Optimizing the Action Potential of Stem Cell-derived Human Cardiomyocytes for Car
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CHANTEST CORPORATION, 14656 NEO PKY, CLEVELAND, OH, 44128
AbstractDESCRIPTION (provided by applicant): Stem Cell-derived Human Cardiomyocytes (SC-hCMs) offer great potential for improving the accuracy of pre-clinical cardiac safety screening. We have recently characterized a population of SC-hCMs that will be made commer cially available in 2010 by our collaborator GE Healthcare, and have demonstrated that these cells show sensitive pharmacology that accurately predicts clinical responses. However, the utility of SC-hCMs in cardiac safety testing, and more broadly, in rege nerative medicine, is partially limited by the fact that they are functionally immature. The resting and action potential properties of the cells resemble embryonic or neonatal CMs rather than adult CMs, and SC-hCMs spontaneously beat in culture which limi ts their utility for detection of rate-dependent compound effects. To address these shortcomings, we propose to genetically engineer functionally mature SC-hCMs by selectively supplementing under- expressed ionic currents. The functionally mature SC-hCMs w ill then be validated for use in improved commercial cardiac safety screens. More broadly, these experiments will serve a proof-of-concept function by identifying ion channels that are under-expressed in terminally differentiated SC-hCMs. Once these ion ch annels are identified, future experiments may focus on inducing stable, elevated ion channel expression early in the differentiation process. PUBLIC HEALTH RELEVANCE: The recent availability of human myocytes derived from stem cells (SC-hCMs) provid es an opportunity to develop pre-clinical cardiac safety assays with better predictive value compared to conventional assays. The benefits to public health are: 1) Improved predictivity in pre-clinical cardiac safety screening, thereby reducing risk of adv erse cardiac events in clinical trials 2) Added cost-efficiencies in the pharmaceutical drug development process, and 3) Long-term potential to increase the utility of SC-hCMs in the field of regenerative medicine.
* information listed above is at the time of submission.