Identification of novel small molecule inhibitors of Arf6 for the treatment of va

描述(申请人提供)：老年性黄斑变性是60岁以上人群法定失明的最常见原因，估计有160万患者受到影响。此外，每年有40多万美国糖尿病患者被诊断出患有危及视力的视网膜水肿和/或新生血管。迄今为止取得成功的主要治疗策略侧重于减少来自不稳定途径的信号。这是抗血管内皮生长因子疗法的基础，这种疗法是昂贵的生物制剂，通过眼内注射进行，通常每月一次。纳维根公司试图探索一种替代和创新的方法来治疗视网膜和脉络膜血管床的病理性血管生成和内皮高渗透性。我们的方法通过刺激血管稳定信号来恢复血管动态平衡。通过指导线索的工作，Navigen的科学联合创始人Dean Li博士的实验室发现了一种新型的内皮特异性受体Robo4，当被其同源配体Slit2激活时，它可以稳定内皮，并通过抑制ADP-核糖化因子-6(Arf6)的激活来抑制病理性细胞因子和生长因子诱导的血管生成和血管泄漏。这些发现表明，Robo4的激活，特别是Arf6的抑制，提供了血管稳定信号，积极地指导 内皮细胞维持细胞间的连接，限制血管渗漏和侵袭。我们的初步数据和发表的文献支持Arf6在血管性眼病中的相关性。这项建议概述了一种策略，以确定新的Arf6小分子抑制剂，并在血管眼病的体外模型中测试这些药物。通过采用一种基于识别Arf6小分子抑制剂的方法，我们预计潜在的市场优势包括：局部或口服给药可行的小分子；阻断血管内皮生长因子和其他细胞因子介导的渗漏和血管生成的广泛方法；以及一种独特的生化途径，可以取代或增强目前以抗血管内皮生长因子为中心的治疗。

DESCRIPTION (provided by applicant): Age-Related Macular Degeneration is the most common cause of legal blindness in people over 60, affecting an estimated 1.6 million patients. Additionally, over 400,000 diabetic Americans are diagnosed each year with vision-threatening retinal edema and/or neovascularization. The main therapeutic strategies that have been successful to date have focused on reducing the signals from the destabilizing pathways. This is the basis of anti-VEGF therapies which are costly biologics administered by intraocular injection, typically once monthly. Navigen seeks to explore an alternative and innovative approach to treating the pathologic angiogenesis and endothelial hyperpermeability of the retinal and choroidal vascular beds. Our approach restores the balance toward vascular homeostasis by stimulating vascular stabilization signals. Through its work on guidance cues, the laboratory of Navigen's scientific co-founder, Dr. Dean Li, identified a novel endothelial- specific receptor, Robo4, that when activated by its cognate ligand, Slit2, stabilizes the endothelium and inhibits pathologic cytokine- and growth factor-induced angiogenesis and vascular leak by inhibiting the activation of ADP-ribosylation factor-6 (Arf6). These findings suggest that Robo4 activation, and specifically inhibition of Arf6, provides vascular stabilization signals that actively instruct the endothelium to maintain cell- cell junctions and limit vascular leak and invasion. Our preliminary data and the published literature support the relevance of Arf6 in vascular eye disease. This proposal outlines a strategy to identify novel small molecule inhibitors of Arf6 and to test these in in vitro models of vascular eye disease. By adopting an approach based on identifying small molecule inhibitors of Arf6, we anticipate that potential market advantages include: a small molecule for which topical or oral administration are feasible; a broad based approach to blocking VEGF and other cytokine mediated leak and angiogenesis, and a distinct biochemical pathway that may either replace or augment current anti-VEGF centric therapies.