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

描述（由申请人提供）：年龄相关性黄斑变性是60岁以上人群致盲的最常见原因，估计影响160万患者。此外，每年有超过40万的美国糖尿病患者被诊断患有威胁视力的视网膜水肿和/或新生血管。迄今为止成功的主要治疗策略集中在减少来自不稳定途径的信号。这是抗vegf治疗的基础，这是一种昂贵的生物制剂，通过眼内注射，通常每月一次。Navigen旨在探索一种替代和创新的方法来治疗病理性血管生成和视网膜和脉络膜血管床的内皮细胞高通透性。我们的方法通过刺激血管稳定信号来恢复血管稳态的平衡。通过对引导信号的研究，Navigen的联合创始人Dean Li博士的实验室发现了一种新的内皮特异性受体Robo4，当它被同源配体Slit2激活时，可以稳定内皮，并通过抑制adp -核糖基化因子-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。这些研究结果表明，Robo4的激活，特别是Arf6的抑制，提供了血管稳定信号，主动指导细胞的凋亡

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.