Yeh Shu-I, Ho Tsung-Chuan, Chu Ting-Wen, Chen Show-Li, Ou Ruchong, Tsao Yeou-Ping
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan.
Transl Vis Sci Technol. 2025 Aug 1;14(8):21. doi: 10.1167/tvst.14.8.21.
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.
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.
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.
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.
OBM1701 in ophthalmic drop shows the potential to be developed into a novel therapy for the treatment of nAMD.
OBM1701是一种源自色素上皮衍生因子的短肽，可通过阻断内皮细胞血管生成来消除角膜新生血管。视网膜色素上皮（RPE）中缺氧诱导因子（HIF）-1α的激活对于脉络膜新生血管（CNV）的发病机制至关重要，而CNV是新生血管性年龄相关性黄斑变性（nAMD）的标志。在此，研究了OBM1701对动物激光诱导的CNV的潜在抑制作用。
激光损伤后两天，每天一次局部应用OBM1701眼药水，持续12天。随后，分别通过荧光素血管造影和脉络膜/RPE平铺片上的异凝集素GS-IB4染色测量CNV血管渗漏和CNV面积。免疫染色用于检测CNV病变中HIF-1α和血管内皮生长因子A（VEGFA）的表达。在体外，分别通过在培养物中添加二甲基草酰甘氨酸和缺氧模拟条件，使ARPE-19细胞和原代猪RPE暴露于缺氧模拟条件下。然后通过实时PCR和蛋白质印迹法评估HIF-1α和VEGFA的基因和蛋白质表达。
OBM1701有效减少了血管渗漏和CNV形成。同时，OBM1701治疗阻断了CNV病变内RPE细胞中HIF-1α和VEGFA的过表达。在培养中，OBM1701预处理抑制了缺氧诱导的HIF-1α和VEGFA表达。
通过动物研究，我们证明OBM1701具有治疗CNV的潜力。我们还建议将RPE作为OBM1701治疗CNV的药物靶点，通过减弱缺氧诱导的HIF-1α/VEGFA信号传导来实现。
眼药水形式的OBM1701显示出有潜力开发成为治疗nAMD的新型疗法。
