials and inform individual patient treatment. This chapter focuses on the application of iPSC-derived cardiomyocytes in large-scale applications relevant to discovery of disease mechanisms and therapeutic targets for heart disease and for assessing the cardiomyopathic and proarrhythmic risk of drugs. We review the current status of large-scale screening of iPSC-derived cardiomyocyte disease models and explore new advances in cell culture, three-dimensional engineered tissues, and instrumentation that might address current weaknesses in the iPSC-cardiomyocyte technology. Our philosophy is that advancing iPSC-derived cardiomyocyte models that faithfully recapitulate disease and enable large-scale chemical or functional genomics screening could shift the paradigm of drug discovery by introducing human disease phenotype into the early stages of the development process, with the potential for increasing the safety and efficacy of new medicines.

Keywords

iPSC Cardiomyocyte Phenotypic screening Drug discovery Disease modeling Cardiotoxicity 

Notes

Acknowledgments

We gratefully acknowledge support from the National Institutes of Health (NIH) (R01HL130840. R01HL128072 and R21HL141019 to MM). TM acknowledges support from AHA (Undergraduate Summer Research Program). DAMF is funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 708459.

Conflict of Interest Statement

The authors have no conflicting interests.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Arne A. N. Bruyneel
    • 1
  • Tyler Muser
    • 1
  • Vaidya Parthasarathy
    • 1
  • Dries Feyen
    • 1
  • Mark Mercola
    • 1
    Email author
  1. 1.Cardiovascular Institute and the Department of MedicineStanford UniversityStanfordUSA

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