Using iPSC-derived heart cells to test safety of drugs is a promising approach. Like adult human heart cells, iPSC-CM produce electrical signals called action potentials. These are the result of coordinated opening and closing of ion channels, which allow charged ions to enter or leave the cells. Drugs interfering with ion channels, either intentionally or as a side-effect, can disturb heart rhythm with potentially lethal effects. Therefore, preclinical safety tests of drug candidates are essential before first trials in humans.
Action potentials of iPSC-CM can be recorded using high-throughput planar patch clamp chips, a microfluidic platform. However, the relative immature phenotype of iPSC-CM results in the lack of one key ion channel type, and excess of another. The group of Dr. Teun de Boer is advancing the automated patch clamping technique by developing high-throughput dynamic clamping. In this technique, an iPSC-CM is connected to a real-time computer simulation of the two key ion channels (Kir2.1 and HCN4). Through the coupling, a hybrid biological-digital model is created in which the balance of ion channels can be corrected. This is achieved by adding or removing virtual ion channels. As a result, action potentials with a more mature shape are obtained, which allows for better predictions of drug safety. Since automated patch clamping is a cornerstone technology that is widely used in safety pharmacology, the advanced dynamic clamping techniques can have a big impact and further increase the relevance of iPSC-CM based models.
Image showing the Nanion Patchliner system
The work on biological-digital twins is supported by the Eurostars program (HybridHeart, E115525) and is performed in close collaboration with consortium partners Nanion Technologies (Munich, Germany) and Elements (Cesena, Italy), leaders in automated patch clamping platforms and high-throughput integrated patch clamp amplifiers, respectively. The first milestones in the project have been reached, establishing the first 8 channel prototype system. Meanwhile, work is continuing of the main goal of the project, a 384 channel system that will establish up to 384 concurrent biological-digital twins, which is expected to be realized by the end of 2023.
For more information on this project, please send an email to t.p.deboer@uu.nl
