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.

The neurovasculature as a target in temporal lobe epilepsy

“…One study showed the tight junction protein claudin‐5 is enriched in brain endothelial cells and was significantly diminished in surgically resected brain tissue from patients with treatment‐resistant epilepsy. Concomitantly, dynamic contrast‐enhanced MRI in these patients showed widespread BBB disruption, and the administration of anti‐claudin‐5 antibody induced convulsions in a non‐human primate [ 161 ]. A knockdown of claudin‐5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality, whilst RepSox, a regulator of claudin‐5 expression, could prevent seizures in experimental epilepsy [ 160 ].…”

A year in review: brain barriers and brain fluids research in 2022

“…By contrast, reducing claudin-5 expression/function may enhance drug delivery across the BBB. Wakayama et al [ 189 ] review the current state of such research and potential safety concerns. While transient reductions in claudin-5 can enhance drug delivery, chronic reductions cause adverse effects in mice and non-human primates.…”