Cardiotoxicity, which results when drugs adversely affect the heart, explains why roughly one third of new pharmaceuticals are withdrawn from the market and why many compounds fail in late-stage clinical testing. To address this, a research team led by Kyle Kolaja, PhD, in the Department of Early and Investigative Safety, Nonclinical Safety, at Roche (SIX: RO, ROG; OTCQX: RHHBY), in Nutley, New Jersey, USA, reported in the June issue of Toxicological Sciences the identification of a model that more accurately detects drug-induced cardiac abnormalities. The novelty of this work is that it integrates two emerging technologies, stem cell derived tissues and impedance-based real-time cell monitoring.
Using the Roche xCELLigence Cardio Instrument, they discovered that changes in cell impedance of stem cell derived cardiomyocytes treated with different compounds were comparable to results from more established low throughput in vitro technology (e.g., measuring electric field potentials via microelectrode arrays).
The xCELLigence Cardio System uses proprietary software and E-Plates 96 to measure electronic cell impedance using sensor electrodes. Computer-controlled signal generation, automatic frequency scanning, and a measurement rate of 12.9 milliseconds per 96-well plate, enable high-speed precise detection of changes in cardiac cell behavior.
Kolaja and his team calculated an index of drug-induced arrhythmias based on the cytotoxic effects of the drugs tested, enabling the calculation of a given drug's "predicted proarrhythmic score" (PPS), a measure of potential cardiotoxicity. According to Kolaja, "We found that measuring impedance provides a rapid means of interrogating a drug's deleterious effect on human cardiac function, and not only helps us in early discovery safety assessment, but opens up new opportunities for investigating, cardiac biology, cell signaling and disease pathogenesis. More importantly, human pluripotent stem cell-based predictive toxicity assays will help researchers predict potential safety issues of promising drug candidates early in the development process and provide insight into the mechanisms of drug-induced organ toxicity."
The authors of this study raise the possibility that this new model system may be amenable to high throughput approaches that go beyond hERG mediated-QT prolongation and delve directly in the functional interplay of the many ion channels used by human heart muscle to affect normal function.
Using the Roche xCELLigence Cardio Instrument, they discovered that changes in cell impedance of stem cell derived cardiomyocytes treated with different compounds were comparable to results from more established low throughput in vitro technology (e.g., measuring electric field potentials via microelectrode arrays).
The xCELLigence Cardio System uses proprietary software and E-Plates 96 to measure electronic cell impedance using sensor electrodes. Computer-controlled signal generation, automatic frequency scanning, and a measurement rate of 12.9 milliseconds per 96-well plate, enable high-speed precise detection of changes in cardiac cell behavior.
Kolaja and his team calculated an index of drug-induced arrhythmias based on the cytotoxic effects of the drugs tested, enabling the calculation of a given drug's "predicted proarrhythmic score" (PPS), a measure of potential cardiotoxicity. According to Kolaja, "We found that measuring impedance provides a rapid means of interrogating a drug's deleterious effect on human cardiac function, and not only helps us in early discovery safety assessment, but opens up new opportunities for investigating, cardiac biology, cell signaling and disease pathogenesis. More importantly, human pluripotent stem cell-based predictive toxicity assays will help researchers predict potential safety issues of promising drug candidates early in the development process and provide insight into the mechanisms of drug-induced organ toxicity."
The authors of this study raise the possibility that this new model system may be amenable to high throughput approaches that go beyond hERG mediated-QT prolongation and delve directly in the functional interplay of the many ion channels used by human heart muscle to affect normal function.
