Human-On-a-Chip Systems For Use in Therapeutic Index Determination and Systemic Toxicity in Pre-Clinical Drug Discovery Applications

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 Aβ 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) and has now proceeded to a Phase III trial.

Learning Objectives

1. Explain the development and applications of human-on-a-chip systems as alternatives to animal models for drug discovery and toxicity testing, with a focus on neurodegenerative diseases such as ALS and Alzheimer’s.

2. Evaluate the integration of microsystems technology, surface modifications, and cellular components in creating functional in vitro models to mimic human organ systems, including motor control, cognitive function, and cardiac subsystems.

3. Analyze the use of human-on-a-chip models for therapeutic efficacy, focusing on their impact in preclinical drug discovery, including case studies such as the ALS and Alzheimer’s models, and their role in advancing clinical trials.