Cortical Tri-Culture Model Validated for Neurodegenerative Drug Discovery
A cortical tri-culture model using human iPSC-derived neurons and astrocytes has been validated for neurodegenerative drug discovery and neurotoxicity screening. The model successfully identified compound modes of action in blinded testing, addressing a critical need for physiologically relevant cortical models. Neurodegenerative diseases affect approximately 15% of the global population, with prevalence expected to increase with aging populations.
A new cortical tri-culture model has been validated for application in discovering drugs for humans and screening for neurotoxicity, offering new possibilities for neurodegenerative disease research. The model, developed through a partnership between Axol Bioscience and Sumitomo Pharma America, uses isogenic human iPSC-derived cortical excitatory neurons, cortical inhibitory interneurons, and astrocytes cultured together on multi-electrode array plates to assess electrophysiological responses to compounds.
In a blinded study investigating eight reference compounds on the cortical tri-culture axoModel via an Axion multi-electrode array system, researchers showed solid identification of reference compound modes of action. The Axion Maestro MEA system was utilized to record 18 electrophysiological parameters, including individual electrode spike parameters, electrode burst parameters, well activity parameters, and overall network parameters. All parameters for different wells were normalized to their baseline values, permitting classification of each blinded compound into six groups and sub-groups according to their observed behavior.
The compounds were arranged in categories including "Little Effect" (minimal significantly different effects compared to vehicle control), "Activators" (producing general increase in activity), and "De-Activators" (inducing general decline in activity). After compounds were arranged in categories and the final report set forth, they were unblinded and outcomes were evaluated in comparison with their known pharmacologies.
Neurodegenerative diseases, including Alzheimer's Disease and Parkinson's Disease, are among the most common causes of physical and cognitive disability, experienced by approximately 15% of the population worldwide. Their prevalence is expected to increase as the world's population ages, meaning there is an increasing need for more effective, safer therapies and curative options. The cortex is a critical area impacted by neurodegenerative diseases and is a common site of drug-induced neurotoxicity, making it a significant target for drug discovery efforts.
A dearth of physiologically relevant cortical models presents a significant roadblock, with standard animal models unable to translate to humans and low complexity from simple cell culture and cell line models. The new tri-culture model addresses this gap by providing a more physiologically relevant system for drug discovery and neurotoxicity screening.