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 development. While peripheral neuropathy remains a common toxic side-effect of new drugs, such toxicity is typically only first identified during late-stage preclinical development or even early clinical trials. Drug-induced neurotoxicity is caused by off-target effects of pharmaceuticals that lead to sensory, motor, and cognitive deficits. While rarely fatal, drug-induced peripheral neurotoxicity can lead to permanent nerve damage and in some cases can be a dose-limiting side effect, leading patients to reduce dosage or stop treatment altogether. “Organ-on-a-chip” technologies are steadily becoming adopted by the pharmaceutical industry because of their ability to help de-risk lead compounds during pre-clinical development. Towards that end, we demonstrated the technical feasibility and successful commercial deployment of a peripheral “nerve-on-a-chip,” consisting of a 3D neuronal/glial spheroid projecting dense axonal fiber tracts, resembling peripheral nerve anatomy. Progress during the prior award phases strongly demonstrated the feasibility of using microengineered neural tissues that are amenable to morphological and physiological measurements analogous to those of clinical tests. The use of structural and functional analyses in vitro led to drug-induced neural toxicity that manifested in ways analogous to clinical neuropathology. Valuable feedback from industry early adopters has enabled us to revise previous assumptions and resolve many technical challenges, and we now seek to deploy the technology at a commercial scale. The aims of this proposal are to manufacture customer-ready multiwell devices with integrated microelectrodes, and to provide a more complete biological characterization of our model using high-throughput transcriptomics. Completion of these aims will position this technology for scalable implementation, enabling us to offer the platform widely to pharmaceutical companies seeking information about peripheral neuropathy earlier in the preclinical drug development process than currently possible.