siRNA targeting Schlemm’s canal endothelial tight junctions enhances outflow facility and reduces IOP in a steroid-induced OHT rodent model
| Autor: | Ester Reina-Torres, Peter Humphries, Darryl R. Overby, Paul S. Cassidy, W. Daniel Stamer, Marian M. Humphries, Jeffrey O'Callaghan, Joseph M. Sherwood, Anna-Sophia Kiang, Ruth Kelly, Colm O'Brien, Matthew Campbell, G. Jane Farrar |
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| Přispěvatelé: | National Institutes of Health |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Small interfering RNA tight junctions lcsh:QH426-470 genetic structures Glaucoma Ocular hypertension 03 medical and health sciences 0302 clinical medicine Schlemm’s canal pores intracameral Genetics medicine lcsh:QH573-671 Molecular Biology Schlemm's canal Tight junction lcsh:Cytology Chemistry trabecular meshwork outflow facility medicine.disease primary open angle glaucoma eye diseases Cell biology Endothelial stem cell lcsh:Genetics 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Paracellular transport ocular hypertension Molecular Medicine Original Article glucocorticoid sense organs Trabecular meshwork intraocular pressure |
| Zdroj: | Molecular Therapy. Methods & Clinical Development Molecular Therapy: Methods & Clinical Development, Vol 20, Iss, Pp 86-94 (2021) |
| ISSN: | 2329-0501 |
| Popis: | 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. Graphical Abstract 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. |
| Databáze: | OpenAIRE |
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