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

摘要-青光眼是影响全球6000多万人失明的主要原因。 高眼压是青光眼发生和发展的主要危险因素 由于对房水流出的抵抗力增强。研究表明，降低眼压可以降低患病风险。 减少高眼压患者转化为青光眼的风险，降低疾病恶化的风险 有现有的青光眼损伤。虽然降眼压疗法能够恢复眼球的结构和功能 增加流出阻力的病变组织是特别可取的，目前几乎没有这样的疗法。 这些病变组织驻留在由小梁网组成的常规流出道中。 (TM)和Schlemm管(SC)。2013年，我们的团队发现血管生成素(Angpt)活性降低- TEK血管信号通路导致严重形式的小鼠原发性先天性青光眼(PCG) SC未能成立。在上一个授予周期中，我们发现Angiopoietin1配体在 TM和激活SC中Tie2/TEK受体所必需的和青光眼疾病的严重性 表型与Angpt/TEK信号强度的剂量密切相关。我们成功拯救了盈科 小鼠的疾病表型，通过抑制血管特异性磷酸酶PTPRB，从而增强TEK信号 以一种与配体无关的方式增强力量。通过与一个国际团队的合作，我们现在已经确定了20个 20名个体中TEK和ANGPT1基因独特的功能丧失突变，提供了一种新的基因 并证实了这一途径在人类疾病中的重要性。在成人原发性高血压患者中 开角型青光眼(POAG)是Angpt/TEK通路中的危险变异体，已被鉴定为一种多肽 靶向Angiopioetin配体通过减少流出导致成年猴高血压OAG的快速发作 设施，将这一途径的重要性延伸到儿童青光眼之外。总的来说，我们的发现在很大程度上 由这笔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，并 并直接导致了青光眼一种新的遗传病因的确定。 在这次竞争更新中，我们建议利用这些开创性的发现来：1)充分描述细胞 Angpt-TEK信号通路在流出道发育和青光眼发病机制中的基础 细胞分析2)从功能上诠释在PCG和POAG患者中发现的2个新的疾病基因 确定它们如何调制Angpt/TEK信号强度，并3)测试新型ANGPT1模拟物的能力 修复青光眼模型中有缺陷的SC和TM，并增强流出功能。到下一个周期结束时，我们 将表征TM和SC中的特定细胞群，识别出导致青光眼的新基因 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.