Develop predictive human cardiomyocyte-based all optical assay for cardiotoxicity

DESCRIPTION provided by applicant Develop predictive human cardiomyocyte based all optical assay for cardiotoxicity Cardiotoxicity is the leading cause of safety driven withdrawal a all stages and limitation of drug compounds The current cardiac safety paradigm nonclinical guidance ICH S B focuses on in vitro hERG assays which prove to be suboptimal in predicting a compoundandapos s cardiotoxicity in human In the context of high cost and low productivity for new drug discovery better cardiac safety evaluation becomes a significant public health issue CSRC HESI and FDA are developing a new cardio safety paradigm Comprehensive In vitro Proarrhythmia Assay CiPA which comprises characterizing electrophysiological effects of compounds in iPSC derived human cardiomyocytes Q Stateandapos s platform can probe electrophysiology of such cells with higher throughput lower cost and higher information content multi modalities voltage Ca pH and ATP than current patch clamp assays and with better temporal and spatial resolution and lower phototoxicity than other optical screening tools Supported by a $ K NINDS SBIR Phase I award and angel funding Q State Biosciences is developing a proprietary turnkey instrument and software system Optopatch for simultaneous optical perturbation and optical measurement of membrane voltage in neurons We propose to adapt Optopach for cardiomyocyte measurements and to develop and validate an Optopatch assay for drug induced cardiotoxicity in human iPSC derived cardiomyocytes Aim Molecular tools Select the most effective actuators converting blue light into electrical stimuli for pacing and reporters converting AP waveforms into near infrared fluorescence signals by comparing promoters trafficking motifs and gene delivery methods and to thoroughly characterize the sensitivity speed photostability and repeatability of the molecular tools Aim Instrumentation Adapt Optopatch hardware and software to optically stimulate and record from andgt cardiomyocytes simultaneously Develop fluidics and environmental controls modify software to support optical pacing image segmentation and calculation of cardiac relevant AP parameters Aim Assay development and testing Optimize assays for acute and chronic cardiotoxicity Validate the assay by quantifying AP changes under a panel of drugs with known mechanisms and cardiac safety profiles We will provide non GLP cardiotoxicity screening services to drug discovery companies at the lead identification and optimization stages supplementing with the potential to eventually replace hERG assays We will also make Optopatch cardio instrumentation and reagents available to the academic community to enable mechanistic studies and broaden the applications of electrophysiology platform PUBLIC HEALTH RELEVANCE Q Stateandapos s technology will allow better prediction of a drug candidateandapos s potential adverse effect to human heart than the assays mandated by the current cardiac safety guidance ICH S B It will contribute to bringing effective healthcare solutions to market at lower cost and higher productivity by preventing drugs with cardiotoxicity from reaching the market and preventing the development of valuable therapeutics from being wrongly terminated which is one of the concerns about the current S B assays Making Q State instrument and reagents available to the academic research community will facilitate better mechanistic studies and therapeutics development to benefit patients with cardiac conditions