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Comprehensive Cardiac Safety Assessment using hiPS-cardiomyocytes (Consortium for Safety Assessment using Human iPS
Kiyoshi Takasuna1, Katsuyuki Kazusa2, Tomohiro Hayakawa2
1Consortium for Safety Assessment using Human iPS Cells (CSAHi), Heart Team, Japan.
Insights
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) show promise for predicting drug-induced cardiotoxicity, outperforming traditional assays but requiring careful consideration of their functional immaturity for comprehensive cardiac safety assessment.
Area of Science:
- Cardiovascular toxicology
- Stem cell biology
- Drug safety evaluation
Background:
- Current cardiac safety assays (hERG, APD, QT) have limitations in predicting drug-induced Torsades de Pointes and other cardiotoxicities.
- Growing concerns exist regarding mechanism-based arrhythmias and cardiac structural/contractile liabilities.
- The Consortium for Safety Assessment using Human iPS cells (CSAHi) was established to explore human iPS/ES cell-derived cardiomyocytes for drug safety.
Purpose of the Study:
- To verify the application of human iPS/ES cell-derived cardiomyocytes for comprehensive drug safety evaluation.
- To assess the strengths and weaknesses of various platforms for predicting diverse cardiotoxicities.
- To compare the predictive relevance of hiPSC-CMs with existing cardiac safety assays.
Main Methods:
- Utilized human iPS/ES cell-derived cardiomyocytes (hiPSC-CMs) in advanced platforms.
- Employed Multi-Electrode Array (MEA), cellular impedance, Motion Field Imaging (MFI), and Ca transient optical imaging.
- Focused on comprehensive screening strategies to predict a range of cardiotoxicities.
Main Results:
- hiPSC-CMs in advanced platforms detected human-relevant pharmacological responses, surpassing traditional hERG, APD, and Langendorff assays.
- MEA, impedance, MFI, and Ca transient assays offer paradigm shifts for predicting QT risk, arrhythmia, and contractile dysfunction.
- Discordances, including false positives and issues with inotropic/chronotropic activity, were observed, potentially due to hiPSC-CM immaturity.
Conclusions:
- hiPSC-CMs represent a significant advancement for predicting drug-induced cardiotoxicity and arrhythmia.
- Platforms utilizing hiPSC-CMs provide a more comprehensive assessment than current standard assays.
- Careful consideration of hiPSC-CM functional immaturity is crucial for optimal cardiac safety assessment using these novel platforms.
Abstract:
Current cardiac safety assessment platforms (in vitro hERG-centric, APD, and/or in vivo animal QT assays) are not fully predictive of drug-induced Torsades de Pointes (TdP) and do not address other mechanism-based arrhythmia, including ventricular tachycardia or ventricular fibrillation, or cardiac safety liabilities such as contractile and structural cardiotoxicity which are another growing safety concerns. We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi; http://csahi.org/en/) in 2013, based on the Japan Pharmaceutical Manufacturers Association (JPMA), to verify the application of human iPS/ES cell-derived cardiomyocytes for drug safety evaluation. The CSAHi HEART team focused on comprehensive screening strategies to predict a diverse range of cardiotoxicities using recently introduced platforms such as the Multi-Electrode Array (MEA), cellular impedance, Motion Field Imaging (MFI), and optical imaging of Ca transient to identify strengths and weaknesses of each platform. Our study showed that hiPS-CMs used in these platforms could detect pharmacological responses that were more relevant to humans compared to existing hERG, APD, or Langendorff (MAPD/contraction) assays. Further, MEA and other methods such as impedance, MFI, and Ca transient assays provided paradigm changes of platforms for predicting drug-induced QT risk and/or arrhythmia or contractile dysfunctions. In contrast, since discordances such as overestimation (false positive) of arrhythmogenicity, oversight, or opposite conclusions in positive inotropic and negative chronotropic activities to some compounds were also confirmed, possibly due to their functional immaturity of hiPS-CMs, hiPS-CMs should be used in these platforms for cardiac safety assessment based upon their advantages and disadvantages.
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