Blood–brain barrier models: in vitro to in vivo translation in preclinical development of CNS-targeting biotherapeutics

Abstract

Introduction: The majority of therapeutics, small molecule or biologics, developed for the CNS do not penetrate the blood–brain barrier (BBB) sufficiently to induce pharmacologically meaningful effects on CNS targets. To improve the efficiency of CNS drug discovery, several in vitro models of the BBB have been used to aid early selection of molecules with CNS exposure potential. However, correlative studies suggest relatively poor predictability of in vitro BBB models underscoring the need to combine in vitro and in vivo BBB penetration assessment into an integrated preclinical workflow.

Areas covered: This review gives a brief general overview of in vitro and in vivo BBB models used in the pre-clinical evaluation of CNS-targeting drugs, with particular focus on the recent progress in developing humanized models. The authors discuss the advantages, limitations, in vitro–in vivo correlation, and integration of these models into CNS drug discovery and development with the aim of improving translation.

Expert opinion: Often, a simplistic rationalization of the CNS drug discovery and development process overlooks or even ignores the need for an early and predictive assessment of the BBB permeability. Indeed, past failures of CNS candidates in clinical trials argue strongly that the early deployment of in vitro and in vivo models for assessing BBB permeability, mechanisms of transport and brain exposure of leads, and the co-development of BBB delivery strategies will improve translation and increase the clinical success of CNS pipelines.

Keywords:

• biomarkers
• blood–brain barrier
• in vitro blood–brain barrier models
• stem cells

Declaration of interest

The authors are employees and are supported by the National Research Council of Canada. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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