Norman Zapata

Clydes In Vivo Cardiomyocyte Assay

The Clydes in vitro cardiomyocyte safety assay is one of the most comprehensive methods used to determine the cardiac function of pharmaceutical products. With extensive collaboration with large pharmas and the FDA, Clyde has developed next generation assays for pro arrhythmic risk, negative inotropy, and voltage-dependent electrophysiology. The company has also published an excitation-coupling assay for parallel assessment of voltage.

The methodology is based on culturing cardiomyocytes in 3D constructs and applying electromechanical stimulation. The resulting cardiomyocytes are characterized by their high contractile ability, although they are not yet mature enough to perform cardiac functions. The in vitro cardiomyocyte assay involves a complex series of steps, including optimization of cell culture media, adjusting electrical and mechanical stimulation conditions, and optimizing the microenvironment for the resulting cardiomyocytes.

The development of highly predictive in vitro cardiomyocyte assays is essential to improve the screening of pharmaceutical drugs for cardiac safety. As with all cell types, human iPSC-CMs are characterized by specific molecular characteristics. The iPSC-CMs provide a homogenous and unlimited source of human-derived cells. Further development of mature iPSC-CMs will enhance the predictive power of these cells in high-throughput screening.

Moreover, hiPSC-cardiomyocytes allow for novel methodological approaches to assess the cardiac contractility of drugs. The advantages of hiPSC-cardiomyocytes over isolated cardiac tissues are many. Nevertheless, the challenges associated with hiPSC-cardiomyocytes are numerous, including their immature, fetal-like properties. In addition, hiPSC-cardiomyocytes do not mimic the functional settings of human physiology.

The cellular model used for drug development is subject to limitations, including fetal-like properties and functional variability. Therefore, it is imperative to evaluate the context in which the model is used. Before incorporating hiPSC-cardiomyocytes into drug development, questions must be addressed. These include the appropriate time of exposure and multiples of exposure, whether the derived cardiomyocytes are capable of expressing the target molecule, and are they sensitive to various drugs?