Microheart muscle based discovery and development of inotropic compounds

Inotropes are compounds affecting heart contraction force, either positively or negatively. They are used to adjust heart pumping in conditions like heart failure, hypertension, or cardiomyopathies. However, current agents have limitations, including: common and risky side effects like arrhythmias and blood pressure changes, short duration of use, dangerous drug interactions, and variable efficacy. There is thus an immediate demand for novel inotropic compounds, along with their corresponding novel molecular mechanisms, to empower drug developers to formulate the next wave of cardiac medications. Organos, Inc. is attempting to solve this difficult problem through the development of advanced cardiac drug discovery platforms and technologies. Organos has produced a high- throughput micro-heart muscle (μHM) system engineered from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). This 384 well format test system has been used to phenotypically characterize a repurposing library of FDA or EMA approved compounds and has uncovered a number of compounds which demonstrate previously undescribed cardiac inotropy. In this proposal, we seek to advance these candidate compounds for potential repurposing and discovery of novel inotropy mechanisms. We propose to first validate our screen results in a more mature engineered tissue platform, a microfluidics based cardiac microphysiological system (MPS), and then verify these results in modern platforms which use adult human primary ventricular myocytes. We will also use bulk RNA sequencing and primary cell phenotypic mapping to attempt to elucidate mechanisms of action of these molecules. Final candidates will be tested in donor human tissue test systems, and rodent in vivo models. The success of this project holds the potential to uncover novel drug mechanisms and therapeutic targets aimed at addressing the need for pharmaceutical inotropic modulation of the heart.