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

• Published in: Molecular therapy. Methods & clinical development Vol. 20; pp. 86 - 94
• Main Authors: Cassidy, Paul S., Kelly, Ruth A., Reina-Torres, Ester, Sherwood, Joseph M., Humphries, Marian M., Kiang, Anna-Sophia, Farrar, G. Jane, O’Brien, Colm, Campbell, Matthew, Stamer, W. Daniel, Overby, Darryl R., Humphries, Pete, O’Callaghan, Jeffrey
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.03.2021; American Society of Gene & Cell Therapy; Elsevier
• Subjects: glucocorticoid; intracameral; intraocular pressure; ocular hypertension; Original; outflow facility; pores; primary open angle glaucoma; Schlemm’s canal; tight junctions; trabecular meshwork; glucocorticoid; outflow facility; ocular hypertension; intraocular pressure; primary open angle glaucoma; tight junctions; intracameral; trabecular meshwork; Schlemm’s canal; pores
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2020.10.022

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. [Display omitted] Cassidy and colleagues show that intracameral inoculation of siRNA targeting Schlemm’s canal endothelial cell tight junction proteins, ZO-1 and tricellulin, can reduce intraocular pressure and increase outflow facility in a murine model of steroid-induced ocular hypertension.