SBIR-STTR Award

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 commercially 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 regenerative 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 limits 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 will 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 channels 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) provides 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 adverse 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.

Thesaurus Terms:
"21+ Years Old; Action Potentials; Address; Adult; Assay; Benchmarking; Best Practice Analysis; Bioassay; Biologic Assays; Biological Assay; Cardiac; Cardiac Myocytes; Cardiocyte; Care, Health; Cell Function; Cell Process; Cell Physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Characteristics; Clinical; Clinical Trials; Clinical Trials, Unspecified; Complementary Dna; Dna, Complementary; Data; Detection; Embryo; Embryonic; Engineering; Engineerings; Event; Fee-For-Service Plans; Fees For Service; Future; Goals; Healthcare; Heart Myocyte; Human; Human, Adult; Human, General; In Vitro; Ion Channel; Ionic Channels; Man (Taxonomy); Man, Modern; Marketing; Membrane Channels; Membrane Potentials; Methods And Techniques; Methods, Other; Molecular; Morphology; Mother Cells; Muscle Cells; Muscle Cells, Cardiac; Muscle Cells, Heart; Muscle Cells, Mature; Muscle Satellite Cell; Muscle, Cardiac; Muscle, Heart; Myocardium; Myocytes; Myocytes, Cardiac; Neonatal; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Pharmacology; Phenotype; Predictive Value; Procedures; Process; Production; Progenitor Cells; Property; Property, Loinc Axis 2; Public Health; Regenerative Medicine; Research Contracts; Rest; Resting Potentials; Risk; Safety; Screening Procedure; Stem Cells; Subcellular Process; Techniques; Transfection; Transmembrane Potentials; Validation; Adult Human (21+); Base; Cdna; Cardiac Muscle; Cardiomyocyte; Clinical Investigation; Commercialization; Cost; Density; Drug Development; Drug Discovery; Experience; Experiment; Experimental Research; Experimental Study; Heart Cell; Heart Muscle; Improved; Muscle Stem Cell; Pre-Clinical; Preclinical; Public Health Medicine (Field); Public Health Relevance; Research Study; Response; Safety Testing; Satellite Cell; Screening; Screenings; Stem Cell Population"

Stem Cell-derived Human Cardiomyocytes (SC-hCMs) offer great potential for improving the accuracy of pre- clinical cardiac safety testing. We have characterized a population of SC-hCMs and have demonstrated that these cells show sensitive pharmacology that accurately predicts clinical responses. However, due to low assay throughput and limited resources, only 15 reference compounds were tested. We now propose to increase throughput in preclinical electrophysiology (EP) screens by utilizing a higher-throughput automated EP instrument. We will expand our preclinical in vitro testing to 77 compounds that have been carefully selected based on their known torsadogenic and/or QT prolonging effects. Results from SC-hCM-based assays will be referenced against complete (8 concentration, 8 replicate) concentration-curves of the same compounds generated from high-throughput screens of cell lines expressing each of the major cardiac ion channels. A statistics-based model will be created in collaboration with the U.S. Food and Drug Administration and a leading in silico modeling firm, Leadscope. This model will be based on the unique databases we create which, together the development of software dedicated to mining public and proprietary cardiac databases will dramatically increase productivity of pre-clinical cardiac safet screening. The set of services and products that will result from this project have the potential t save millions of dollars annually by reducing attrition of marketed but cardiotoxic drugs, to improve the safety of drugs in development, and to increase efficiency of drug development by allowing companies to focus on the most promising and safe drug candidates.

Public Health Relevance:
The recent availability of human myocytes derived from stem cells (SC-hCMs) provides 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 productivity in pre-clinical cardiac safety screening, thereby reducing risk of adverse cardiac events in clinical trials, and 2) Added cost-efficiencies in the pharmaceutical drug development process.