Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Ophthalmology, the Fourth Affiliated Hospital of China Medical University, Eye Hospital of China Medical University, Key Lens Research Laboratory of Liaoning Province, Shenyang, China.
JCI Insight. 2022 Jul 8;7(13):e157896. doi: 10.1172/jci.insight.157896.
Most patients with neovascular age-related macular degeneration (nvAMD), the leading cause of severe vision loss in elderly US citizens, respond inadequately to current therapies targeting a single angiogenic mediator, vascular endothelial growth factor (VEGF). Here, we report that aqueous fluid levels of a second vasoactive mediator, angiopoietin-like 4 (ANGPTL4), can help predict the response of patients with nvAMD to anti-VEGF therapies. ANGPTL4 expression was higher in patients who required monthly treatment with anti-VEGF therapies compared with patients who could be effectively treated with less-frequent injections. We further demonstrate that ANGPTL4 acts synergistically with VEGF to promote the growth and leakage of choroidal neovascular (CNV) lesions in mice. Targeting ANGPTL4 expression was as effective as targeting VEGF expression for treating CNV in mice, while simultaneously targeting both was more effective than targeting either factor alone. To help translate these findings to patients, we used a soluble receptor that binds to both VEGF and ANGPTL4 and effectively inhibited the development of CNV lesions in mice. Our findings provide an assay that can help predict the response of patients with nvAMD to anti-VEGF monotherapy and suggest that therapies targeting both ANGPTL4 and VEGF will be a more effective approach for the treatment of this blinding disease.
大多数患有新生血管性年龄相关性黄斑变性（nvAMD）的患者，这种疾病是美国老年公民视力严重丧失的主要原因，对目前针对单一血管生成介质血管内皮生长因子（VEGF）的治疗反应不佳。在这里，我们报告说，第二种血管活性介质血管生成素样 4（ANGPTL4）的眼内液水平可以帮助预测 nvAMD 患者对抗 VEGF 治疗的反应。与可以通过较少频率的注射有效治疗的患者相比，需要每月接受抗 VEGF 治疗的患者的 ANGPTL4 表达更高。我们进一步证明，ANGPTL4 与 VEGF 协同作用，促进脉络膜新生血管（CNV）病变在小鼠中的生长和渗漏。针对 ANGPTL4 的表达与针对 VEGF 的表达一样有效，可用于治疗小鼠的 CNV，而同时针对两者比单独针对任何一种因素更有效。为了帮助将这些发现转化为患者，我们使用了一种可溶性受体，该受体可与 VEGF 和 ANGPTL4 结合，并有效抑制了小鼠 CNV 病变的发展。我们的发现提供了一种可以帮助预测 nvAMD 患者对抗 VEGF 单药治疗反应的检测方法，并表明针对 ANGPTL4 和 VEGF 的治疗方法将是治疗这种致盲疾病的更有效方法。
