Peripheral Nerve-on-a-chip for Predictive Preclinical Pharmaceutical Testing

PROJECT SUMMARY The drug development pipeline is plagued by unacceptable rates of attrition due in large part to toxicities that are not identified in pre clinical stages of developmentThe ability to de risk lead compounds during pre clinical development with advancedorganoid on a chiptechnologies shows tremendous promiseDrug induced neurotoxicity is caused by off target effects of pharmaceuticals that lead to sensorymotorand cognitive deficitsWhile rarely fataldrug induced neurotoxicity can lead to permanent nerve damage and in some cases can be a dose limiting side effectleading patients to reduce dosage or stop treatment altogetherAlthough the peripheral nervous system bears the brunt of this neurological toxicitydevelopment of microphysiological models of the peripheral nervous system is laggingTowards that endthe technology described herein allows forD growth of high density axonal fiber tractsresembling peripheral nerve anatomyProgress during the prior award phase strongly demonstrated the feasibility of using microengineered neural tissues that are amenable to morphological and physiological measurements analogous to those of clinical testsThe use of structural and functional analyses should mean drug induced neural toxicity will manifest in these measurements in ways that mimic clinical neuropathologyThe goals of this proposal are to establish our human model using relevant physiological measurements in tissues fabricated from human iPS cellsand to validate the model system with a library of compoundscomparing against conventional cell culture modelsValidating the peripheral nerve model system with drugs known to induce toxicity via a range of mechanisms will demonstrate the ability of the system to predict various classifications of neuropathyyielding a high content assay far more informative than traditional in vitro systems PROJECT NARRATIVE Current methods available for bringing drugs to market have resulted in high attrition rates as compounds progress through the drug pipelineresulting in unacceptable clinical trial toxicity and skyrocketing pharmaceutical pricesImproving the predictive power of preclinical models represents the fastest and most competitive method to advance the safety and time to market for new therapeuticsAs an added benefitdecreased drug development costs should also expand the availability of novel treatment options for patients