Abstract
Purpose :
Neovascular age-related macular degeneration (nAMD) is a common cause of irreversible vision loss in the elderly. The Wnt/β-catenin pathway plays essential roles in development and progression of nAMD and may serve as an attractive target for the development of therapeutics for nAMD. This study aimed to uncover the mode of action of IPT012 and examine its therapeutic effect in vitro and in vivo.
Methods :
In vitro cellular studies were conducted using retinal pigment epithelial cell lines (ARPE-19 and hTERT-RPE1), and human umbilical vein endothelial cells. In vivo efficacy was examined and the concentrations of IPT012 in plasma and choroid tissue were measured in laser-induced choroidal neovascularization rabbit models.
Results :
IPT012, a novel pyranocoumarin derivative, decreased the expression of angiogenic/inflammatory factors and suppressed epithelial-mesenchymal transition in retinal pigment epithelial (RPE) cells by promoting β-catenin degradation. In addition, it repressed the expression of cyclin D1 and c-myc, downstream target genes of β-catenin, thereby inhibiting the proliferation and tube formation of human umbilical vein endothelial cells (HUVECs). In contrast, IPT012 enantiomer did not affect the levels of β-catenin and its target genes in RPE cells and HUVECs. Intravitreal IPT012 implant significantly reduced choroidal neovascularization in laser-induced choroidal neovascularization rabbit model. Notably, sustained delivery of IPT012 by was highly permeable to choroid tissue without any blood exposure and downregulated the levels of β-catenin and angiogenic/inflammatory factors in vivo.
Conclusions :
Our findings demonstrate that IPT012 functions through suppression of the Wnt/β-catenin pathway with conceivable advantages over existing cytokine-targeted anti-angiogenic therapies.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.