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.

Many prospective new drugs fail in clinical trials because of toxicity or because of poor uptake, distribution or elimination of the active compound in the human body. Much of the efficacy and safety of a drug will depend on how that drug is metabolized into an active or inactive form, and on the toxic metabolites that might be generated in the process. Since hESC-derived cells have the same attributes as their normal counterparts in the body, they could be used to predict many pharmacological characteristics of a drug.

Hepatocytes, the major cells of the liver, metabolize most compounds and therefore can be used to predict the metabolism or toxicity of a drug compound. Currently, rat and mouse metabolism models only approximate human metabolism. The development of several drugs has been terminated late in human clinical trials because rodent systems utilized early in the development process failed to predict that the drug would be toxic to humans. Human hepatocyte cell lines available today do not have the same attributes as their normal counterparts in the body and must be transformed in order to maintain their proliferative capacity in culture. Access to fresh primary human liver tissue for use in toxicity studies is very limited and substantial variability can be observed depending on the individual donor, the time and process of collection and the culture conditions for the experiments.

The understanding of whether a drug candidate will interrupt normal function of heart muscle cells - cardiomyocytes - is also a key step in drug development. As with hepatocytes, transformed cell lines are of only limited use for cardiac function tests; access to primary human heart tissue is very limited; and animal models are not fully reliable predictors of human responses.

Derivation of specific, standardized functional cell types from hESCs - in particular, hepatocytes and cardiomyocytes - could provide a reliable supply of cells to perform metabolism, biodistribution and toxicity testing of drug development candidates. We believe that an unlimited supply of hESC-derived cells which retain normal cellular functions could address bottlenecks in new drug research and accelerate the drug development process.

In June 2009, we entered into a global exclusive license and alliance agreement with GE Healthcare to develop and commercialize cellular assay products derived from hESCs for use in drug discovery, development and toxicity screening.