New cell-based system can screen drug candidates for cardiac toxicity long before they leave lab

Dec 17, 2012

A new stem cell-derived system for screening experimental drugs for cardiotoxicity could identify dangerous side effects early in the development process, thereby potentially saving time, lives and money, according to Evan F. Cromwell, PhD, of Molecular Devices, LLC, Sunnyvale, CA, in a presentation at the American Society for Cell Biology's Annual Meeting, Dec 17 in San Francisco.

Vioxx is probably the most notorious example of a removed from the market after because of adverse cardiac side effects, Dr. Cromwell explained, but it was not the only drug to fail because of unexpected negative effects on the heart.

Cardiotoxicity remains one of the primary reasons wash out in preclinical or even full clinical trials, he said. There is often a huge cost for these failures, both to the whose long-term investments can be wiped out in a single study and to consumers who face the risk of unintended harm.

Currently cardiotoxicity is detected using electrophysiology-based assays for interactions of compounds with potassium ion channels. However, available assays are not effective at assessing potential adverse interactions with other biochemical or contractile processes.

The need for better cardiotoxicity assays more predictive of myocardial performance led Dr. Cromwell, Oksana Sirenko, PhD, and colleagues at the California biotech, , to develop an in vitro system that employs stem cell-derived cardiomyocytes to screen for potential adverse cardiac effects.

Stem cell-derived cardiomyocytes are especially suitable for an in vitro system, Dr. Cromwell explains, because they express ion channels vital for the cardiomyocytes' function and demonstrate spontaneous mechanical and similar to that of native . When these cultured cardiomyocytes form a confluent layer and reach sufficient maturity, they begin to contract spontaneously. The team then employs a fast kinetic fluorescence imaging method to monitor fluctuations in intracellular calcium ion (Ca2+) levels during contractions. This provides a direct assessment of Ca2+ handling with surrogate assessments of electrophysiological activity in the muscle cell membrane and beat rate.

Phenotypic deviations from normal contractions that can be measured in the improved assay include beat rate, peak width and pattern irregularities. This multiparametric characterization of a compound's perturbation of cardiomyocyte contractions can also yield insights into mechanisms of action (MOA).

Dr. Cromwell reports, "We have characterized numerous pharmacological compounds and detected concentration-dependent modulation of beating rate and atypical patterns consistent with their MOA." This assay shows great promise to exclude preclinical candidates that have cardiotoxicity or other cardio safety issues, according to Dr. Cromwell.

Explore further: Micro fingers for arranging single cells

More information: "Predictive assays for high throughput assessment of cardiac toxicity and drug safety," Sunday, Dec.16, 2012, 2- 3:30 pm, Session: New Technologies for Cell Biology I, presentation: 938, poster: B1496

Related Stories

The birth of new cardiac cells

Dec 05, 2012

Recent research has shown that there are new cells that develop in the heart, but how these cardiac cells are born and how frequently they are generated remains unclear. In new research from Brigham and Women's Hospital (BWH), ...

Recommended for you

Micro fingers for arranging single cells

Apr 24, 2015

Functional analysis of a cell, which is the fundamental unit of life, is important for gaining new insights into medical and pharmaceutical fields. For efficiently studying cell functions, it is essential ...

Detailed structure of human ribosome revealed

Apr 24, 2015

A team at the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC - CNRS/Université de Strasbourg/Inserm) has evidenced, at the atomic scale, the three-dimensional structure of the complete ...

How to kill a protein

Apr 24, 2015

For decades scientists have been looking closely at how our cells make proteins. But the inverse is equally important: how cells kill them.

How RNA machinery navigates our genomic obstacle course

Apr 24, 2015

Once upon a time, scientists thought RNA polymerase—the molecule that kicks off protein synthesis by transcribing DNA into RNA—worked like a wind-up toy: Set it down at a start site in our DNA and it ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.