Abstract:
Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, there is a need for the development of less invasive treatments. Here, we designed an allosteric inhibitor of end binding-3 (EB3) protein, termed EBIN, which reduces the effects of environmental stresses on endothelial cells by limiting pathological calcium signaling. Delivery of EBIN via eye drops in mouse and non-human primate (NHP) models of wet AMD prevents both neovascular leakage and choroidal neovascularization. EBIN reverses the epigenetic changes induced by environmental stresses, allowing an activation of a regenerative program within metabolic-active endothelial cells comprising choroidal neovascularization (CNV) lesions. These results suggest the therapeutic potential of EBIN in preventing the degenerative processes underlying wet AMD.
摘要:
湿性年龄相关性黄斑变性(AMD),特征是脉络膜产生的新血管渗漏,是失明的主要原因。由于目前治疗湿性AMD需要定期玻璃体内注射抗血管内皮生长因子(VEGF)生物制剂,需要开发侵入性较小的治疗方法。这里,我们设计了一种末端结合3(EB3)蛋白的变构抑制剂,被称为EBIN,通过限制病理性钙信号来减少环境压力对内皮细胞的影响。在湿性AMD的小鼠和非人灵长类动物(NHP)模型中通过滴眼剂递送EBIN可防止新生血管渗漏和脉络膜新生血管形成。EBIN逆转了环境压力诱导的表观遗传变化,允许在包含脉络膜新生血管(CNV)病变的代谢活性内皮细胞内激活再生程序。这些结果表明EBIN在预防湿性AMD的退行性过程中具有治疗潜力。