Abstract

Human on a Chip Systems Applied to Neurodegenerative and Rare Diseases

James Hickman, Professor, University of Central Florida

We have been constructing multi-organ human-on-a-chip systems for toxicology and efficacy with up to 6 organs and have demonstrated long-term (>28 days) evaluation of drugs and compounds, that have shown similar response to results seen from clinical data or reports in the literature. Application of these systems for neurodegenerative and rare diseases such as ALS, Alzheimer’s, CIDP, MMN, Myasthenia gravis, as well as its application to opioid overdose and recovery will be described. These models utilize a pumpless platform with serum free recirculating medium, which is a low volume system that can evaluate parent compounds as well as metabolites, if the liver is included. Our research focus is on the establishment of functional in vitro systems to address phenotypic deficits to create organs and subsystems to model motor control, muscle function, myelination and cognitive function, as well as the potential for including cardiac, BBB, kidney, GI tract and liver subsystems. Acute and chronic compound testing in systems for concurrent measurement of both efficacy and toxicity has also been done in the same system for therapeutic index estimation. A specific embodiment of this technology is the creation of a functional human NMJ system to understand ALS where we have investigated the four primary mutations found in ALS patients; SOD1, FUS, TDP43 and C9ORF72 and demonstrated variations of the disease phenotype as well as response to therapeutics. We also will describe an Alzheimer’s disease model based on long-term potentiation, a correlate for learning and memory, which has reproduced aspects of amyloidopathy and tauopathy, and shown drug selective reversal with current AD therapeutics. Sanofi has used efficacy data from one of our models to file an IND that has enabled a clinical trial (#NCT04658472) and is described in our recent joint publication (Rumsey et al. 2022). We will also describe a multi-organ innate immune system that was able to reproduce the pro-inflammatory and restorative phenotypes from macrophages.