scholarly journals Assessing Drug-Induced Long QT and Proarrhythmic Risk Using Human Stem-Cell-Derived Cardiomyocytes in a Ca2+ Imaging Assay: Evaluation of 28 CiPA Compounds at Three Test Sites

2019 ◽  
Vol 170 (2) ◽  
pp. 345-356 ◽  
Author(s):  
Hua Rong Lu ◽  
Haoyu Zeng ◽  
Ralf Kettenhofen ◽  
Liang Guo ◽  
Ivan Kopljar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Microelectrode Array ◽  
Torsade De Pointes ◽  
Transient Assay ◽  
Potential Drug ◽  
Human Stem Cell ◽  
Long Qt ◽  
Drug Induced ◽  
Vitro Assay

Abstract The goal of this research consortium including Janssen, MSD, Ncardia, FNCR/LBR, and Health and Environmental Sciences Institute (HESI) was to evaluate the utility of an additional in vitro assay technology to detect potential drug-induced long QT and torsade de pointes (TdP) risk by monitoring cytosolic free Ca2+ transients in human stem-cell-derived cardiomyocytes (hSC-CMs). The potential proarrhythmic risks of the 28 comprehensive in vitro proarrhythmia assay (CiPA) drugs linked to low, intermediate, and high clinical TdP risk were evaluated in a blinded manner using Ca2+-sensitive fluorescent dye assay recorded from a kinetic plate reader system (Hamamatsu FDSS/µCell and FDSS7000) in 2D cultures of 2 commercially available hSC-CM lines (Cor.4U and CDI iCell Cardiomyocytes) at 3 different test sites. The Ca2+ transient assay, performed at the 3 sites using the 2 different hSC-CMs lines, correctly detected potential drug-induced QT prolongation among the 28 CiPA drugs and detected cellular arrhythmias-like/early afterdepolarization in 7 of 8 high TdP-risk drugs (87.5%), 6 of 11 intermediate TdP-risk drugs (54.5%), and 0 of 9 low/no TdP-risk drugs (0%). The results were comparable among the 3 sites and from 2 hSC-CM cell lines. The Ca2+ transient assay can serve as a user-friendly and higher throughput alternative to complement the microelectrode array and voltage-sensing optical action potential recording assays used in the HESI-CiPA study for in vitro assessment of drug-induced long QT and TdP risk.

Human stem cell research for potential drug-induced cardiac arrhythmias and neuronal side effects: Janssen's strategy

2017 ◽  
Vol 280 ◽  
pp. S24
Author(s):  
Hua Rong Lu ◽  
Ivan Kopljar ◽  
Kreir Mohamed ◽  
Ard Teisman ◽  
David J. Gallacher
Keyword(s):  
Stem Cell ◽  
Side Effects ◽  
Stem Cell Research ◽  
Cardiac Arrhythmias ◽  
Potential Drug ◽  
Human Stem Cell ◽  
Drug Induced

In vitro assessments of drug-induced delayed cardiotoxicity using human stem cell-derived cardiomyocytes

2020 ◽  
Vol 105 ◽  
pp. 106851
Author(s):  
Hua Rong Lu ◽  
Eddy Vlaminckx ◽  
Danny Geysken ◽  
Gabriela T. Carrasqueiro ◽  
Mohamed Kreir ◽  
...  
Keyword(s):  
Stem Cell ◽  
Human Stem Cell ◽  
Drug Induced

scholarly journals Comparison of the Simulated Response of Three in Silico Human Stem Cell-Derived Cardiomyocytes Models and in Vitro Data Under 15 Drug Actions

2021 ◽  
Vol 12 ◽  
Author(s):  
Michelangelo Paci ◽  
Jussi T. Koivumäki ◽  
Hua Rong Lu ◽  
David J. Gallacher ◽  
Elisa Passini ◽  
...  
Keyword(s):  
Experimental Data ◽  
Stem Cell ◽  
In Silico ◽  
Drug Testing ◽  
Drug Application ◽  
Human Stem Cell ◽  
Drug Induced ◽  
Drug Actions ◽  
Experimental Findings

