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HiPSC-CMs from different sex and ethnic origin donors exhibit qualitatively different responses to several classes of
Haoyu Zeng1, Jixin Wang1, Holly Clouse1
1Merck & Co., Inc., Safety and Exploratory Pharmacology, West Point, PA, USA.
Insights
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) show variable responses to drug testing. Donor diversity impacts cardiac safety assessments, necessitating pre-established acceptance criteria for reliable drug liability evaluation.
Area of Science:
- Cardiovascular Pharmacology
- Stem Cell Biology
- Drug Discovery
Background:
- Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are crucial for preclinical drug safety testing.
- Assessing drug-induced cardiac liabilities requires understanding potential variability in hiPSC-CM responses.
- Donor diversity in hiPSC-CMs may influence drug response profiles.
Purpose of the Study:
- To investigate qualitative differences in hiPSC-CM responses to various pharmacological reagents based on donor origin.
- To determine if hiPSC-CMs from diverse genetic backgrounds exhibit distinct drug sensitivity.
- To evaluate the suitability of different hiPSC-CM lines for cardiac safety assessment in drug development.
Main Methods:
- Challenged six hiPSC-CM syncytia from diverse donors (sex, ethnicity) with eight classes of pharmacological reagents.
- Included hERG channel blockers (cisapride, dofetilide), calcium channel modulators, adrenergic agonists, HCN channel blockers, and sodium channel blockers.
- Focused analysis on qualitative differences (e.g., presence or absence of effect) in drug response.
Main Results:
- Female donor hiPSC-CMs showed uniform sensitivity to dofetilide and cisapride, while male donor hiPSC-CMs were less sensitive.
- One hiPSC-CM line exhibited no chronotropic effect in response to Isoproterenol.
- Two hiPSC-CM lines displayed high sensitivity to tetrodotoxin at low concentrations.
Conclusions:
- Not all hiPSC-CM lines are universally suitable for cardiac safety assessment due to variable drug responses.
- Pre-defined acceptance criteria are essential for selecting appropriate hiPSC-CMs for drug testing.
- Ensuring hiPSC-CM suitability is critical for reliable evaluation of drug candidates' cardiac liabilities in CiPA-style studies.
Abstract:
We investigated whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) created from diverse origins could have qualitatively (not just quantitatively) different responses to pharmacological reagents. Specifically, we challenged six hiPSC-CM syncytia made from a female Caucasian, a female black non-Hispanic, a female white non-Hispanic, a male Caucasian non-Hispanic, a male Asian Indian, and a male-Asian, respectively, with eight different classes of pharmacological reagents (hERG channel blocker cisapride and dofetilide, calcium channel opener FPL64176, β-adrenergic agonist Isoproterenol, HCN channel blocker Ivabradine, IKs current blocker L-000768673, sodium channel blocker tetrodotoxin, and calcium channel blocker verapamil). We focused our analysis and comparison on qualitative differences (e.g., yes or no), and, found the following: hiPSC-CMs from female donors were uniformly more sensitive to dofetilide or cisapride, whereas those from male donors of all races were less sensitive to the two typical hERG blockers; isoproterenol had no chronotropic effect at all in one line; and two lines reacted to tetrodotoxin at very low concentrations and were more sensitive to external stimulation. We conclude that not all hiPSC-CMs are suitable for drug testing in terms of cardiac safety assessment, and pre-set acceptance criteria need to be established before any hiPSC-CMs can be used in CiPA-style study to evaluate cardiac liabilities of drug candidates.
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