Electronic Optimization of Stem Cell Derived Human Cardiac Myocytes

DESCRIPTION provided by applicant As part of the FDA approval process for novel therapeutic drugs safety screening demonstrating that the new drug does not have deleterious effects on the human cardiac action potential is required Healthy human heart cells are not available for such preclinical drug testing There is currently no consensus on the best experimental approach to provide the most efficient economical and faithful determination if the drug is likely to lengthen the cardiac action potential Long QT and result in the potentially fatl arrhythmia known as Torsade de Pointes The FDA is actively seeking new reliable models for preclinical drug testing Recently Human cardiac myocytes were derived from induced pluripotent stem cells iPSCDCMs Human iPSCDCMs cells are in plentiful supply and are able to withstand comprehensive electrophysiology to determine the drug cell interactions Although most ionic currents in these cells closely resemble those from freshly isolated heart cells one important channel is missing The inward rectifier current IK As a result of this missing current the cells do not have a physiological resting potential are spontaneously active and have an anomalous response to drugs Viral transfection of Kir the molecular basis of IK has proved difficult resulting in foreshortened action potentials or complete lack f ability to stimulate action potentials at all We have developed a novel technology which restores IK using electronic expression Using a mathematical model IK is almost instantaneously calculated based on the membrane potential of the cell The calculated current is then applied to the cell electronically through an electrode resulting in a virtual IK which interacts with the other membrane currents Synthetic IK is easily adjusted to be appropriate for cell type and cell capacitance The Phase I goal is to develop and optimize this research equipment into a reliable robust easy to use andquot plug and playandquot device The first set of milestones center on development of a commercial prototype we will optimize the electronics the software and the system Next we will deploy the device in the lab and determine benchmarks and performance attributes which will be needed to validate and sell the device Completion of these Phase I milestones will position us to undertake drug testing and further validation in Phase II Our technology will deliver a rapid and precise human cardiac action potential model suitable for preclinical drug testing This will have a significant impact on human health as well as a strong economic impact Our device enables easy identification of atrial and ventricular iPSCDCMs thus increasing reliability of results and reducing the number of experiments required for statistical significance Our approach uses Human cells which also reduces the likelihood of false positives false negatives This improved preclinical safety testing will more accurately identify drugs with adverse side effects earlier in the development process This improved accuracy will avoid wasted expenditures on unsuccessful candidate compounds and will reduce the abandonment of potentially beneficial drugs PUBLIC HEALTH RELEVANCE Drug safety screening is required for all new drugs to determine if they have the potential to prolong the cardiac action potential and lead to the potentially fatal Torsade de Pointes Currently this testing is not carried out on human cells This project will optimize a novel device which enables human induced pluripotent stem cell derived cardiac myocytes to be used as a faithful model of the human heart thus significantly improving drug screening in terms of accuracy as well as reducing the time needed to obtain results