siRNA targeting Schlemm's canal endothelial tight junctions enhances outflow facility and reduces IOP in a steroid-induced OHT rodent model

Paul S Cassidy; Ruth A Kelly; Ester Reina-Torres; Joseph M Sherwood; Marian M Humphries; Anna-Sophia Kiang; G Jane Farrar; Colm O'Brien; Matthew Campbell; W Daniel Stamer; Darryl R Overby; Pete Humphries; Jeffrey O'Callaghan

doi:10.1016/j.omtm.2020.10.022

siRNA targeting Schlemm's canal endothelial tight junctions enhances outflow facility and reduces IOP in a steroid-induced OHT rodent model

Mol Ther Methods Clin Dev. 2020 Oct 31:20:86-94. doi: 10.1016/j.omtm.2020.10.022. eCollection 2021 Mar 12.

Authors

Affiliations

¹ Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
² Department of Bioengineering, Imperial College London, London, UK.
³ Department of Ophthalmology, Mater Misericordiae University Hospital, Dublin, Ireland.
⁴ Neurovascular Research Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
⁵ Department of Ophthalmology, Duke University, Durham, NC, USA.

Abstract

Systemic or localized application of glucocorticoids (GCs) 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 small interfering RNA (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. In this study, 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-characterized chronic steroid-induced mouse model of ocular hypertension, thus representing a potential focused clinical application for this therapy in a sight-threatening scenario.

Keywords: Schlemm’s canal; glucocorticoid; intracameral; intraocular pressure; ocular hypertension; outflow facility; pores; primary open angle glaucoma; tight junctions; trabecular meshwork.

Abstract

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