Intracameral inoculation of endothelial tight junction siRNA-targeting drug enhances outflow facility and reduces intraocular pressure in a rodent model of steroid-induced ocular hypertension.

Abstract Systemic or localised application of glucocorticoids (GC) can lead to iatrogenic ocular hypertension, which is a leading cause of secondary open angle glaucoma and visual impairment. Previous work has shown that dexamethasone increases zonula occludens-1 (ZO-1) protein expression in trabecular meshwork (TM) cells, and that an antisense oligonucleotide inhibitor of ZO-1 can abolish the dexamethasone induced increase in trans-endothelial flow resistance in cultured Schlemm’s canal (SC) endothelial and TM cells. We have previously shown that intracameral inoculation of siRNA targeting SC endothelial cell tight junction components, ZO-1 and tricellulin, increases aqueous humor outflow facility ex vivo in normotensive mice by reversibly opening SC endothelial paracellular pores. Here we show that targeted siRNA downregulation of these SC endothelial tight junctions reduces intraocular pressure (IOP) in vivo, with a concomitant increase in conventional outflow facility in a well-characterised chronic steroid-induced mouse model of ocular hypertension, thus representing a potential focused clinical application for this therapy in a sight-threatening scenario.