A Human Brain-Chip for modelling brain pathologies and screening of BBB crossing therapeutic strategies

Abstract

ABSTRACTThe limited translatability of preclinical experimental findings to human patients remains an obstacle for successful treatment of brain diseases. Relevant models to elucidate mechanisms behind brain pathogenesis, such as human cell-based systems, and support successful targeting and prediction of drug responses in humans are in urgent need given the species differences in brain and blood-brain barrier (BBB) functions. Here, we examined and advanced a Brain-Chip which recapitulates aspects of the human cortical parenchyma and the BBB in one model. We utilized human primary astrocytes and pericytes, hiPSC-derived cortical neurons, hiPSC-derived brain microvascular endothelial-like cells, and included for the first time on chip hiPSC-derived microglia. Using TNFα to emulate neuroinflammation, we demonstrate that our model recapitulatesin vivo-relevant responses. Importantly, we show microglia-derived responses, highlighting the ability of the model to capture cell-specific contributions in human disease associated pathology. We next tested BBB crossing of human transferrin receptor antibodies and conjugated adeno-associated viruses, and demonstrate successfulin vitro/in vivocorrelation in identifying crossing differences. These findings highlight the potential of the Brain-Chip as a time-saving and reliable model to support therapeutic development for brain diseases.