Bioengineering Mature Human Pluripotent Stem Cell-Derived Cardiomyocytes for Predictive Drug-Induced Toxicity Testing

PROJECT SUMMARY Nearlyof drugs under development fail to reach the marketMany of these failures occur due to cardiotoxicityusually when the candidate molecule induces cardiac arrhythmiasIn a few notable casessome drugs pass pre clinical screens and clinical trialsonly to be removed from the market once toxic effects are discovered in large patient populationsThese failures represent a tremendous source of waste and constitute a significant part of the$billion cost of bringing a single drug to marketConsequentlythe FDA now mandates that all drugs undergo in vitro cardiotoxicity testing before being tested in humansThis has led to a significant and growing market for tools and technologies that enable earlier detection of toxic effects before exposure to patientsHowevercurrent screening methods fall short of predicting how a drug will behave in the bodyindeed there is a pressing need for more predictive model systemsHuman induced pluripotent stem cell derived cardiomyocytesiPSC CMsare an attractive model for in vitro preclinical toxicity screeningthey are relatively easy to maintainare derived from human tissueand have the potential to reduce the need for animal experimentationHoweverat presentiPSC CM based assays do not properly replicate the function of the human heartThese cells exhibit phenotypes similar to that of fetal tissue and do not respond as expected to drugs of known effectin some casesknown bad actor drugs fail to induce arrhythmiaswhile others only show in vivo cardiotoxicity when exposed to supra physiological doses of the drug in questionThe drug discovery industry and its regulators realize the potential of iPSC CMs for early cardiotoxicity screeningbut also understand that at present there are significant limitations to their use in the drug development processThusit is clear that the production of mature cardiac tissues that accurately recapitulate in vivo drug responses represents a significant opportunity for reducing cost and waste in drug developmentNanoSurface BiomedicalIncaims to develop an enhanced iPSC CM cell line that has been optimized for highly predictive drug induced cardiotoxicity screeningWe hypothesize that iPSC CMs that give more predictive results in in vitro cardiotoxicity detection can be made by combining nanoscale extracellular cues with biochemical and molecular biological stimuli that drive their maturationWe will first focus on demonstrating that these enhanced iPSC CMs can correctly classify drugs that are currently improperly screenedPhaseAimAfter validationwe will generate a stable cell line that encompasses the maturation factors determined in Phasein preparation for scaling and commercial productionPhaseAimCommercialization efforts will further be facilitated by characterizing transcriptomicstructuraland functional phenotypes of the predictive cell line and in identifying a set of key physiological metrics that will be used for in line quality controlPhaseAimLastwe will validate and generate data for market release with our research partners in the drug development industry and regulatory bodiesPhaseAimPROJECT NARRATIVE In this projectthe company will optimizevalidateand scale methods to produce engineered cardiac tissues which can be used to pre clinically assess how the human heart will react to drugsWe anticipate that the combination of various cuesmechanicalelectricalbiomolecularand biochemicalwill greatly enhance the utility of cardiac tissues in providing more predictive toxicity data than currently available using existing technologiesThis product has great potential to dramatically reduce the cost of drug developmentimprove clinical outcomesand save lives across a wide spectrum of diseases and conditions