TY - JOUR
KW - SARS-CoV-2
KW - azithromycin
KW - cardiomyocytes
KW - heart muscle
KW - hydroxychloroquine
KW - induced pluripotent stem cells
KW - microphysiological systems
KW - polytherapy
AU - Bérénice Charrez
AU - Verena Charwat
AU - Brian A. Siemons
AU - Ishan Goswami
AU - Courtney Sakolish
AU - Yu-Syuan Luo
AU - Henrik Finsberg
AU - Andrew G. Edwards
AU - Evan W. Miller
AU - Ivan Rusyn
AU - Kevin E. Healy
AB - Despite global efforts, it took 7 months between the proclamation of global SARS-CoV-2 pandemic and the first FDA-approved treatment for COVID-19. During this timeframe, clinicians focused their efforts on repurposing drugs, such as hydroxychloroquine (HCQ) or azithromycin (AZM) to treat hospitalized COVID-19 patients. While clinical trials are time-consuming, the exponential increase in hospitalizations compelled the FDA to grant an emergency use authorization for HCQ and AZM as treatment for COVID-19, although there was limited evidence of their combined efficacy and safety. The authorization was revoked 4 months later, giving rise to controversial political and scientific debates illustrating important challenges such as premature authorization of potentially ineffective or unsafe therapeutics, while diverting resources from screening of effective drugs. Here we report on a preclinical drug screening platform, a cardiac microphysiological system (MPS), to rapidly identify clinically relevant cardiac liabilities associated with HCQ and AZM. The cardiac MPS is a microfabricated fluidic system in which cardiomyocytes derived from human induced pluripotent stem cells self-arrange into a uniaxially beating tissue. The drug response was measured using outputs that correlate with clinical measurements such as action potential duration (proxy for clinical QT interval) and drug-biomarker pairing. The cardiac MPS predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities in tissues treated with HCQ. We found no change in QT interval upon acute exposure to AZM, while still observing a significant increase in arrhythmic events. These results suggest that this MPS can not only predict arrhythmias, but it can also identify arrhythmias even when QT prolongation is absent. When exposed to HCQ and AZM polytherapy, this MPS faithfully reflected clinical findings, in that the combination of drugs synergistically increased QT interval when compared to single drug exposure, while not worsening the overall frequency of arrhythmic events. The high content cardiac MPS can rapidly evaluate the cardiac safety of potential therapeutics, ultimately accelerating patients' access to safe and effective treatments.
BT - Frontiers in Pharmacology
DA - 2021
DO - 10.3389/fphar.2021.684252
LA - eng
N2 - Despite global efforts, it took 7 months between the proclamation of global SARS-CoV-2 pandemic and the first FDA-approved treatment for COVID-19. During this timeframe, clinicians focused their efforts on repurposing drugs, such as hydroxychloroquine (HCQ) or azithromycin (AZM) to treat hospitalized COVID-19 patients. While clinical trials are time-consuming, the exponential increase in hospitalizations compelled the FDA to grant an emergency use authorization for HCQ and AZM as treatment for COVID-19, although there was limited evidence of their combined efficacy and safety. The authorization was revoked 4 months later, giving rise to controversial political and scientific debates illustrating important challenges such as premature authorization of potentially ineffective or unsafe therapeutics, while diverting resources from screening of effective drugs. Here we report on a preclinical drug screening platform, a cardiac microphysiological system (MPS), to rapidly identify clinically relevant cardiac liabilities associated with HCQ and AZM. The cardiac MPS is a microfabricated fluidic system in which cardiomyocytes derived from human induced pluripotent stem cells self-arrange into a uniaxially beating tissue. The drug response was measured using outputs that correlate with clinical measurements such as action potential duration (proxy for clinical QT interval) and drug-biomarker pairing. The cardiac MPS predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities in tissues treated with HCQ. We found no change in QT interval upon acute exposure to AZM, while still observing a significant increase in arrhythmic events. These results suggest that this MPS can not only predict arrhythmias, but it can also identify arrhythmias even when QT prolongation is absent. When exposed to HCQ and AZM polytherapy, this MPS faithfully reflected clinical findings, in that the combination of drugs synergistically increased QT interval when compared to single drug exposure, while not worsening the overall frequency of arrhythmic events. The high content cardiac MPS can rapidly evaluate the cardiac safety of potential therapeutics, ultimately accelerating patients' access to safe and effective treatments.
PY - 2021
EP - 684252
T2 - Frontiers in Pharmacology
TI - Heart Muscle Microphysiological System for Cardiac Liability Prediction of Repurposed COVID-19 Therapeutics
VL - 12
SN - 1663-9812
ER -