Abstract
Purpose :
Corneal scarring is a leading cause of vision impairment worldwide and there is an unmet need for new therapies that regulate corneal stromal wound healing to preserve corneal clarity. The transcriptional coactivator Yes-associated protein (YAP) drives fibrosis in many tissues. Verteporfin, a YAP inhibitor, is FDA-approved for treatment of choroidal neovascularization with photodynamic therapy and has been shown to prevent fibrosis and scar formation in several organs. The goal of this study is to evaluate the effect of verteporfin on corneal scarring after mechanical injury.
Methods :
10ng/mL transforming growth factor β1 (TGFβ-1) was used to induce differentiation of corneal stromal stem cells (CSSCs) into myfibroblasts in the presence of varying doses of verteporfin. Reverse-transcription polymerase chain reaction (RT PCR) was used to quantify the expression of alpha-smooth muscle actin (αSMA). For in vivo studies, 20 female Brown Norway rats underwent superficial keratectomy in one eye. Eyes were randomized into 4 study groups to receive a postoperative subconjunctival injection of 1 mg/mL verteporfin (n=6), hyaluronic acid carrier (HA) (n=5), 1 mg/mL verteporfin + HA (n=5), or sham injection (n=4). Corneal epithelial wound closure and corneal opacity was graded using a standard scale over a 2-week period. At 14 days post-operative, eyes were enucleated and processed for immunohistochemistry. Statistical significance was determined using ANOVAs and t tests.
Results :
TGFβ-1 increased the expression of αSMA in CSSCs (p<0.001). Addition of 1mg/mL verteporfin significantly decreased αSMA expression (p<0.001). In a rat model of corneal injury, verteporfin + HA showed accelerated corneal epithelial wound healing compared with verteporfin, HA and sham groups (p<0.1). Verteporfin + HA but not verteporfin alone significantly improved corneal opacity compared with HA and sham groups (p<0.001). Immunohistochemistry of eyes treated with verteporfin + HA showed decreased αSMA expression and YAP activation (p<0.5).
Conclusions :
Verteporfin reduces myofibroblast differentiation in corneal cells. When delivered with a HA carrier, verteporfin decreases YAP activity and prevents corneal scarring after mechanical injury in a rat model. Given that verteporfin is already FDA approved for use in the eye, it is a promising agent to be repurposed for the treatment of corneal scarring.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.