Abstract P1131: Modeling Contractile Diseases Using Scalable 3D Engineered Heart Tissues For Drug Discovery

Abstract

Model systems that accurately recapitulate healthy and diseased function in a dish are critical for the development of novel therapeutics. For cardiac diseases, direct assessment of contractile output constitutes the most reliable metric with which to assess overall tissue function, as other ‘proxy’ measurements are poor predictors of muscle strength. 3D engineered muscle tissues (EMTs) derived from iPSCs hold great potential for modeling contractile function. Here, we have developed a platform and device that utilizes 3D EMTs in conjunction with a label-free magnetic sensing array. The platform enables facile and reproducible fabrication of 3D EMTs using virtually any cell source and is coupled with a highly parallel direct measurement of contractile strength. This approach enables the stratification of healthy and diseased phenotypes and facilitates compound safety and efficacy screening for evaluation of a drug’s effect on contractile output. We will present data from a drug (BMS-986094) that failed clinical trials due to unanticipated cardiotoxicity. We go on to show both the acute and chronic effects of doxorubicin in cardiac EMTs. Contractile force decreased in a dose dependent-like manner when the drug was applied continuously. Interestingly, a single 1uM bolus induced a transient effect that could be washed out over time. A repeat bolus, however, irreversibly abolished contraction, suggesting that repeat dosing may have a cardiotoxic effect on the muscle. These data demonstrate a first-and-only commercial platform for high-throughput assessment of 3D cardiac muscle contraction with potential for widespread adoption within the drug development field.