In the small molecule drug discovery field, the “bottom-up” approach, which is based on structural considerations of known targets, has not been as fruitful as was once promised; in 2004, only 36 new drugs were approved by the United States Food and Drug Administration, and 24 in 2005. Until recently, transformed human cell lines were used as the major cellular platform for pharmaceutical drug screening, sometimes referred to as the “top-down” approach. The major concern with the use of transformed cell lines is that compounds identified as “hits” may not have direct relevance to the “normal” biological processes that are being targeted; as a result, false leads consume resources set aside for the subsequent testing on animal models and in clinical trials. Use of normal primary human somatic cells for large-scale screening is not currently feasible due to the limited number of cells that can be obtained from biopsy and subsequent propagation in culture.
Human embryonic stem cells (hESCs) offer a potential solution to this bottleneck. First established in 1998 by James Thomson and co-workers, hESCs can be grown in large numbers and maintained in a pluripotent state in culture. They can also be induced in culture to differentiate into cells in a relatively “normal” fashion that is faithful to developmental programs. Thus, three properties make hESCs an ideal platform for drug discovery: (1) hESCs can provide virtually inexhaustible quantities of target cells, which is necessary for screening of large numbers of compounds; (2) hESCs can differentiate into mature cells with phenotypes that mimic their counterparts in normal development; and (3) compared with animal cells, hESCs and their derivatives will provide a much more accurate platform for the “top-down” drug screening approach.
In this proposal, we will use the differentiation of hESCs into pancreatic-like cells as a cell culture tool to test whether our culture technology can be used to successfully identify small molecule effectors that affect cellular function of this particular lineage, with the intent of potentially using these molecules for future clinical applications such as cell replacement therapy or drug treatment for diabetics. If we can demonstrate proof-of-principle that hESC-derived lineage-specific cells could be used to identify clinically applicable small molecule effectors, this will be a major step toward improving the pharmaceutical R&D productivity and lead to an increase in the number of successful small molecules that graduate from the clinical trial pipeline.
In this proposal, we will employ human embryonic stem cells (hESCs) and their derivatives in culture as cellular tools to screen for small drug-like molecules that may have effects on pancreatic beta cell progenitors, with the intent of eventually applying these small molecules for clinical therapy on diabetic patients. In Type I and some Type II diabetic patients, the endogenous pancreatic beta cells, which secrete insulin in response to elevated glucose concentrations in the blood, are insufficient. As a result, these patients require injection of exogenous insulin as a current treatment. However, insulin injection cannot match the physiological response conferred by beta cells, and complications inevitably develop over time. If small molecule effectors could be found that mediate beta cell progenitor activation, proliferation and/or maturation, these effectors would be useful for generation of large quantities of high quality transplantable insulin-secreting cells or their progenitors from hESCs in culture for cell replacement therapy. Alternatively, if proven to be safe in the body, these effectors could also be used directly in diabetic patients to encourage the remaining endogenous beta cell progenitors to proliferate or differentiate. Since diabetes is currently an endemic disease in the United States, if successful, our work may have an impact on the health of a large number of Americans, including Californians.