Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative

Takasuna, Kiyoshi; Asakura, Kiyoshi; Araki, Seiichi; Ando, Hiroyuki; Kazusa, Katsuyuki; Kitaguchi, Takashi; Kunimatsu, Takeshi; Suzuki, Shinobu; Miyamoto, Naokazu

doi:10.1016/j.vascn.2016.09.004

Cited by 53 publications

(30 citation statements)

References 64 publications

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“…[10][11][12][13][14][15] Additionally, human stem cell-derived in vitro models have also made considerable inroads into routine testing for cardiovascular liabilities. 16 The ability to generate cells from individual donors that replicate patient-specific congenital 17 and disease-specific 18 phenotypes is an exciting development that promises to enable personalized drug safety evaluation, an approach that has recently been tested in dozens of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes. 18,19 Thus, iPSC-based cardiomyocytes are known to be useful in identifying both congenital and drug-induced cardiotoxicity hazards, 17,20,21 particularly at the individual patient level.…”

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confidence: 99%

Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration‐QTc Relationships

Blanchette

Grimm

Dalaijamts

et al. 2018

Clin Pharma and Therapeutics

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“Thorough QT/corrected QT (QTc)” (TQT) studies are cornerstones of clinical cardiovascular safety assessment. However, TQT studies are resource intensive, and preclinical models predictive of the threshold of regulatory concern are lacking. We hypothesized that an in vitro model using induced pluripotent stem cell (iPSC)‐derived cardiomyocytes from a diverse sample of human subjects can serve as a “TQT study in a dish.” For 10 positive and 3 negative control drugs, in vitro concentration‐QTc, computed using a population Bayesian model, accurately predicted known in vivo concentration‐QTc. Moreover, predictions of the percent confidence that the regulatory threshold of 10 ms QTc prolongation would be breached were also consistent with in vivo evidence. This “TQT study in a dish,” consisting of a population‐based iPSC‐derived cardiomyocyte model and Bayesian concentration‐QTc modeling, has several advantages over existing in vitro platforms, including higher throughput, lower cost, and the ability to accurately predict the in vivo concentration range below the threshold of regulatory concern.

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mentioning

confidence: 99%

Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration‐QTc Relationships

Blanchette

Grimm

Dalaijamts

et al. 2018

Clin Pharma and Therapeutics

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“…Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) have been applied to cardiac safety assessment in the non-clinical stages of drug development. Human iPS-CMs express fundamental cardiac ion channels and can generate action potential (Honda et al, 2011;Ma et al, 2011), which makes them a useful nonclinical tool for assessing the proarrhythmic potential of drugs (Ando et al, 2017;Kitaguchi et al, 2017;Takasuna et al, 2017;Nozaki et al, 2016). Moreover, the hiPS-CMs can be formed into a two-dimensional sheet that is electrically coupled and contracts synchronously as a functional cluster, which are properties that allow us to evaluate cardiac contraction and conduction (Izumi-Nakaseko et al, 2017;Pointon et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Conduction and contraction properties of human iPS cell-derived cardiomyocytes: analysis by motion field imaging compared with the guinea-pig isolated heart model

Isobe

Honda

Komatsu³

et al. 2018

J. Toxicol. Sci.

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We used motion field imaging to characterize the conduction and contraction of a sheet of cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs). A hiPS-CMs sheet of 2.8 mm × 2.8 mm allowed us to simultaneously measure the conduction and the contraction properties in the same cells. Pharmacological responses in the hiPS-CMs of four typical cardiac functional modulators, Na channel blocker (lidocaine), Ca channel blocker (diltiazem), gap-junction inhibitor (carbenoxolone), and β-adrenergic stimulator (isoproterenol), were investigated, and the results were compared to those found using the isolated guinea-pig heart model perfused by the Langendorff method. The conduction speed of excitation waves in hiPS-CMs was decreased by lidocaine, diltiazem, and carbenoxolone, and increased by isoproterenol, and these results were in accordance with the changes in the conduction parameters of electrocardiogram (QRS duration, PR interval, and P duration) in the Langendorff guinea-pig heart model. The maximum speeds for contraction and relaxation, which respectively represent the contraction and relaxation kinetics of hiPS-CMs, were decreased by lidocaine and diltiazem, and increased by isoproterenol. These results also corresponded to alterations in the contractile and relaxation parameters found by measuring left ventricular pressure (LVdP/dt and LVdP/dt) in the Langendorff guinea-pig heart model. From these lines of evidence, it was suggested that hiPS-CMs enable us to evaluate the cardiac toxicities associated with conduction disturbance or contractile dysfunction, and thereby would be useful as an integrated assessment of cardiac function.

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“…72 Because it is unclear which aspects of network firing activity (i.e., action potential width, bursting, mean activity, interspike statistics, oscillations) are most important for cognitive function, traditional classifiers or deep-learning approaches could be used to predict what property of simulated activity is associated with human cognition. A similar approach has been followed in the Comprehensive in Vitro ProArrythmia Assay (CiPA) 73 or Consortium for Safety Assessment using hiPSCs, 74 with the objective to develop a predictive model for cardiac safety based on electrophysiological data with human iPSC differentiated into cardiomyocytes.…”

Section: Use Of Qsp In Phenotypical Drug Discoverymentioning

confidence: 99%

Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges

Geerts

Wikswo

Graaf³

et al. 2019

CPT Pharmacom & Syst Pharma

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The substantial progress made in the basic sciences of the brain has yet to be adequately translated to successful clinical therapeutics to treat central nervous system (CNS) diseases. Possible explanations include the lack of quantitative and validated biomarkers, the subjective nature of many clinical endpoints, and complex pharmacokinetic/pharmacodynamic relationships, but also the possibility that highly selective drugs in the CNS do not reflect the complex interactions of different brain circuits. Although computational systems pharmacology modeling designed to capture essential components of complex biological systems has been increasingly accepted in pharmaceutical research and development for oncology, inflammation, and metabolic disorders, the uptake in the CNS field has been very modest. In this article, a cross-disciplinary group with representatives from academia, pharma, regulatory, and funding agencies make the case that the identification and exploitation of CNS therapeutic targets for drug discovery and development can benefit greatly from a system and network approach that can span the gap between molecular pathways and the neuronal circuits that ultimately regulate brain activity and behavior.

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Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative

Cited by 53 publications

References 64 publications

Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration‐QTc Relationships

Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration‐QTc Relationships

Conduction and contraction properties of human iPS cell-derived cardiomyocytes: analysis by motion field imaging compared with the guinea-pig isolated heart model

Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges

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