iPS cells can help speed traditional drug development

by Paul Krzyzanowski

Imagine that you've just discovered a novel drug that potentially solves a medical problem, one that accelerates wound healing in skin or can reduce the size of cancerous tumors. You can show the effects beautifully in your model tissue culture system and mice obviously respond to the treatment. You decide to call your technology transfer office and at the very last digit, you hesitate, and wonder whether the drug will show any adverse reactions in humans; one side effect can render it useless.

The likelihood of this scenario is quite high; an estimated 75% of drug toxicity problems are not detected until reaching at least preclinical stages of drug development, and only after large amounts of time, funds, and heartache have already been expended. The need for in vitro systems to test for human side effects is clear.

Both human embryonic stem cells (hES) and induced pluriplotent stem (iPS) cells can be coaxed to generate differentiated cells analogous to those in the human body. The Stem Cell Network's Mick Bhatia leads a recently awarded Ontario Government grant intended to identify novel compounds that can promote differentiation of pluripotent cells into different lineages. This work complements that of several other Ontario groups that are developing methods to create pancreatic islets, lung epithelial cells, cardiomyocytes (heart muscle cells), blood and endothelial cells, neural cells and retinal cells.

Two major goals of the project are to identify drugs promoting endogenous tissue repair and to develop tools to generate replacement tissues. However, differentiated cells that behave like their endogenous counterparts (both stem cell or otherwise) are also of use for traditional pharmaceutical development. Using derivative cells in toxicology screens can reveal higher order compound effects at cell or tissue levels instead of simply flagging drugs as being generally cytotoxic or non-toxic. So, the question of whether a potential drug compound inadvertently stops insulin secretion from pancreatic cells or disturbs cardiac rhythms can partially be answered in advance.

The benefits of using hES and iPS cells for this kind of screening have been noted by most of the larger industrial research companies, and many are pursuing either development of stem cell-based screening systems for their own research programs or for productization of screening technology. In 2006, Novocell (now ViaCyte) demonstrated conversion of hES into insulin-producing cells and in 2008 partnered with Pfizer in a drug discovery collaboration using this system. In the same year, GlaxoSmithKline partnered with the Harvard Stem Cell Institute to develop various stem cell-based screening technologies. The following year, Geron and GE Healthcare entered a deal to commercialize hES derived cellular assay products, and soon thereafter Cellartis and AstraZeneca extended their previous collaboration to continue developing hES derived hepatocytes (liver cells) and cardiomyocytes, specifically for developing products for compound screening, drug metabolism studies, and safety assessments.

These developments in toxicology screening suggests that in the not-too-distant future, broad based side-effect assays will become mandatory at earlier stages of pharmaceutical development, possibly prior to any interest being expressed by initial investors. Looking further forward, if conducting stem cell based toxicology screens becomes commonplace, this data might even be required to support claims in basic research publications.