Electronic Optimization of Stem Cell Derived Human Cardiac Myocytes

Project Summary As part of the FDA approval process for novel therapeutic drugssafety screening demonstrating that the candidate drug does not have deleterious effects on the human cardiac action potential is requiredHealthy human heart cells are not available for such preclinical drug testingThere is currently no consensus on the best experimental approach to provide the most efficienteconomicaland faithful determination if the drug is likely to lengthen the cardiac action potentialLong QTand result in the potentially fatal arrhythmia known as Torsade de PointesThe FDA is actively seeking new reliable models for preclinical drug testingThe FDAHESIand Pharma recognize that human cardiac myocytes derived from induced pluripotent stem cellsiPSCDCMsoffer a great opportunity to improve drug safety screeningHuman iPSCDCMs cells are in plentiful supplyand are able to withstand comprehensive electrophysiology to determine the drug cell interactionsAlthough most ionic currents in these cells closely resemble those from freshly isolated heart cellsone important channel is missingThe inward rectifier currentIKAs a result of this missing currentthe cells do not have a physiological resting potentialare spontaneously activeand have an anomalous response to drugsViral transfection of Kirthe molecular basis of IKhas proved difficultresulting in foreshortened action potentialsor complete lack of ability to stimulate action potentials at allWe have developed a novel technologywhich restores IKusing electronic expressionUsing a mathematical modelIKis almost instantaneously calculatedbased on the membrane potential of the cellThe calculated current is then applied to the cell electronically through an electroderesulting in a virtual IKwhich interacts with the other membrane currentsSynthetic IKis easily adjusted to be appropriate for cell type and cell capacitanceWe met all our Phase I optimization goalsThe Phase II goal is validate our device against the FDA CiPA assaydevelop new ionic current waveformsautomate cell type identificationfield test the deviceand develop a high throughput version of the CybercyteFinallywe will prepare the device for commercializationOur technology will have a significant impact on human healthas well as a strong economic impactOur device enables easy identification of atrial and ventricular iPSCDCMsthus increasing reliability of resultsand reducing the number of experiments required for statistical significanceOur approach uses Human cellswhich also reduces the likelihood of false positives false negativesThis improvedhigh througput preclinical safety testing will more accurately identify drugs with adverse side effects earlier in the development processThis improved accuracy will avoid wasted expenditures on unsuccessful candidate compounds and will reduce the abandonment of potentially beneficial drugs Project Narrative Drug safety screening is required for all new drug candidates to determine if they have the potential to prolong the cardiac action potential and lead to the potentially fatal Torsade de PointesWe will develop and validate our novel deviceincluding a high throughput versionas a commercial system which enables human induced pluripotent stem cell derived cardiac myocytes to be used as a faithful model of the human heartand produce more physiologically and clinically relevant data compared with the current screeningwhich is performed on non human cellsand has severe limitations in its predictive abilityOur device is a major step forward in drug safety screeningas it will improve accuracy and reduce the costs associated with drug development