Therapeutics for central nervous system (CNS) diseases, including neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, have longer development times and lower approval rates when compared to non-CNS drugs. The blood-brain barrier (BBB), made of the brain microvascular endothelial cells (BMECs) that line cerebral capillaries, presents a major obstacle to overcome when treating neurodegenerative diseases because it excludes most molecules in the blood from being transported to the brain. Despite the importance of understanding whether a drug will cross the BBB, it is difficult to assess human brain permability as in vivo mouse models do not accurately predict drug transport to the human brain and traditional in vitro models often do not adequately recapitulate the barrier phenotype observed in vivo. In this work, we adapt, characterize and apply a fully human BBB model derived from human induced pluripotent stem cells with excellent barrier properties that mimic the in vivo BBB, measured by transendothelial electrical resistance and permeability to different types of molecules. The differentiated BMECs consistently have an extremely high transendothelial electrical resistance which exceeds typical in vitro values by an order of magnitude and is within what is believed to be the physiologically relevant range. The differentiated cells are polarized and preferentially exclude a substrate of the efflux pump P-gp from the brain side of the model. The transport rates of an antibody therapeutic as well as several small molecule drugs in this model are comparable to in vivo values. The model was applied to the study of antibody transport across the BBB in two model disease states: general neuroinflammation and Alzheimer's disease. We measured barrier properties and the transport rate of antibodies into the brain in both disease models. These results suggest that this in vitro BBB model is extremely adaptable and can be applied to a number of different disease states to investigate changes that occur on a cellular level in neurodegenerative and other diseases.

Stem cell-based blood-brain barrier model for drug transport studies

251st National Meeting (2016)

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