Abstract
The development of effective central nervous system (CNS) drugs has been hampered by the lack of robust strategies to mimic the blood-brain barrier (BBB) and cerebrovascular impairments in vitro. Recent technological advancements in BBB modeling using induced pluripotent stem cells (iPSCs) allowed to overcome some of these obstacles, nonetheless the pertinence for their use in drug permeation study remains to be established. This mandatory information requires a cross comparison of in vitro and in vivo pharmacokinetic data in the same species to avoid failure in late clinical drug development. Here, we measured the BBB permeabilities of 8 clinical positron emission tomography (PET) radioligands with known pharmacokinetic parameters in human brain in vivo with a newly developed in vitro iPSC-based human BBB (iPSC-hBBB) model. Our findings showed a good correlation between in vitro and in vivo drug brain permeability (R2 = 0.83; P = 0.008) which contrasted with the limited correlation between in vitro apparent permeability for a set of 18 CNS/non-CNS compounds using the in vitro iPSCs-hBBB model and drug physicochemical properties. Our data suggest that the iPSC-hBBB model can be integrated in a flow scheme of CNS drug screening and potentially used to study species differences in BBB permeation.
Highlights
For central nervous system (CNS) drugs, the step from in vitro activity to in vivo efficacy depends critically on the ability of the drug to cross the blood-brain barrier (BBB)
We showed the expression of the endogenous pluripotency marker genes OCT4, SOX2, REX1 and NANOG (Fig. 1B) while no expression was shown for those genes in the primary cells
We provide evidence of the physiological relevance of the induced pluripotent stem cells (iPSCs)-hBBB model in predicting human brain permeability to drugs by means of evaluation of the BBB permeability of radioligands studied correlatively in vivo with quantitative PET imaging in humans and in vitro
Summary
For central nervous system (CNS) drugs, the step from in vitro activity to in vivo efficacy depends critically on the ability of the drug to cross the blood-brain barrier (BBB). These 2D/3D models are based on the use of iPSCs in static or microfluidic conditions[11,12,13,14,15,16,17,18,19,20] Whatever their ressemblance to the in vivo BBB, in vitro BBB models must be carefully assessed for their ability to predict accurately the passage of drugs into the CNS in vivo. We report the development of a human BBB model using two different iPSC lines based on the optimization of the protocol previously reported[15]. Using these iPSC lines, we addressed their differentiation into brain endothelial cells (BECs) and their capacity to generate a tight monolayer in co-culture with glial cells. Even if the BBB permeabilities showed the similar ranking of the tested compounds between both in vitro iPSC-hBBB and primary rat models, we noticed species differences considering their interactions with ABC transporters
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