The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease.
The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease.
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DOI：
10.1126/scitranslmed.aac4882
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发表时间：
2015-10-14
影响因子：
17.1
通讯作者：
Arap W
中科院分区：
文献类型：
--
作者：
Sidman RL;Li J;Lawrence M;Hu W;Musso GF;Giordano RJ;Cardó-Vila M;Pasqualini R;Arap W
已有血管的血管生长（血管生成）是许多严重疾病的基础，包括主要致盲性视网膜疾病，如早产儿视网膜病变 (ROP) 和老年性黄斑变性 (AMD)。这一观察结果推动了抗体抑制剂的开发，该抑制剂可阻止 AMD 的一个核心因子——血管内皮生长因子 (VEGF) 与其受体 VEGFR-1 和 VEGFR-2 的结合。然而，一些患者对当前的抗 VEGF 药物不敏感或产生耐药性，并且需要重复玻璃体内注射这些大分子，成本高昂且存在临床问题。在这里，我们评估了一种小型环状反向倒转肽模拟物 D(Cys-Leu-Pro-Arg-Cys)，缩写为 D(CLPRC)，以下称为 Vasotide，它通过选择性结合 VEGF 受体、VEGFR-1 和 Neuropilin-1 (NRP-1) 来抑制视网膜血管生成。在激光诱导的人类湿性 AMD 猴模型、称为视网膜血管瘤增殖 (RAP) 的 AMD 亚型小鼠基因敲除模型和小鼠氧诱导早产儿视网膜病变 (ROP) 模型中，通过滴眼液或腹膜内注射给予 Vasotide，可显着减少所有三种动物模型中的视网膜血管生成。该原型候选药物是一种很有前途的新型 VEGF 配体双受体抑制剂，有可能转化为更安全、侵入性较小的应用，以对抗视网膜疾病中的病理性血管生成。
Blood vessel growth from preexisting vessels (angiogenesis) underlies many severe diseases including major blinding retinal diseases such as retinopathy of prematurity (ROP) and aged macular degeneration (AMD). This observation has driven development of antibody inhibitors that block a central factor in AMD, named vascular endothelial growth factor (VEGF), from binding to its receptors VEGFR-1 and VEGFR-2. However, some patients are insensitive to current anti-VEGF drugs or develop resistance, and the required repeated intravitreal injection of these large molecules is costly and clinically problematic. Here, we have evaluated a small cyclic retro-inverted peptidomimetic, D(Cys-Leu-Pro-Arg-Cys), abbreviated as D(CLPRC), and hereafter named Vasotide, that inhibits retinal angiogenesis by binding selectively to the VEGF receptors, VEGFR-1 and Neuropilin-1 (NRP-1). Delivery of Vasotide in eye drops or via intraperitoneal injection in a laser-induced monkey model of human wet AMD, a mouse genetic knockout model of the AMD subtype called retinal angiomatous proliferation (RAP), and a mouse oxygen-induced model of retinopathy of prematurity (ROP) markedly decreased retinal angiogenesis in all three animal models. This prototype drug candidate is a promising new dual receptor inhibitor of the VEGF ligand with potential for translation into safer, less invasive applications to combat pathological angiogenesis in retinal disorders.