The Microphysiological Systems (MPS) World Summit 2024 is scheduled for June 10 to 14, 2024, at the Seattle Convention Center in Seattle, Washington. This premier event brings together academic researchers, industry professionals, and regulatory agencies to discuss the latest developments in MPS technology. The summit features keynote presentations, scientific sessions, workshops, and networking opportunities, fostering collaboration and innovation in the field.
Progress in neurological drug development has faced significant hurdles, primarily stemming from the difficulty of accurately modeling human neurological function using animal models alone. The advent of iPSC-derived neurons has emerged as a powerful tool for studying neurological function and disease in a human cell-based in vitro setting. A crucial aspect of accurately modeling the central nervous system involves the concurrent differentiation of neurons and glial cells in a 3D organoid organization, including astrocytes and the oligodendrocyte lineage pathway, which consists of oligodendrocyte precursor cells (OPCs), oligodendrocytes (OLs), and myelinating OLs.
Astrocytes are integral in maintaining neuronal homeostasis and network function, while myelin sheaths formed by OLs enable efficient neuronal conduction. The presence of these cell types in the 3D model enables a more comprehensive representation of the neurological landscape. Notably, the differentiation of OPCs into OLs is a fundamental differentiation transition with potential implications for modeling and treating demyelinating diseases, like multiple sclerosis.
AxoSim’s proprietary 3D BrainSim® model addresses this need by differentiating neuron and glial cell types from iPSCs over a 12-week culture period. The time scale and robustness of the differentiation process can be monitored through both qualitative and quantitative methods, including immunohistochemistry (IHC), qPCR, and Western blot assays. Leveraging this model, AxoSim has assessed the impact of compounds introduced into the culture media, including components promoting OL differentiation and the pro-myelinating compound clemastine, providing insights on their effects on the timeline and extent of glial differentiation.
Rett syndrome (RTT) is a progressive neurodevelopmental disorder caused by mutations in the X-linked gene MECP2. Although recent scientific discoveries have greatly improved our understanding of the disease mechanism, currently there is no disease-modifying treatment available for RTT patients. One of the challenges in developing therapeutics for RTT is the lack of a screening system that recapitulates the core biology of the disease. Using human induced pluripotent stem cells (hiPSCs), we recently developed a highly homogenous cortical organoid high-throughput screening (HTS) platform that can efficiently screen large compound libraries in a reproducible fashion. The platform employs a functional readout and is able to detect a highly reproducible RTT neural network phenotype across multiple spheroids and batches. Here, we describe the use of this platform to reveal novel potential therapeutics for RTT. We screened the IRSF SMART library (compounds curated for treating RTT) and identified acetylcholine esterase (AChE) inhibitors and histone deacetylase (HDAC) inhibitors as the most promising therapeutic targets based on global functional rescue. We developed an algorithm to quantify the count, size, and shape of activity peaks, then engineered additional waveform features to capture the disease-specific biology of RTT organoids. In all, >50 waveform features define the RTT functional phenotype and contribute to global functional rescue. While both compound classes exhibited global rescue, AChE inhibitors rescued a distinct set of features compared to both HDAC inhibitors and top clinical candidates Anavex 2-73 and trofinetide with distinct biological targets. In summary, we show that our human cortical organoid HTS platform exhibits a robust RTT phenotype and can be used to identify promising therapeutic compounds in preclinical research in a human-first fashion.
