Author:
Delgado-Tirado Santiago,Amarnani Dhanesh,Zhao Guannan,Rossin Elizabeth J.,Eliott Dean,Miller John B.,Greene Whitney A.,Ramos Leslie,Arevalo-Alquichire Said,Leyton-Cifuentes David,Gonzalez-Buendia Lucia,Isaacs-Bernal Daniela,Whitmore Hannah A. B.,Chmielewska Natalia,Duffy Brandon V.,Kim Eric,Wang Heuy-Ching,Ruiz-Moreno Jose M.,Kim Leo A.,Arboleda-Velasquez Joseph F.
Abstract
AbstractProliferative vitreoretinopathy (PVR) is the leading cause of retinal detachment surgery failure. Despite significant advances in vitreoretinal surgery, it still remains without an effective prophylactic or therapeutic medical treatment. After ocular injury or retinal detachment, misplaced retinal cells undergo epithelial to mesenchymal transition (EMT) to form contractile membranes within the eye. We identified Runt-related transcription factor 1 (RUNX1) as a gene highly expressed in surgically-removed human PVR specimens. RUNX1 upregulation was a hallmark of EMT in primary cultures derived from human PVR membranes (C-PVR). The inhibition of RUNX1 reduced proliferation of human C-PVR cells in vitro, and curbed growth of freshly isolated human PVR membranes in an explant assay. We formulated Ro5-3335, a lipophilic small molecule RUNX1 inhibitor, into a nanoemulsion that when administered topically curbed the progression of disease in a novel rabbit model of mild PVR developed using C-PVR cells. Mass spectrometry analysis detected 2.67 ng/mL of Ro5-3335 within the vitreous cavity after treatment. This work shows a critical role for RUNX1 in PVR and supports the feasibility of targeting RUNX1 within the eye for the treatment of an EMT-mediated condition using a topical ophthalmic agent.
Funder
Fundacion Alfonso Martin Escudero
Departamento Administrativo de Ciencia, Tecnología e Innovación
National Eye Institute
E. Matilda Ziegler Foundation for the Blind
Karl Kirchgessner Foundation
U.S. Department of Defense
Publisher
Springer Science and Business Media LLC
Cited by
22 articles.
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