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

Autor:	Cassidy PS; Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland., Kelly RA; Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland., Reina-Torres E; Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.; Department of Bioengineering, Imperial College London, London, UK., Sherwood JM; Department of Bioengineering, Imperial College London, London, UK., Humphries MM; Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland., Kiang AS; Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland., Farrar GJ; Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland., O'Brien C; Department of Ophthalmology, Mater Misericordiae University Hospital, Dublin, Ireland., Campbell M; Neurovascular Research Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland., Stamer WD; Department of Ophthalmology, Duke University, Durham, NC, USA., Overby DR; Department of Bioengineering, Imperial College London, London, UK., Humphries P; Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland., O'Callaghan J; Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.; Neurovascular Research Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2020 Oct 31; Vol. 20, pp. 86-94. Date of Electronic Publication: 2020 Oct 31 (Print Publication: 2021).
DOI:	10.1016/j.omtm.2020.10.022
Abstrakt:	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. Competing Interests: The authors declare no competing interests. (© 2020 The Author(s).)
Databáze:	MEDLINE
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