Modulating human iPSC-CM electrophysiology for in vitro drug screening

Abstract

Every year drugs are retracted from the market due to serious side effects, of which 45% negatively influences heart rhythm. This can be prevented with proper testing during drug development to determine the safety for the human heart. However, in drug development mostly animals are used to study the effects of drugs, yet an animal heart responds differently to drugs than a human heart. A human alternative is necessary to correctly predict the safety of new drugs and decrease the amount of tests in animals. This transition has been boosted by the development of stem cell-derived heart muscle cells (iPSC-CMs): cells from the skin that have been transformed to stem cells and subsequently to heart muscle cells. iPSC-CMs harbor one major disadvantage: they do not resemble human adult heart muscle cells electrically and are hyperactive, which decreases the accuracy of their drug response. In this thesis we applied various techniques to modulate the electrical characteristics of iPSC-CMs to create a better model for animal-free drug screening. We succeeded in decreasing the hyperactivity of iPSC-CMs and observed a more accurate drug response. We observed variation between iPSC-CMs in what approach they needed to decrease the hyperactivity, which needed to be tailored for each individual cell. Because of this variation it is difficult to pick one strategy which works best for all iPSC-CMs. The variation between iPSC-CMs is a worldwide problem; besides, guidelines for the production and use of iPSC-CMs are currently lacking, which hampers the transition to test animal-free greatly.