(1144-A) Development of a high-throughput compatible, neuronal spheroid ALS disease model
Monday, February 5, 2024
12:00 PM – 1:00 PM EST
Location: Exhibit Halls AB
Abstract: The NCATS 3D Tissue Bioprinting Lab has previously established a method for generating functional brain region-specific neural spheroids compatible with high-throughput screening (HTS). This platform can be manipulated to mimic different brain regions and model different neurological diseased states, thereby serving as a robust tool for drug discovery. Building off this work, our goal herein is to develop a HTS-compatible neural spheroid model of amyotrophic lateral sclerosis (ALS) using iPSC-derived motor neurons, GABAergic neurons, and astrocytes to mimic the motor cortex of the brain. ALS is a fatal neurodegenerative disease that affects both cortical motor neurons and spinal cord motor neurons. Although the underlying mechanism driving motor neuron degeneration is not fully understood, mutations in the transactivation response DNA-binding protein 43kDa (TDP-43) have been linked to ALS pathology. Therefore, we include genetically engineered motor neurons with TDP-43 mutations in our spheroids to model the diseased state. Using a high-throughput fluorescence imaging plate reader, we measure intracellular calcium activity as the primary functional readout for our model and assess several parameters of the resulting calcium oscillation waveform to determine a phenotype for a given spheroid type. Our first objective is to establish a reproducible, HT-compatible phenotype for wild type (WT) “healthy” motor neuron spheroids as well as ALS disease spheroids and validate using control compounds with known effects on different neuronal subtypes. Once these phenotypes are established and validated, the model can be used for HTS using different NCATS compound libraries with the goal of facilitating drug discovery.