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

被引:10
|
作者
Wakayama, Erika [1 ]
Kuzu, Taiki [2 ,3 ]
Tachibana, Keisuke [3 ]
Hirayama, Ryuichi [4 ]
Okada, Yoshiaki [3 ]
Kondoh, Masuo [3 ]
机构
[1] Osaka Univ, Fac Pharmaceut Sci, Osaka, Japan
[2] Ritsumeikan Univ, Coll Pharmaceut Sci, Kusatsu, Japan
[3] Osaka Univ, Grad Sch Pharmaceut Sci, Suita, Osaka 5650871, Japan
[4] Osaka Univ, Grad Sch Med, Osaka, Japan
关键词
blood-brain barrier; claudin; regulatory science; tight junction; CLOSTRIDIUM-PERFRINGENS ENTEROTOXIN; EXTRACELLULAR LOOP; DRUG-DELIVERY; DOMAIN; SCHIZOPHRENIA; MODULATION; JUNCTIONS; FRAGMENT; BINDING; STRANDS;
D O I
10.1111/nyas.14787
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:62 / 69
页数:8
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