publication date: Oct 19, 2011
|
author/source: Roche Diagnostics
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chronotropic/ionotropic agents, hERG trafficking inhibitors and drugs withdrawn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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States, is a wholly owned member of the Roche
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