Abstract
Purpose :
Anterior surface injury (e.g., trauma or burn) or corneal ulceration due to infection or neuropathy results in epithelial-to-mesenchymal transition (EMT), keratocyte activation, fibroblast-to-myofibroblast transition (FMT), and culminates in aberrant production of collagens and other extracellular matrix molecules. This process is termed corneal fibrosis and may lead to hazing and vision loss if located centrally or to irregular astigmatism and visual distortions if located peripherally. Few to no therapies are currently available to prevent or treat corneal fibrosis and this is therefore an area of high unmet medical need. miR-29b is a potent anti-fibrotic microRNA that inhibits EMT, FMT and collagen expression in multiple organs and tissues. This study investigated the use of remlarsen, a miR-29b mimic currently in clinical trials to inhibit pathologic cutaneous fibrosis, to prevent corneal fibrosis.
Methods :
Remlarsen was administered topically to the rat cornea in the context of an alkali burn for up to 14 days (N=6-12 per group). Eyes were scored for corneal haze, then evaluated histologically for corneal thickness and expression of a-SMA, a marker of EMT and FMT. mRNA expression of collagens and other fibrosis-associated genes was assessed using quantitative RT-PCR. One or two-way ANOVA or non-parametric tests were used to assess statistical significance.
Results :
Remlarsen treatment accelerated the healing of corneal alkali burns, resulting in a more rapid restoration of epithelial thickness and a reduction in stromal thickness as compared to saline treated burned eyes. Remlarsen treatment reduced the expression of multiple collagens and fibrosis associated genes from 7-14 days post-burn and reduced a-SMA protein expression in the epithelium and stroma at 14 days. Furthermore, remlarsen treatment reduced corneal hazing and scarring beginning at 10 days post-burn. Dose and treatment schedule were optimized in preparation for IND-enabling toxicology studies.
Conclusions :
Our results are consistent with remlarsen’s mode of action as a potent antifibrotic in the context of tissue injury. In the rat alkali burn model, remlarsen accelerated repair and inhibited EMT, FMT, collagen mRNA expression and corneal hazing and scarring. These findings indicate that remlarsen may offer a novel therapeutic for prevention of corneal fibrosis following injury or ulceration.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.