The drug development pipeline is plagued by unacceptable rates of attrition due in large part to toxicities that are not identified in pre-clincal stages of development. The ability to de-risk lead compounds during pre-clinical development with advanced organoid-on-a-chip technologies show tremendous promise. Chemotherapeutics in particular, while clinically effective against a wide array of cancers, are commonly associated with dose-limiting systemic toxicities, causing many patients to alter dose regimens and some to cease treatment altogether. Although the peripheral nervous system bears the brunt of this damage, development of nerve-on-a-chip assays is lagging. Towards that end, the technology described herein allows for 3D growth of high density axonal fiber tracts, resembling peripheral nerve anatomy. Preliminary data demonstrate 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 should mean chemotherapy-induced neural toxicity will manifest in these measurements in ways that mimic clinical neuropathology. The goal of this proposal is to demonstrate the scientific merit of using changes in the structure-function relationship as an improved measure of peripheral neurotoxicity in vitro. To do this, we will apply chemotherapeutic drugs with known peripheral neurotoxicity, measure physiological endpoints, and compare with morphological changes as well as documented clinical pathophysiology. By analyzing induced changes due to oxaliplatin, paclitaxel, vincristine, and bortezomib, each of which triggers a distinct toxic mechanism of action, we will demonstrate the ability of our model to detect toxicity in a manner currently unavailable to pharmaceutical scientists.
Current methods available for bringing drugs to market have resulted in high attrition rates as compounds progress through the drug pipeline, resulting in unacceptable clinical trial toxicity and skyrocketing pharmaceutical prices. Improving the predictive power of preclinical models represents the fastest and most competitive method to advance the safety and time to market for new therapeutics. As an added benefit, decreased drug development costs should also expand the availability of novel treatment options for patients.
| Khoshakhlagh, Parastoo; Sivakumar, Ashwin; Pace, Lauren A et al. (2018) Methods for fabrication and evaluation of a 3D microengineered model of myelinated peripheral nerve. J Neural Eng 15:064001 |
