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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Cassidy, PS; Kelly, RA; Reina-Torres, E; Sherwood, JM; Humphries, MM; Kiang, A-S; Farrar, GJ; O'Brien, C; Campbell, M; Stamer, WD; Overby, DR; Humphries, P; O'Callaghan, J

Published Date

  • March 12, 2021

Published In

Volume / Issue

  • 20 /

Start / End Page

  • 86 - 94

PubMed ID

  • 33376757

Pubmed Central ID

  • 33376757

International Standard Serial Number (ISSN)

  • 2329-0501

Digital Object Identifier (DOI)

  • 10.1016/j.omtm.2020.10.022

Language

  • eng

Conference Location

  • United States