Open AccessEvaluation of a novel combination of TRAM-34 and ascorbic acid for the treatment of corneal fibrosis in vivo
Author(s) -
A Fuchs,
Praveen Kumar Balne,
Elizabeth A. Giuliano,
Nishant R. Sinha,
Rajiv R. Mohan
Publication year - 2022
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0262046
Subject(s) - fibrosis , ascorbic acid , in vivo , cornea , medicine , pirfenidone , corneal neovascularization , ctgf , pathology , tgfbi , downregulation and upregulation , ophthalmology , neovascularization , chemistry , cancer research , transforming growth factor , growth factor , biology , idiopathic pulmonary fibrosis , angiogenesis , biochemistry , food science , microbiology and biotechnology , receptor , lung , gene
Corneal injury and aberrant wound healing commonly result in corneal fibrosis and subsequent vision loss. Intermediate-conductance calmodulin/calcium-activated K+ channels (K Ca 3.1) have been shown to promote fibrosis in non-ocular and ocular tissues via upregulation of transforming growth factor beta (TGFβ). TRAM-34 is a selective inhibitor of K Ca 3.1 and reduces fibrosis by downregulation of TGFβ-induced transdifferentiation of stromal fibroblasts to myofibroblasts. Ascorbic acid has been demonstrated to be effective in promoting corneal re-epithelialization and reduction of neovascularization via anti-VEGF and anti-MMP mechanisms. This study evaluates tolerability and efficacy of a novel combination of TRAM-34 (25μM) and ascorbic acid (10%) topical treatment for corneal fibrosis using an established in vivo rabbit model and conducting clinical eye examinations. Markers of corneal fibrosis were evaluated in all corneas at study endpoint via histopathology, immunofluorescence, and quantitative real-time PCR. The eyedrop treated eyes showed significantly improved clinical outcomes based on modified McDonald Shadduck scores, reduction of clinical haze on Fantes scores, and reduction of central corneal thickness (CCT). At cellular and molecular levels, eyedrop treatment also significantly reduced expression of alpha smooth muscle actin (α-SMA) mRNA and protein, collagen III mRNA, and fibronectin mRNA compared to non-treated eyes. Our study suggests that a tested new bimodal eyedrop is well tolerated and effectively reduces corneal fibrosis/haze in rabbits in vivo .