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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)86-94
Number of pages9
JournalMolecular Therapy - Methods and Clinical Development
Volume20
DOIs
StatePublished - Mar 12 2021
Externally publishedYes

Keywords

  • glucocorticoid
  • intracameral
  • intraocular pressure
  • ocular hypertension
  • outflow facility
  • pores
  • primary open angle glaucoma
  • Schlemm's canal
  • tight junctions
  • trabecular meshwork

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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