A human iPSC-derived heart-on-a-chip technology can directly measure in vivo cardiac performance and it can be used to assess the effects of novel compounds on contractility early in the drug discovery and development process.
HUMAN HEALTH ISSUE
Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide (Benjamin et al., 2018). Patients with heart failure (HF) comprise a growing percentage of the CVD population. HF is instigated by both genetic, eg, inherited cardiomyopathy and acquired risk factors eg, coronary heart disease or hypertension (Stienen, 2015). Cardiotoxicity and HF can also be an unwanted consequence of treatment with a range of drugs in clinical usage (McNaughton et al., 2014; Onakpoya et al., 2016; Siramshetty et al., 2016). There remains the need for both novel therapies to prevent and treat HF as well as improved ways to assess the cardiac safety liabilities of candidate drug therapies.
ANIMAL FREE SCIENCE POTENTIAL
The uses of human induced pluripotent stem cells (iPSCs) holds great promise as a foundation to bridge the human translation gap. However, experimental models, which rely on iPSCs alone lack relevant physiological hallmarks and drug responses seen in human heart muscle. TARA biosystems developed an organ-on-a-chip technology that can directly measure in vivo cardiac performance. The research also showed how the platform could be used to model different heart diseases by using iPSCs from patients. The findings published by Zhao et al. in the Journal of Toxicological Sciences, show that TARA’s 3D-cardiac tissue platform predicts responses to a wide range of drugs known to affect cardiac function in humans, something that has been a challenge in pre-clinical animal models until now.
“These results are exciting because they demonstrate how TARA’s advanced biology can really make an impact on the translation of clinical compounds. Replicating complex physiology in systems that up to now could only be seen in animals positions our technology as a faster, cheaper, and more human-relevant alternative to animal testing.” – Michael P. Graziano, PhD, chief scientific officer of TARA Biosystems
ABSTRACT
Recent advances in techniques to differentiate human induced pluripotent stem cells (hiPSCs) hold the promise of an unlimited supply of human derived cardiac cells from both healthy and disease populations. That promise has been tempered by the observation that hiPSC-derived cardiomyocytes (hiPSC-CMs) typically retain a fetal-like phenotype, raising concern about the translatability of the in vitro data obtained to drug safety, discovery, and development studies. The Biowire II platform was used to generate 3D engineered cardiac tissues (ECTs) from hiPSC-CMs and cardiac fibroblasts. Long term electrical stimulation was employed to obtain ECTs that possess a phenotype like that of adult human myocardium including a lack of spontaneous beating, the presence of a positive force-frequency response from 1 to 4 Hz and prominent postrest potentiation. Pharmacology studies were performed in the ECTs to confirm the presence and functionality of pathways that modulate cardiac contractility in humans. Canonical responses were observed for compounds that act via the β-adrenergic/cAMP-mediated pathway, eg, isoproterenol and milrinone; the L-type calcium channel, eg, FPL64176 and nifedipine; and indirectly effect intracellular Ca2+ concentrations, eg, digoxin. Expected positive inotropic responses were observed for compounds that modulate proteins of the cardiac sarcomere, eg, omecamtiv mecarbil and levosimendan. ECTs generated in the Biowire II platform display adult-like properties and have canonical responses to cardiotherapeutic and cardiotoxic agents that affect contractility in humans via a variety of mechanisms. These data demonstrate that this human-based model can be used to assess the effects of novel compounds on contractility early in the drug discovery and development process.
Sources:
Zhao, Y., et al. (2019) A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling. Cell. doi.org/10.1016/j.cell.2018.11.042.
News Medical: TARA’s organ-on-a-chip technology can directly measure in vivo cardiac performance, study shows. November, 18 2019.
