Abstract

Human-on-a-Chip Systems as Pre-Clinical Models for Neurological Diseases and Disorders

James Hickman, Professor, University of Central Florida

One of the primary limitations in drug discovery and toxicology research is the lack of good model systems between the single cell level and animal or human systems. This is especially true for neurodegenerative diseases such as ALS and Alzheimer’s as well as spinal cord injury. In addition, with the banning of animals for toxicology testing in many industries body-on-a-chip systems to replace animals with human mimics is essential for product development and safety testing. Our research focus is on the establishment of functional in vitro systems to address this deficit where we seek to create organs and subsystems to model motor control, muscle function, myelination and cognitive function, as well as cardiac and liver subsystems. The idea is to integrate microsystems fabrication technology and surface modifications with protein and cellular components, for initiating and maintaining self-assembly and growth into biologically, mechanically and electronically interactive functional multi-component systems. Specific embodiments of this technology are the creation of a functional human NMJ system to understand ALS and a long-term potentiation (LTP) for AD utilizing clinically relevant functional readouts. We have investigated four mutations found in ALS patients; SOD1, FUS, TDP43 and C9ORF72. The models have demonstrated variations of the disease phenotype compared to WT for NMJ stability and functional dynamics. We have also demonstrated the LTP model can reproduce ABeta pathology and tauopathy in human cortical neurons and demonstrated how AD therapeutics can recover these effects Examples will be given of some of the other human-on-a-chip systems being developed for CNS and PNS disease applications as well as the results  Sanofi has used as efficacy data from one of our models to file the first IND only from MPS data that has enabled a clinical trial (#NCT04658472).