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Human iPSC-based cardiac microphysiological system for drug screening applications.

Mathur A, Loskill P, Shao K, Huebsch N, Hong S, Marcus SG, Marks N, Mandegar M, Conklin BR, Lee LP, Healy KE - Sci Rep (2015)

Bottom Line: Drug discovery and development are hampered by high failure rates attributed to the reliance on non-human animal models employed during safety and efficacy testing.Pharmacological studies using the cardiac MPS show half maximal inhibitory/effective concentration values (IC₅₀/EC₅₀) that are more consistent with the data on tissue scale references compared to cellular scale studies.We anticipate the widespread adoption of MPSs for drug screening and disease modeling.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA [2] Department of Materials Science and Engineering, University of California at Berkeley, Berkeley, California 94720, USA.

ABSTRACT
Drug discovery and development are hampered by high failure rates attributed to the reliance on non-human animal models employed during safety and efficacy testing. A fundamental problem in this inefficient process is that non-human animal models cannot adequately represent human biology. Thus, there is an urgent need for high-content in vitro systems that can better predict drug-induced toxicity. Systems that predict cardiotoxicity are of uppermost significance, as approximately one third of safety-based pharmaceutical withdrawals are due to cardiotoxicty. Here, we present a cardiac microphysiological system (MPS) with the attributes required for an ideal in vitro system to predict cardiotoxicity: i) cells with a human genetic background; ii) physiologically relevant tissue structure (e.g. aligned cells); iii) computationally predictable perfusion mimicking human vasculature; and, iv) multiple modes of analysis (e.g. biological, electrophysiological, and physiological). Our MPS is able to keep human induced pluripotent stem cell derived cardiac tissue viable and functional over multiple weeks. Pharmacological studies using the cardiac MPS show half maximal inhibitory/effective concentration values (IC₅₀/EC₅₀) that are more consistent with the data on tissue scale references compared to cellular scale studies. We anticipate the widespread adoption of MPSs for drug screening and disease modeling.

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Dose-dependent study of different drugs on the cardiac MPS.(a) Isoproterenol causes a dose-dependent increase in beat rate and an EC50 value of 315 nM. (b) Verapamil induces a dose-dependent decrease in beat rate with incidences of arrhythmia observed at higher concentrations and an IC50 value of 950 nM. (c, d) Metoprolol and E4031 induce a dose-dependent decrease in beat rate with IC50 values of 2.3 μM and 1.9 nM respectively. Grey areas indicate unbound estimated therapeutic plasma concentration in patients (ETPC)2835. Note there is not an ETPC highlighted for E-4031 because the drug is used solely for research purposes and only one clinical trial was conducted. Error bars indicate mean ± S.D.
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f4: Dose-dependent study of different drugs on the cardiac MPS.(a) Isoproterenol causes a dose-dependent increase in beat rate and an EC50 value of 315 nM. (b) Verapamil induces a dose-dependent decrease in beat rate with incidences of arrhythmia observed at higher concentrations and an IC50 value of 950 nM. (c, d) Metoprolol and E4031 induce a dose-dependent decrease in beat rate with IC50 values of 2.3 μM and 1.9 nM respectively. Grey areas indicate unbound estimated therapeutic plasma concentration in patients (ETPC)2835. Note there is not an ETPC highlighted for E-4031 because the drug is used solely for research purposes and only one clinical trial was conducted. Error bars indicate mean ± S.D.

Mentions: Our results demonstrate good concordance with clinical observations. Administration of Isoproterenol increased the beat rate with an EC50 of 315 nM (Fig. 4a and Supplementary Movie 5 and 6). This value from the MPS is significantly higher than the reported values for 2D hiPSC-CMs24, and is comparable to contractility measurements obtained in acute experiments performed on human ventricular heart tissue slices25. Thus, our cardiac MPS provides data that is consistent with data obtained on adult human tissues, which are significantly limited in quantity and more likely to vary in genetic background2627.


