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Heart Muscle Microphysiological System for Cardiac Liability Prediction of Repurposed COVID-19 Therapeutics

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 hospitalize...

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Autores principales: Charrez, Bérénice, Charwat, Verena, Siemons, Brian A., Goswami, Ishan, Sakolish, Courtney, Luo, Yu-Syuan, Finsberg, Henrik, Edwards, Andrew G., Miller, Evan W., Rusyn, Ivan, Healy, Kevin E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378272/
https://www.ncbi.nlm.nih.gov/pubmed/34421592
http://dx.doi.org/10.3389/fphar.2021.684252
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author Charrez, Bérénice
Charwat, Verena
Siemons, Brian A.
Goswami, Ishan
Sakolish, Courtney
Luo, Yu-Syuan
Finsberg, Henrik
Edwards, Andrew G.
Miller, Evan W.
Rusyn, Ivan
Healy, Kevin E.
author_facet Charrez, Bérénice
Charwat, Verena
Siemons, Brian A.
Goswami, Ishan
Sakolish, Courtney
Luo, Yu-Syuan
Finsberg, Henrik
Edwards, Andrew G.
Miller, Evan W.
Rusyn, Ivan
Healy, Kevin E.
author_sort Charrez, Bérénice
collection PubMed
description 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 The authorization was revoked 4 months later, giving rise to controversial political and scientific debates illustrating important challenges such as premature authorization of potentially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.
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spelling pubmed-83782722021-08-21 Heart Muscle Microphysiological System for Cardiac Liability Prediction of Repurposed COVID-19 Therapeutics Charrez, Bérénice Charwat, Verena Siemons, Brian A. Goswami, Ishan Sakolish, Courtney Luo, Yu-Syuan Finsberg, Henrik Edwards, Andrew G. Miller, Evan W. Rusyn, Ivan Healy, Kevin E. Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2021-08-04 /pmc/articles/PMC8378272/ /pubmed/34421592 http://dx.doi.org/10.3389/fphar.2021.684252 Text en Copyright © 2021 Charrez, Charwat, Siemons, Goswami, Sakolish, Luo, Finsberg, Edwards, Miller, Rusyn and Healy. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Charrez, Bérénice
Charwat, Verena
Siemons, Brian A.
Goswami, Ishan
Sakolish, Courtney
Luo, Yu-Syuan
Finsberg, Henrik
Edwards, Andrew G.
Miller, Evan W.
Rusyn, Ivan
Healy, Kevin E.
Heart Muscle Microphysiological System for Cardiac Liability Prediction of Repurposed COVID-19 Therapeutics
title Heart Muscle Microphysiological System for Cardiac Liability Prediction of Repurposed COVID-19 Therapeutics
title_full Heart Muscle Microphysiological System for Cardiac Liability Prediction of Repurposed COVID-19 Therapeutics
title_fullStr Heart Muscle Microphysiological System for Cardiac Liability Prediction of Repurposed COVID-19 Therapeutics
title_full_unstemmed Heart Muscle Microphysiological System for Cardiac Liability Prediction of Repurposed COVID-19 Therapeutics
title_short Heart Muscle Microphysiological System for Cardiac Liability Prediction of Repurposed COVID-19 Therapeutics
title_sort heart muscle microphysiological system for cardiac liability prediction of repurposed covid-19 therapeutics
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378272/
https://www.ncbi.nlm.nih.gov/pubmed/34421592
http://dx.doi.org/10.3389/fphar.2021.684252
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