Modifying the blood–brain barrier by targeting claudin‐5: Safety and risks

Abstract The blood–brain barrier is a major obstacle to the delivery of drugs to the central nervous system. In the blood–brain barrier, the spaces between adjacent brain microvascular endothelial cells are sealed by multiprotein complexes known as tight junctions. Among the many components of the tight junction, claudin‐5 has received the most attention as a target for loosening the tight‐junction seal and allowing drugs to be delivered to the brain. In mice, transient knockdown of claudin‐5 and the use of claudin‐5 binders have been shown to enhance the permeation of small molecules from the blood into the brain without apparent adverse effects. However, sustained knockdown of claudin‐5 in mice is lethal within 40 days, and administration of an anti‐claudin‐5 antibody induced convulsions in a nonhuman primate. Here, we review the safety concerns of claudin‐5–targeted technologies with respect to their clinical application.