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

 描述(申请人提供)：青光眼是导致失明的主要原因，全世界有6000多万人患有青光眼。青光眼的视力丧失是由于视网膜神经节细胞的进行性丧失导致视神经变形。虽然引发各种形式青光眼的致病因素仍不清楚，但房水引流受损引起的眼压升高已被确定为一个主要的危险因素。因此，目前的内科和外科治疗都是为了促进前房液体排出，以降低高眼压。虽然这些疗法显示出一些好处，但没有一种是治愈的。寻找治疗方法的最大障碍是对导致房水引流减少和视网膜神经节丢失的分子事件缺乏了解，阻碍了基于潜在疾病机制的治疗方法的发展。我们已经证明，在小鼠中，血管生成素-Tie2信号通路的遗传破坏会导致高眼压、眼球和原发性先天性青光眼(PCG)的经典特征，PCG是一种对儿童特别有害的疾病，占儿童失明的5%，占盲校登记的18%。我们的小鼠的主要缺陷是Schlemm管和角膜缘淋巴管的丢失，导致房水引流的缺陷。在174例PCG儿童中，我们发现了TIE2基因及其配体血管生成素1(ANGPT1)的10个突变，表明这一途径在人类疾病中发挥着重要作用。在这个方案中，我们将检验假设：1)包括流出道在内的眼前角的发育取决于Tie2受体的活动水平，并且引流血管的大小和/或功能的减小足以导致高眼压，从而导致视网膜神经节细胞缺失和青光眼。2)PCG患儿TIE2和ANGPT1基因突变降低了TIE2受体的信号功能，导致Schlemm管改变和前房流出。3)角膜缘区TIE2信号的激活可增加Schlemm管的大小和功能，促进房水排出，降低眼压，防止视网膜神经节和视力丧失。为了验证这些假设，我们组建了由眼科医生、视觉科学家、遗传学家、蛋白质组专家、血管生物学家和多种独特试剂组成的多学科团队，使我们能够确定：1)Angpt-Tie2信号的一系列下调对基因工程小鼠的虹膜角膜发育、眼压和青光眼症状的影响2)PCG儿童中的TIE2和ANGPT1突变如何影响受体的活性3)TIE2通过遗传或小分子手段激活TIE2是可以挽救青光眼表型。我们的研究为确定青光眼和高眼压的新分子机制提供了前所未有的机会，并通过开发第一个生物靶向治疗方法提供了治疗青光眼和高眼压的创新方法。

 DESCRIPTION (provided by applicant): Glaucoma is a leading cause of blindness, afflicting more than 60 million people worldwide. Vision loss in glaucoma is due to progressive loss of retinal ganglion cells leading to deformation of the optic nerve. While the pathogenic events triggering the various forms of glaucoma remain obscure, increased intraocular pressure (IOP) due to impaired aqueous humor drainage has been identified as a major risk factor. Accordingly, current medical and surgical therapies are designed to promote fluid drainage from the anterior chamber to reduce ocular hypertension. While these therapies show some benefit, none are curative. The greatest obstacle to finding a cure has been a poor understanding of the molecular events leading to decreased aqueous humor drainage and retinal ganglion loss, preventing the development of therapies based on underlying disease mechanisms. We have shown that genetic disruption of the Angiopoietin-Tie2 signaling pathway in mice results in high IOP, bupthalmos and classic features of primary congenital glaucoma (PCG), a particularly devastating form of the disease in children that accounts for 5% of childhood blindness and 18% of blind-school registry. The primary defect in our mice is loss of Schlemm's canal and corneal limbal lymphatics resulting in defects of aqueous humor drainage. In 174 children with PCG, we have identified 10 mutations in the TIE2 gene and its ligand, Angiopoietin 1 (ANGPT1), suggesting this pathway plays a major role in human disease. In this proposal we will test the hypotheses that: 1) The development of the anterior angle of the eye including the outflow tract is dependent on the level of activity of the Tie2 receptor and reduced size and/or function of the draining vessels is sufficient to cause ocular hypertension, resulting in retinal ganglion cell los and glaucoma. 2) The TIE2 and ANGPT1 mutations observed in children with PCG reduce signaling function of the TIE2 receptor leading to alterations in Schlemm's canal and outflow of the anterior chamber. 3) Activation of TIE2 signaling within the corneal limbal region will enhance the size and function of Schlemm's canal, promoting aqueous humor drainage, reducing IOP and preventing retinal ganglion and vision loss. To test these hypotheses we have assembled a multidisciplinary team of ophthalmologists, vision scientists, geneticists, proteomics experts, vascular biologists and a number of unique reagents permitting us to determine: 1) the impact of a range of reductions in Angpt-Tie2 signaling on development of the irido-corneal angle, IOP and features of glaucoma in genetically engineered mice 2) how the TIE2 and ANGPT1 mutations in children with PCG affect activity of the receptor 3) whether activation of TIE2 using genetic or small molecule approaches rescues the glaucoma phenotype. Our studies provide an unprecedented opportunity to determine novel molecular mechanisms of glaucoma and ocular hypertension and an innovative approach to treat glaucoma and ocular hypertension through development of the first biologically-targeted therapy.