Invivosciences, Inc. — Department of Health and Human Services SBIR Phase I: NHLBI

Description

HLSThe US FDA is considering to establish a new cardiac safety assessment approach defined by a new paradigm calledComprehensive in vitro Proarrhythmia AssayCIPAThe CIPA willassess drug effects on each cardiac ion channel type individually using a highthroughput assay ion channel assayscompute net effect on repolarization and risks for torsade pointesTdPusing a mathematical modelandconfirm the computational prediction by measuring the drug s effects on action potentials in induced pluripotent stem celliPSCderived human cardiac myocytesCMsThis paradigm shiftif successfulcould reduce the cost of cardiac safety analyses by replacing or lowering the requirement to perform an expensive$millionthorough QT study during clinical trialsProtecting consumers from drug induced arrhythmia and sudden deaths is a paramount importance for the regulators and pharmaceutical companies as well as lowing the cost of drug developmentMany cardiac safety scientistshoweverare skeptical about CIPA s approach since CMs derived from human iPSCs exhibit a poor excitation contraction coupling due to their immaturityIn additiona proposed CIPA mathematical model was developed to simulate electrophysiology of human adult CMsso there is a mismatch between experimental system and computational toolTo address these concernswe proposed three specific aims in twphases by following FastTrack SBIR processesPhase I feasibility Aimwill measure drug induced changes in AP and CaT using human adult heart slices isolated from human donorsHere we will confirm our successful handling and analyzing human adult heart sliceswhich will be based on a recently published protocol by our collaboratorDrIgor Efimovat George Washington UniversityAfter this validationwe will move on to perform the following two studiesAimCompare drug induced changes in AP and CaT in NuHearts generated from adult CMs and cardiac fibroblasts from same human donor heartsAimValidate and improve the computational models and train an artificial intelligence to predict cardiac safety risks of unknow compoundsAfter our successful completion proposed projectswe can establish an unprecedented cardiac safety assessment platform that can predict safety issues using a well trained AI without doing any experiments using human heart slices that are rarely accessible for most of the safety laboratories or biotech firms Because nearly one third of drug candidates fails to reach market due to its cardiac safety concernsa better safety assessment approach without increasing its cost is needed to improve productivity of pharmaceutical industryThe proposed project combines computational and experimental analyses of cardiac safety parameters using adult heart cells isolated from a donor heart and its stem cell derived heart muscle cells to build a better but cost effective cardiac safety assessment systemA successfully validated system enables drug developers to arcuately predict a new drug s cardiac safety profile by only running cost effective experiments using stem cell derived heart muscle cells that are accessible to many drug developers