hESC-Derived Cells for Drug Screening and Toxicology

Three of the major hurdles of pharmaceutical drug development are: (i) identifying compounds with activity in diseased tissue; (ii) understanding the metabolism and biodistribution of the compound; and (iii) determining the potential toxic side effects of the compound. Undesirable activity of a compound being evaluated as a drug candidate in any one of these areas can impact the development and commercialization of the drug. The earlier in development that a compound is found to have undesirable characteristics, the faster these characteristics can be potentially corrected. This potentially translates into reduced costs and time in drug development, and less harmful patient exposure in clinical trials.

While Geron's focus is on the development of hESC-derived cells for therapeutic application, each of the cell types we are developing could also be useful in drug discovery applications. In June 2009, we entered into a global exclusive license and alliance agreement with GE Healthcare UK Limited (GE Healthcare) to develop and commercialize cellular assay products derived from hESCs for use in drug discovery, development and toxicity screening.

Two particularly important cell types for use in in vitro cell-based assays for metabolism studies and toxicity screening are hepatocytes (liver cells) and cardiomyocytes (heart muscle cells).

Hepatocytes are responsible for metabolizing most compounds and can therefore be used to predict how drugs are metabolized, how they might interact with each other in the body, and to what extent they may be toxic to the liver. Another key step in drug development is to understand whether or not a drug will interrupt the normal function of cardiomyocytes in the heart. Cardiotoxicity and hepatotoxicity are the principal reasons clinical trials have been halted and approved drugs have been withdrawn from market.

Currently, animal models, primary human tissue and cell lines are used to assess drug metabolism and toxicities. However, these systems have certain limitations. Animal models have an important role in drug metabolism and toxicity studies, but they are not fully reliable predictors of human responses because of basic physiological differences between species. It is not uncommon for the development of a drug to be halted during clinical trials because animal systems did not predict the drug's metabolism or toxicity in humans. A human in vitro system commonly used is fresh primary human liver tissue and cells, but access is very limited and the tissue can be variable depending on the donor or the methods used in processing or culturing the samples. Transformed human cell lines have been generated to address supply or variability, but the lines available today do not have the same attributes as their normal counterparts in the body. For example, human hepatocytes must be transformed (genetically altered) in order to maintain their proliferative capacity in culture, and cell lines used in cardiotoxicity studies are often non-cardiac cells modified to express particular ion channels and thus do not reflect the normal physiology of a cardiomyocyte.

In contrast, fully functional cells manufactured in bulk from hESCs could be a reliable, uniform and predictive new tool for pharmaceutical companies to perform in vitro metabolism, biodistribution, drug-drug interaction and toxicity testing of drug development candidates.

There is active interest in the development of predictive, robust and cost-effective in vitro assays from stem cells for drug research and development and it is expected that the pharmaceutical industry will embrace cell-based assays derived from hESCs when they become available. It has been reported that clinical safety and toxicology account for approximately 30% of drug attrition in the clinic. It is also important to highlight the health impact and possible risk to patients when toxicities are not detected early in development. The FDA has called for new and more predictive tools for early drug safety studies and may encourage widespread adoption of effective hESC-derived cellular assay products.

The first product being developed under the Geron-GE Healthcare alliance is human cardiomyocytes derived from hESCs. hESC-derived cardiomyocytes exhibit the normal electrophysiological function of human ventricular myocytes and respond appropriately when exposed to cardiac drugs, including drugs that block hERG channels. Robust sodium and calcium currents with the expected pharmacological responses are present and well-suited for screening assays. hESC-derived cardiomyocytes could, for the first time, allow the prediction of drug effects on the human heart.

Geron has been working with ChanTest, a leading provider of ion channel screening services, to confirm that hESC-derived cardiomyocytes display electrophysiological properties of normal human cardiomyocytes and contain the key voltage-gated ion channels operating in a normal cellular background.

Another cellular assay product to be developed under the Geron-GE Healthcare alliance is human hepatocytes derived from hESCs. hESC-derived hepatocytes show a number of metabolic functions of human hepatocytes, including expression of members of the cytochrome P450 family of enzymes, which are responsible for drug metabolism.