Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA.
Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL, USA.
Cell Mol Life Sci. 2022 Jan 10;79(1):63. doi: 10.1007/s00018-021-04111-2.
Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized Scg3 binding exclusively to disease-related disorganized retinal neovessels and neovascular tufts, whereas VEGF bound to both disorganized and well-organized neovessels. Homozygous deletion of the Scg3 gene showed undetectable effects on physiological retinal neovascularization but markedly reduced the severity of OIR-induced pathological angiogenesis. Furthermore, anti-Scg3 humanized antibody Fab (hFab) inhibited pathological angiogenesis with similar efficacy to anti-VEGF aflibercept. Aflibercept dose-dependently blocked physiological angiogenesis in neonatal retinas, whereas anti-Scg3 hFab was without adverse effects at any dose and supported a therapeutic window at least 10X wider than that of aflibercept. Therefore, Scg3 stringently regulates pathological but not physiological angiogenesis, and anti-Scg3 hFab satisfies essential criteria for development as a safe and effective disease-targeted anti-angiogenic therapy for ROP.
传统的血管生成因子，如血管内皮生长因子（VEGF），无差别地调节病理性和生理性血管生成，其抑制剂可能会引起不良反应。分泌颗粒蛋白 III（Scg3）最近被报道为一种糖尿病限制的、与 VEGF 无关的血管生成因子，但它在早产儿视网膜病变（ROP）中的疾病选择性尚未确定，ROP 是一种早产儿视网膜疾病，同时存在病理性和生理性血管生成。在这里，我们使用氧诱导的视网膜病变（OIR）小鼠，一种 ROP 的替代模型，定量分析了 Scg3 与患病和健康发育中的新生血管的特异性结合，这与 VEGF 的普遍结合形成鲜明对比。功能免疫组织化学显示 Scg3 特异性结合疾病相关的紊乱视网膜新生血管和新生血管丛，而 VEGF 结合紊乱和组织良好的新生血管。Scg3 基因的纯合缺失对生理性视网膜新生血管化没有明显影响，但明显减轻了 OIR 诱导的病理性血管生成的严重程度。此外，抗 Scg3 人源化抗体 Fab（hFab）抑制病理性血管生成的效果与抗 VEGF 阿柏西普相当。阿柏西普在新生鼠视网膜中剂量依赖性地阻断生理性血管生成，而抗 Scg3 hFab 在任何剂量下均无不良反应，其治疗窗口至少比阿柏西普宽 10 倍。因此，Scg3 严格调节病理性血管生成，但不调节生理性血管生成，抗 Scg3 hFab 满足开发为 ROP 安全有效的疾病靶向抗血管生成治疗的基本标准。
