The therapeutic effect of a biodegradable long-acting intravitreal implant containing IPT015 on neovascular age-related macular degeneration by promoting β-catenin degradation

초록

Purpose : Neovascular age-related macular degeneration (nAMD) is a major cause of irreversible vision loss in adults aged 50 and older. Anti-vascular endothelial growth factor (anti-VEGF) therapies have proven effective in treating pathological ocular neovascularization. However, it has limitations, including repeated intraocular injections required to maintain its therapeutic effects and a poor response in some patients. This study aimed to elucidate the mechanism of action of IPT015 and evaluate its therapeutic effect in vitro and in vivo against nAMD. Methods : We performed in vitro cellular studies in retinal pigment epithelial (RPE) cells (ARPE-19), retinal Müller glial cells (MIO-M1), and human umbilical vein endothelial cells (HUVECs). The in vivo efficacy of IPT015 was examined through intravitreal injection and ocular implants in DL-α-aminoadipic acid (AAA)-induced retinal neovascularization (RNV) rabbit models. Results : IPT015, a prenylated chalcone originally isolated from the cortex of Broussonetia papyrifera, inhibited the Wnt/β-catenin pathway by promoting the degradation of intracellular β-catenin. IPT015 reduced the expression of angiogenic/proinflammatory factors in RPE, Müller, and HUVEC cells. Additionally, IPT015 suppressed the expression of fibrotic markers in RPE cells and inhibited capillary tube formation in HUVEC cells. IPT015 intravitreal injection significantly reduced vascular leakage in DL-AAA-induced rabbit models. Sustained delivery of IPT015 using poly (lactic-co-glycolic acid) (PLGA) intravitreal implants resulted in prolonged regression of retinal neovascularization. Conclusions : Our findings demonstrate that IPT015 implants prevent retinal neovascularization through the sustained release and suppression of the Wnt/β-catenin pathway. Thus, these implants offer additional therapeutic options for the treatment of nAMD.