The human Central Nervous System (CNS) has a unique structural organization critical to its complex functions. Efforts to model this intricate network in vitro have encountered major bottlenecks and recent work has focused on generating 3D brain organoids that better recapitulate brain development and function in vitro. While closely mimicking key features of the human CNS, the complexity of current protocols and the variability of the organoids produced still pose major hurdles for routine implementation in drug discovery. StemoniX has recently introduced microBrain® 3D, a highly homogenous off-the-shelf human induced Pluripotent Stem Cell (hiPSC)-derived spheroid screening platform composed of cortical neurons and astrocytes in 384 well format. Coordinated spontaneous neuronal activity of the microBrain 3D spheroids results in highly rhythmic calcium oscillations that can be monitored via high throughput calcium flux analysis. The platform has been optimized to have a highly homogenous and consistent functional signal across wells, plates, and batches; making the system a turnkey approach for CNS drug discovery. Here, the platform was used to investigate neurodevelopmental disorders. hiPSC-neurons derived from Rett Syndrome (RTT) patients were integrated into the platform to generate microBrain 3D-RTT* spheroids that were used as a substrate to screen for therapeutic rescue. Our results demonstrate:
- The robust and reproducible baseline phenotype of the microBrain 3D spheroids.
- Clear abnormal phenotypes of the microBrain 3D-RTT spheroids.
- The easy integration of the microBrain 3D platform into higher throughput screening.
- Compound-based rescue of the microBrain 3D-RTT phenotype.
- The potential for the microBrain 3D platform to model neurological diseases and advance CNS based drug discovery.