With an estimated 90% of lead candidates from in vitro screens ending up as also-rans—despite the spiraling costs of development—new ways of eliminating these candidates earlier in the drug discovery process need to be developed. A major theme running through Visiongain’s recent London-based “Cell Based Assays” conference is that while current tests are good at picking up blatant red flags such as carcinogenesis and necrosis, they can be nearly colorblind to the shades of pink represented by heart arrhythmias and the accumulation of toxic metabolites, for example.
“The holy grail of early-stage drug discovery is the subtleties in and around toxicity that really kills programs—it’s not overt cell death,” noted Quin Wills, CSO and co-founder of SimuGen.
The screens for more subtle toxicities—where they exist—tend to be more time- and labor-intensive, and are often relegated to use on later-stage candidates in which substantial resources have already been invested. “In pharma there is a great desire to move to assays using primary cultured cells farther upstream in screening cascades,” said Steven Shamah, director of cell biology for SRU Biosystems. Thus, there is a need for high(er)-throughput cell-based methods that can say more than just that the cell is dead.
Billions and Billions of Cells
Sometimes the bottleneck in cell-based screening is the availability of the high-quality cells themselves. “Even when pharma does have the opportunity to use human primary cells, they end up with cells that are of highly variable composition, quality, from different donors at different ages, with different underlying morbidity, environmental influences, postmortem intervals, and a number of variables that they can’t control,” pointed out Stephen Minger, GE Healthcare’s global director of R&D for cell technologies.
To address this issue, GE Healthcare acquired the rights to develop Geron’s (www.geron.com) human embryonic stem (HES) cells for the nonclinical research market. HES cells are highly stable and can be grown to unlimited numbers in culture. “They represent a tremendously valuable source of cells where you can provide a consistent quality of cells with a consistent genetic background, week-in, week-out,” Minger says, “that could, in principle, give rise to every type that pharma might want to use for their safety studies or even in primary drug discovery.”
Minger and his team differentiate industrial-scale quantities of HES cells into highly functional populations of human cardiomyocytes, which have been characterized developmentally, morphologically, biochemically, and functionally, and have been validated both internally and externally. The cells were screened against large panels of compounds that are known to interfere with action potentials, and were found to be equal to or better than current FDA-mandated safety tests. “In some cases,” he added, “they’re predictive when the standard animal tests are not in picking out long QT [delayed repolarization].”
GE Healthcare is developing a range of assays that, when combined with their capabilities in high-content imaging, can look at both the population and individual cell level for compounds that interfere with both electrophysiological properties and with subcellular organelles like the mitochondria and membrane integrity. Ultimately, they are trying to develop a whole range of cell types—HES-derived hepatocytes are already in the pipeline—with broad genetic diversity gained from utilizing cells from national banks. “Now, all of a sudden, you almost have a Phase I in a dish.”