Profiling of Seizurogenic Liability Compounds Using High-Throughput Human iPSC-derived Neuronal 3D Cultures

Spheroid-based cellular platforms are considered to enable more complex, biologically relevant, and predictive assays assays for compound screening, safety evaluation, and toxicity studies. The StemoniX microBrain® 3D Assay Ready 384-well Platform comprises a high throughput spheroid co-culture of cortical glutamatergic and GABA-ergic neurons and astrocytes; thus, more closely resembling the tissue constitution of native human brain tissue. The platform shows robust well-to-well size homogeneity. The neural networks established in this model express typical neuronal and astrocytic identity and functional markers, creating a highly functional neuronal circuitry. High throughput kinetic fluorescence imaging of calcium-sensitive dyes indicates spontaneous, synchronized, readily detectable calcium oscillations, with baseline activity patterns that are reproducible across wells and inter-plates. To validate the capabilities of the platform for safety pharmacology, a set of training compounds including drugs known to cause seizures in animal models through independent mechanisms was evaluated. Compound-induced changes in the calcium oscillation patterns had good correlation to the expected effect of the pharmacological entities tested, indicating good predictivity of the platform. In conclusion, high throughput functional assays using human iPSC-derived neuronal spheroids in the microBrain 3D platform provides robust data for safety pharmacology assessment of seizure liabilities and neurotoxicity assessment.

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