Cardiomyocytes from Embryonic Cells
Cardiomyocytes have also been the focus of development at GE Healthcare, whose scientists have been exploring the use of the cells in drug discovery, drug development, and toxicology applications. Robert Graves, Ph.D., senior applications scientist, described toxicology testing of the company’s embryonic stem cell-derived cardiomyocytes.
Dr. Graves said that the currently used tests for cardiotoxicity rely on animal cell models, ex vivo tests, or animal tissues. “It’s well-known that there are problems with the predictivity of animal cells. At times it’s only 50 percent. You might as well toss a coin.”
Cardiomyocytes derived from human embryonic cells would be accurately predictive, as well as being a renewable resource producing a consistent supply of cells that can be used across a range of platforms, he contended.
Cardiotoxicity occurs through a number of mechanisms that interfere with heart function, such as blocking the electrophysiology, or the contractility, of the heart. Drugs can also be toxic to the mitochondria, which the heart requires in large quantities to supply its energy needs.
GE’s system makes use of high-content analysis through imaging. For example, changes in the size and shape of the mitochondria can indicate toxicity affecting these organelles.
Four-color imaging assays extract as many as 20 parameters from the assays. The process yields the same kind of toxicity data as a conventional assay, but it also has the potential to indicate the mechanism of toxicity.
In a collaborative study with Genentech, GE used its cardiomyocytes in conjunction with high-content analysis to look at specific sets of compounds. Data from the first set of 26 showed excellent correlation between assay and historical data, said Dr. Graves.
In a blinded analysis, GE scientists graded the compounds according to the assay parameters collected. Compounds recorded in the literature as having cardiotoxicity were in a group scored with the highest toxicity classification.
“We believe this was an indication that this cardiomyocyte-based assay was going to be more predictive than standard cell-based assays,” said Dr. Graves. “There’s a need for a sea change in toxicology, to take a more holistic approach, and not focus on single issues like hERG assays for cardiotoxicology.”