Cardiac toxicity is a major concern in drug development and it is imperative that clinical candidates are thoroughly tested for adverse effects earlier in the drug discovery process. In a new research study (1), Abassi et al. investigated the use of Roche-s (SIX: RO, ROG; OTCQX: RHHBY) xCELLigence Cardio Instrument in conjunction with embryonic stem cell derived cardiomyocytes (ESCC) for assessment of compound risk in the drug discovery process. The xCELLigence Cardio Instrument is an impedance-based microelectronic detection system that monitors the beating function of cardiomyocytes.
Researchers Abassi et al. used the system to carry out dose-response profiling of over 60 pharmaceutical compounds, including ion channel modulators, chronotropic/ionotropic agents, hERG trafficking inhibitors and drugs withdrawn from the market due to TdP arrhythmia. The system proved to be sensitive and quantitative for detecting modulators of cardiac function, including compounds missed by electrophysiology. Key finding was that pro-arrhythmic compounds produced distinct signature profiles that reflect arrhythmia. The time series data can be used to identify compounds which induce arrhythmia by complex mechanisms such as hERG trafficking inhibition. Furthermore, the time resolution allows for assessment of compounds which simultaneously impact both beating and viability of cardiomyocytes.
Microelectronic monitoring of stem cell derived cardiomyocyte beating provides a high throughput, quantitative and predictive assay system that can be used for assessment of cardiac liability earlier in the drug discovery process. The convergence of stem cell technology with microelectronic monitoring should facilitate cardiac safety assessment.
“The combination of the xCELLigence Cardio system with ESC cardiomyocytes is an assay system that could aid in basic research and importantly, can be used for screening of compound toxicity and risk assessment,” comments Ruedi Stoffel, Life Cycle Leader of Cellular Analysis at Roche Applied Science. “Furthermore, the system can be used with mouse ESCC, as well as other beating cardiomyocytes such as those derived from human induced-pluripotent stem cell, human embryonic stem cell and primary cardiomyocytes isolated from neonatal rats, thus further expanding the capabilities of the system.”
The last two decades have witnessed the withdrawal or issuance of safety warning due to cardiotoxicity for a number of blockbuster drugs from a wide variety of chemical and pharmacological classes including macrolide antibiotics, antihistamines, psychotropic agents, antifungals and gastrointestinal prokinetics. One-third of all drugs withdrawn for the period of 1990-2006 have been directly due to cardiotoxicity. One of the main challenges in preclinical cardio-safety assessment has been the lack of a predictive and biologically relevant model system available in sufficiently high quantities to be used for screening of cardiotoxic and pro-arrhythmic drugs, especially during the hit to lead or lead optimization stage.
(1) Abassi YA, Xi B, Li N, Ouyang W, Seiler A, Watzele M, Kettenhofen R, Bohlen H, Ehlich A, Kolossov E, Wang X, Xu X. (2011) Br J Pharmacol. doi: 10.1111/j.1476-5381.2011.01623.x. [Epub ahead of print]
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