Objectives: Improvements in human stem cell-derived cardiomyocyte (hSC-CM) technology have promoted their use for drug testing and disease investigations. Several in silico hSC-CM models have been proposed to augment interpretation of experimental findings through simulations. This work aims to assess the response of three hSC-CM in silico models (Koivumäki2018, Kernik2019, and Paci2020) to simulated drug action, and compare simulation results against in vitro data for 15 drugs.Methods: First, simulations were conducted considering 15 drugs, using a simple pore-block model and experimental data for seven ion channels. Similarities and differences were analyzed in the in silico responses of the three models to drugs, in terms of Ca2+ transient duration (CTD90) and occurrence of arrhythmic events. Then, the sensitivity of each model to different degrees of blockage of Na+ (INa), L-type Ca2+ (ICaL), and rapid delayed rectifying K+ (IKr) currents was quantified. Finally, we compared the drug-induced effects on CTD90 against the corresponding in vitro experiments.Results: The observed CTD90 changes were overall consistent among the in silico models, all three showing changes of smaller magnitudes compared to the ones measured in vitro. For example, sparfloxacin 10 µM induced +42% CTD90 prolongation in vitro, and +17% (Koivumäki2018), +6% (Kernik2019), and +9% (Paci2020) in silico. Different arrhythmic events were observed following drug application, mainly for drugs affecting IKr. Paci2020 and Kernik2019 showed only repolarization failure, while Koivumäki2018 also displayed early and delayed afterdepolarizations. The spontaneous activity was suppressed by Na+ blockers and by drugs with similar effects on ICaL and IKr in Koivumäki2018 and Paci2020, while only by strong ICaL blockers, e.g. nisoldipine, in Kernik2019. These results were confirmed by the sensitivity analysis.Conclusion: To conclude, The CTD90 changes observed in silico are qualitatively consistent with our in vitro data, although our simulations show differences in drug responses across the hSC-CM models, which could stem from variability in the experimental data used in their construction.

Could in vitro animal assays be replaced by human stem cell-based assays for drug-induced cardiac risks: Beyond QT-prolongation/CIPA?

2016 ◽  
Vol 81 ◽  
pp. 385-386
Author(s):  
Hua Rong Lu ◽  
An Hermans ◽  
Ivan Kopljar ◽  
Jutta Rohrbacher ◽  
Ard Teisman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Qt Prolongation ◽  
Human Stem Cell ◽  
Drug Induced

scholarly journals A hydrogel platform for in vitro three dimensional assembly of human stem cell-derived islet cells and endothelial cells

2019 ◽  
Vol 97 ◽  
pp. 272-280 ◽  
Author(s):  
Punn Augsornworawat ◽  
Leonardo Velazco-Cruz ◽  
Jiwon Song ◽  
Jeffrey R. Millman
Keyword(s):  
Endothelial Cells ◽  
Stem Cell ◽  
Islet Cells ◽  
Three Dimensional ◽  
Human Stem Cell

Characterization of Clonogenic Progenitors in Autologous Peripheral Blood Stem Cell Grafts: Evaluation of a Simple In Vitro Assay Suitable for Routine Clinical Use

Hematology ◽  
2003 ◽  
Vol 8 (5) ◽  
pp. 313-318 ◽  
Author(s):  
Dmitri Motorin ◽  
Anne Bakken ◽  
Jenny Foss Abrahamsen ◽  
Peter Ernst ◽  
Øystein Bruserud
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cell ◽  
In Vitro Assay ◽  
Blood Stem Cell ◽  
Clinical Use ◽  
Vitro Assay

In vitro assessing the risk of drug-induced cardiotoxicity by embryonic stem cell-based biosensor

2011 ◽  
Vol 155 (1) ◽  
pp. 214-219 ◽  
Author(s):  
Qingjun Liu ◽  
Hui Yu ◽  
Zhou Tan ◽  
Hua Cai ◽  
Weiwei Ye ◽  
...  
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Drug Induced

Current Progress in the Creation, Characterization, and Application of Human Stem Cell-derived in Vitro Neuromuscular Junction Models

2021 ◽  
Author(s):  
Eileen Lynch ◽  
Emma Peek ◽  
Megan Reilly ◽  
Claire FitzGibbons ◽  
Samantha Robertson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Neuromuscular Junction ◽  
Human Stem Cell ◽  
The Creation
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