Activation of the Angiopoietin-Tie2/TEK Pathway to Treat Ocular Hypertension and Glaucoma

青光眼是导致失明的主要原因，影响全球6000多万人。 升高的眼内压（IOP）是青光眼发展和进展的主要危险因素， 这是由于对房水流出的阻力增加。已证明降低IOP可降低风险 降低高眼压症患者转变为青光眼的风险，并降低眼部疾病恶化的风险 患有现有的青光眼损伤。虽然降低IOP的治疗能够恢复视网膜的结构和功能， 增加流出阻力的患病组织是特别需要的，但目前很少有这样的治疗方法。 这些病变组织位于由小梁网组成的传统流出道中 (TM)Schlemm氏管（SC）2013年，我们的研究小组发现，血管生成素（Angpt）的活性降低- TEK血管信号传导途径导致小鼠中严重形式的原发性先天性青光眼（PCG）， SC的失败。在上一个研究周期中，我们发现血管生成素1配体表达于 TM是激活SC中Tie 2/TEK受体和青光眼疾病严重性所必需的 表型与Angpt/TEK信号强度的剂量密切相关。我们成功救出了PCG 通过抑制血管特异性磷酸酶PTPRB，从而增强TEK信号， 以不依赖配体的方式增强。通过与一个国际团队的合作，我们现已确定了20个 在20个个体中TEK和ANGPT 1基因的独特功能丧失突变，提供了一种新的遗传学证据。 PCG的原因，并确认这一途径在人类疾病中的重要性。成人原发性 开角型青光眼（POAG），已经鉴定了Angpt/TEK通路中的风险变体，并且肽体 靶向血管阿片肽配体通过减少流出导致成年猴高压OAG快速发作 设施，扩大这一途径的重要性超越儿童青光眼。总而言之，我们的发现在很大程度上 由该赠款的第一个周期资助，导致了对青光眼发病机制的重大新见解， 发展的流出道，并直接导致确定一个新的遗传原因的青光眼。 在这次竞争性更新中，我们建议利用这些开创性的发现：1）充分表征细胞 通过单克隆抗体研究Angpt-TEK信号在流出道发育和青光眼发病机制中的基础 细胞分析2）功能性注释在PCG和POAG患者中鉴定的2个新的疾病基因， 确定它们如何调节Angpt/TEK信号强度和3）测试新的ANGPT 1模拟物 修复青光眼模型中有缺陷的SC和TM，增强流出功能。到下一个周期结束时，我们 将对TM和SC中的特定细胞群进行表征，确定青光眼的新基因 并为临床开发提供先导化合物。

SUMMARY - Glaucoma is a leading cause of blindness affecting more than 60 million people worldwide. Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of glaucoma and results from increased resistance to aqueous humor outflow. IOP reduction has been shown to reduce the risk of conversion to glaucoma in eyes with ocular hypertension and reduce the risk of disease worsening in eyes with existing glaucoma damage. While IOP-lowering therapies capable of restoring structure and function of the diseased tissues that increase outflow resistance are particularly desirable, few such therapies currently exist. These diseased tissues reside in the conventional outflow tract that is comprised of the trabecular meshwork (TM) and Schlemm’s canal (SC). In 2013, our group discovered that reduced activity of the Angiopoietin (Angpt)- TEK vascular signaling pathway results in a severe form of primary congenital glaucoma (PCG) in mice due to failure of the SC to form. During the last grant cycle, we showed that the Angiopoietin1 ligand is expressed in the TM and is required to activate the Tie2/TEK receptor in the SC and that severity of glaucoma disease phenotype correlates tightly with the dose of Angpt/TEK signal strength. We were able to rescue the PCG disease phenotype in mice, by inhibiting the vascular-specific phosphatase PTPRB, thereby boosting TEK signal strength in a ligand-independent manner. In collaboration with an international team, we have now identified 20 unique loss-of-function mutations in the TEK and ANGPT1 genes in 20 individuals, providing a new genetic cause of PCG and confirming the importance of this pathway in human disease. In adult patients with primary open angle glaucoma (POAG), risk variants in the Angpt/TEK pathway have been identified and a pepti-body targeting Angiopioetin ligands causes rapid onset of high pressure OAG in adult monkeys by reducing outflow facility, extending importance of this pathway beyond childhood glaucoma. Altogether, our findings, largely funded by the first cycle of this grant, have led to major new insights into the pathogenesis of glaucoma and development of the outflow tract and have led directly to the identification of a new genetic cause of glaucoma. In this competitive renewal, we propose to leverage these seminal discoveries to:1) fully characterize the cellular basis of Angpt-TEK signaling in development of the outflow tract and pathogenesis of glaucoma through single cell analysis 2) functionally annotate 2 new disease genes identified in patients with PCG and POAG and determine how they modulate Angpt/TEK signal strength and 3) test the ability of a novel ANGPT1-mimetic to repair defective SC and TM in glaucoma models and enhance outflow facility. By the end of the next cycle, we will have characterized specific cell populations in the TM and SC, identified new genes responsible for glaucoma and provide lead compounds to take forward to clinical development.