Development of Engineered hES cell lines suitable for antibiotic selection of cardiomyocytes.
One common form of cardiotoxicity associated with drugs is an electrical abnormality known as induced long QT syndrome (LQTS). Due to the risk of progression from LQTS to life-threatening irregular heart rhythms, the pharmaceutical industry devotes much effort to eliminate LQTS-inducing compounds early during the drug development process. One way to try to predict the risk of drug-induced LQTS in humans is by animal models or by using cell-based assays. Animal models may or may not accurately reflect the biology of humans, and while use of animals in drug studies is increasingly raising ethical concerns. Currently, the most commonly used cell-based assays have serious predictive limitations, since the cells employed are not derived from heart cells, and may even be derived from animals rather than humans. Human cardiac-like cells are likely to give a more clinically model of drug action in people; hence there is great scientific and commercial interest in the application of human embryonic stem (hES) cells to derive cardiac-like cells for use in cellular assays and clinical applications.
Current strategies to make cardiac cells from hES produce limited numbers of the appropriate cell type, mixed in with other types of cells. Selecting the cardiac cells requires laborious mechanical procedures to enrich for the cells the researcher desires. We propose to genetically modify an hES cell line to express genes which specifically render cardiac cells fluorescent and resistant to antibiotics. These cells could then be isolated either by well-established techniques based upon separation of fluorescent cells from non-fluorescent cells, or by treatment of the cells with the antibiotic, to eliminate those cells which are not resistant to the drug (i.e., non-cardiac cells). These cells will then be tested for their reproducible performance in drug cardiotoxicity assays. The engineered cells may yield important insights into drug-induced LQTS and sudden cardiac death, and may eliminate potentially cardiotoxic drugs at an early stage in drug development, leading to more cost-effective drugs and improved health care.
Cardiac drug side effects are a major reason for compound withdrawal from development or clinical trials. The successful application of hES-derived cardiomyocytes in vitro toxicology screens will improve the safety profiles of new drugs, potentially eliminating harmful ones and avoiding errant elimination of beneficial compounds which otherwise might be dropped, with obvious health benefits to patients. Additionally, early elimination of cardiotoxic drugs from the development process reduces the financial risk to drug companies, resulting in more cost-effective development of drugs, which should be passed onto California consumers. Generation of this engineered line will yield a valuable tool for pharmaceutical development, and could yield more jobs in California’s biotechnology field. Additionally, demonstration of the utility of these cell lines in the cardiotoxicity assays may lead to the development of new products, instrumentation technologies, and other related businesses located in the State of California.