Culture-based blood-brain-barrier (BBB) models are crucial tools to enable rapid screening of brain-penetrating drugs. However, reproducibility of <i>in vitro</i> barrier properties remains as a major challenge. Here, we report that self-assembling multicellular BBB organoids display reproducible BBB features and functions, and can be utilized as a screening tool for brain-penetrating molecules. The organoid core is comprised mainly of astrocytes, while brain endothelial cells and pericytes encase the outer surface of the organoid, acting as a ‘barrier’ that regulates transport of molecules, and which can be permeabilized in the presence of VEGF. The barrier is characterized by the presence of intact tight junctions and efflux-pump (i.e. P-glycoprotein) activity. Furthermore, we have used this model to successfully demonstrate the transport of angiopep-2 (a well-known brain delivery vector) and its conjugates (containing cargoes of various sizes such as peptide, protein and affibody), thereby displaying the versatility of this model to screen and study a wide range of therapeutic agents. We demonstrate that this model is superior to the conventional transwell model in maintaining essential BBB characteristics (i.e., tight/adherens junctions and P-glycoprotein expression) and as a drug-screening tool. We have utilized the organoid model to screen and identify several molecules with high brain-penetration potential, which are then verified in mice. The BBB organoid platform represents an accurate, versatile and cost-effective <i>in vitro</i> tool that can be easily scaled to a high-throughput format, offering a next-generation tool for BBB modeling that could accelerate therapeutic discovery for the treatment of various neuro-pathologies.

BBB organoid platform for modeling therapeutic delivery to the brain

2019 Fall National Meeting

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