Case Studies: Phenotypic Screening of Complex Neuronal Models of Disease

Abstract: Neurological disorders such as Autism Spectrum Disorders (ASDs) and Alzheimer’s are both debilitating, and on the rise which, from an HTS perspective have been in major need of scalable models of their respective disease. Brain cancer research has also been hindered by lack of physiologically relevant models to better predict drug outcomes. Hence, the relevant model to screen potential drugs should be patient specific and disease relevant cell based neuronal models. At UF Scripps, we established multiple cell-based High Throughput Screening (HTS) assays utilizing neurons with ASD mutations. We have also collaborated to study the neurotropic effects of compounds and natural products on Brain Derived Neurotropic Factor (BDNF) induction; a key element to probe for Alzheimer’s. We have pushed the boundaries of scalability of these models from 384 well to 1536 well format and in many cases have implemented them into 3D assays. Additionally, we have implemented multiple readouts including nanoluciferase based approaches, as well as neurite outgrowth induction via HCA. The end result is that we have a suite of robust HTS- amenable phenotypic assays for testing more physiologically relevant models of neuronal and cancer disease. This affords us the ability to rapidly evaluate thousands of drug-like compounds or natural products for ASD, Alzheimer’s, and Glioblastoma. Future studies will focus on validating and determining the functional aspects of these compounds on the patient derived neurons thus paving way for potential early drug discoveries.