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


METHODS
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.


CONCLUSIONS
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.
Human Health Therapeutics Portfolio, National Research Council of Canada , 1200 Montreal Road, Bldg M-54 Ottawa, ON K4P 1R7 , Canada +1 613 993 3730 ; +1 613 941 4475 ; Danica.Stanimirovic@nrc-cnrc.gc.ca.
Danica B
DB
Stanimirovic
Mahmud
M
Bani-Yaghoub
Martin
M
Perkins
Arsalan S
AS
Haqqani
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D013045:Species Specificity
D000911:Antibodies, Monoclonal
biomarkers; blood–brain barrier; in vitro blood–brain barrier models; stem cells