OBM1701 Alleviates Choroidal Neovascularization in Experimental Animals Via Suppressing the Expression of HIF-1α in Retinal Pigment Epithelial Cells.

Abstract

Purpose: OBM1701, a pigment epithelium-derived factor-derived short peptide, can eliminate corneal neovascularization by blocking endothelial cell angiogenesis. Activation of hypoxia-inducible factor (HIF)-1α in the retinal pigment epithelium (RPE) is critical for the pathogenesis of choroidal neovascularization (CNV), the hallmark of neovascular age-related macular degeneration (nAMD). Here, the potential inhibitory effect of OBM1701 on laser-induced CNV in animals was investigated.

Methods: Two days after the laser injury, topical OBM1701 eye drops were applied once daily for 12 days. Subsequently, CNV vascular leakage and CNV area were measured by fluorescein angiography and isolectin GS-IB4 staining on choroidal/RPE flatmounts, respectively. Immunostaining was used to detect the expression of HIF-1α and vascular endothelial growth factor A (VEGFA) in CNV lesions. In vitro, ARPE-19 cells and primary porcine RPE were exposed to hypoxia mimetic condition by adding dimethyloxalylglycine and oxygen deprivation in cultures, respectively. Then the gene and protein expression of HIF-1α and VEGFA were evaluated by real-time PCR and Western blotting.

Results: OBM1701 effectively reduced vascular leakage and CNV formation. Meanwhile, OBM1701 treatment blocked the overexpression of HIF-1α and VEGFA in RPE cells located within CNV lesions. In culture, OBM1701 pretreatment suppressed hypoxia-induced HIF-1α and VEGFA expressions.

Conclusions: Through animal studies, we demonstrate that OBM1701 has the potential to treat CNV. We also suggest RPE as a drug target for OBM1701 to treat CNV, by attenuating the hypoxia-induced HIF-1α/VEGFA signaling.

Translational relevance: OBM1701 in ophthalmic drop shows the potential to be developed into a novel therapy for the treatment of nAMD.