Human iPSC-based cardiac microphysiological system for drug screening applications.

Mathur A, Loskill P, Shao K, Huebsch N, Hong S, Marcus SG, Marks N, Mandegar M, Conklin BR, Lee LP, Healy KE - Sci Rep (2015)

Dose-dependent study of different drugs on the cardiac MPS.(a) Isoproterenol causes a dose-dependent increase in beat rate and an EC50 value of 315 nM. (b) Verapamil induces a dose-dependent decrease in beat rate with incidences of arrhythmia observed at higher concentrations and an IC50 value of 950 nM. (c, d) Metoprolol and E4031 induce a dose-dependent decrease in beat rate with IC50 values of 2.3 μM and 1.9 nM respectively. Grey areas indicate unbound estimated therapeutic plasma concentration in patients (ETPC)2835. Note there is not an ETPC highlighted for E-4031 because the drug is used solely for research purposes and only one clinical trial was conducted. Error bars indicate mean ± S.D.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352848&req=5

f4: Dose-dependent study of different drugs on the cardiac MPS.(a) Isoproterenol causes a dose-dependent increase in beat rate and an EC50 value of 315 nM. (b) Verapamil induces a dose-dependent decrease in beat rate with incidences of arrhythmia observed at higher concentrations and an IC50 value of 950 nM. (c, d) Metoprolol and E4031 induce a dose-dependent decrease in beat rate with IC50 values of 2.3 μM and 1.9 nM respectively. Grey areas indicate unbound estimated therapeutic plasma concentration in patients (ETPC)2835. Note there is not an ETPC highlighted for E-4031 because the drug is used solely for research purposes and only one clinical trial was conducted. Error bars indicate mean ± S.D.
Mentions: Our results demonstrate good concordance with clinical observations. Administration of Isoproterenol increased the beat rate with an EC50 of 315 nM (Fig. 4a and Supplementary Movie 5 and 6). This value from the MPS is significantly higher than the reported values for 2D hiPSC-CMs24, and is comparable to contractility measurements obtained in acute experiments performed on human ventricular heart tissue slices25. Thus, our cardiac MPS provides data that is consistent with data obtained on adult human tissues, which are significantly limited in quantity and more likely to vary in genetic background2627.

Bottom Line: Drug discovery and development are hampered by high failure rates attributed to the reliance on non-human animal models employed during safety and efficacy testing.Pharmacological studies using the cardiac MPS show half maximal inhibitory/effective concentration values (IC₅₀/EC₅₀) that are more consistent with the data on tissue scale references compared to cellular scale studies.We anticipate the widespread adoption of MPSs for drug screening and disease modeling.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA [2] Department of Materials Science and Engineering, University of California at Berkeley, Berkeley, California 94720, USA.

ABSTRACT
Drug discovery and development are hampered by high failure rates attributed to the reliance on non-human animal models employed during safety and efficacy testing. A fundamental problem in this inefficient process is that non-human animal models cannot adequately represent human biology. Thus, there is an urgent need for high-content in vitro systems that can better predict drug-induced toxicity. Systems that predict cardiotoxicity are of uppermost significance, as approximately one third of safety-based pharmaceutical withdrawals are due to cardiotoxicty. Here, we present a cardiac microphysiological system (MPS) with the attributes required for an ideal in vitro system to predict cardiotoxicity: i) cells with a human genetic background; ii) physiologically relevant tissue structure (e.g. aligned cells); iii) computationally predictable perfusion mimicking human vasculature; and, iv) multiple modes of analysis (e.g. biological, electrophysiological, and physiological). Our MPS is able to keep human induced pluripotent stem cell derived cardiac tissue viable and functional over multiple weeks. Pharmacological studies using the cardiac MPS show half maximal inhibitory/effective concentration values (IC₅₀/EC₅₀) that are more consistent with the data on tissue scale references compared to cellular scale studies. We anticipate the widespread adoption of MPSs for drug screening and disease modeling.

Show MeSH
Related in: MedlinePlus