Neovascular age-related macular degeneration (nvAMD) is the leading cause of severe vision loss in the elderly in the developed world. While the introduction of therapies targeting vascular endothelial growth factor (VEGF) has provided the first opportunity to significantly improve vision in patients with nvAMD, many patients respond inadequately to current anti-VEGF therapies. It was recently demonstrated that expression of a second angiogenic mediator, angiopoietin-like 4 (ANGPTL4), synergizes with VEGF to promote choroidal neovascularization (CNV) in mice and correlates with reduced response to anti-VEGF therapy in patients with nvAMD. Here, we report that expression of ANGPTL4 in patients with nvAMD increases following treatment with anti-VEGF therapy and that this increase is dependent on accumulation of hypoxia-inducible factor (HIF)-1α in response to inhibition of VEGF/KDR signaling in the retinal pigment epithelium (RPE). We therefore explored HIF-1 inhibition with 32-134D, a recently developed pharmacologic HIF-inhibitor, for the treatment of nvAMD. 32-134D prevented the expression of both VEGF and ANGPTL4 and was at least as effective as aflibercept in treating CNV in mice. Moreover, by preventing the increase in HIF-1α accumulation in the RPE in response to anti-VEGF therapy, combining 32-134D with aflibercept was more effective than either drug alone for the treatment of CNV. Collectively, these results help explain why many patients with nvAMD respond inadequately to anti-VEGF therapy and suggest that the HIF inhibitor 32-134D will be an effective drug—alone or in combination with current anti-VEGF therapies—for the treatment of patients with this blinding disease.

中文翻译：

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VEGF 抑制通过 RPE 增加 HIF 调节的血管生成基因的表达，从而限制湿润的 AMD 眼对阿柏西普的反应


新生血管性年龄相关性黄斑变性 （nvAMD） 是发达国家老年人严重视力丧失的主要原因。虽然针对血管内皮生长因子 （VEGF） 的疗法的引入为显著改善 NVAMD 患者的视力提供了第一个机会，但许多患者对当前的抗 VEGF 疗法反应不足。最近证明，第二种血管生成介质血管生成素样 4 （ANGPTL4） 的表达与 VEGF 协同促进小鼠脉络膜新生血管形成 （CNV），并与 nvAMD 患者对抗 VEGF 治疗的反应降低相关。在这里，我们报道了 nvAMD 患者在接受抗 VEGF 治疗后 ANGPTL4 的表达增加，并且这种增加取决于缺氧诱导因子 （HIF）-1α 的积累，以响应视网膜色素上皮 （RPE） 中 VEGF/KDR 信号传导的抑制。因此，我们探索了 32-134D（一种最近开发的药物 HIF 抑制剂）对 HIF-1 的抑制作用，用于治疗 nvAMD。32-134D 阻止了 VEGF 和 ANGPTL4 的表达，并且在治疗小鼠 CNV 方面至少与阿柏西普一样有效。此外，通过阻止 RPE 中 HIF-1α 积累的增加以响应抗 VEGF 治疗，32-134D 与阿柏西普联合治疗 CNV 比单独使用任何一种药物更有效。总的来说，这些结果有助于解释为什么许多 nvAMD 患者对抗 VEGF 治疗反应不足，并表明 HIF 抑制剂 32-134D 将是一种有效的药物——单独或与当前的抗 VEGF 疗法联合使用——用于治疗患有这种致盲疾病的患者。