Targeting Scleral Stiffness as a Novel Therapeutic Approach in Glaucoma

 描述（由申请人提供）：青光眼是失明的主要原因，目前的治疗是不够的。在这里，我们提出测试一种新的治疗方法的基础上硬化的视乳头周围巩膜，这是一个全新的范例来治疗青光眼。我们的中心假设是，增加视乳头周围巩膜硬度将减少眼内压诱导的柔软、精细的视神经乳头（ONH）组织的变形（“屏蔽”），这反过来将通过减少对ONH细胞及其周围基质的生物力学损伤来保护视网膜神经节细胞（RGC）功能。如果成功，这种疗法将独立于眼内压（IOP）降低，并与之协同。我们提出了3个具体目标（SA）来检验这一假设。在SA 1中，我们将优化和表征巩膜硬化剂（交联剂和BMP-2）如何影响巩膜、视网膜和IOP对ONH的生物力学“损伤”。在SA 2中，我们将评估青光眼实验模型中后巩膜硬度增加对RGCs功能和活力的影响。最后，在SA 3中，我们将巩膜硬化的影响局限于视乳头周围巩膜，优化青光眼患者巩膜硬化的未来治疗方法的疗效。除了上面概述的新颖范例之外，这个项目具有创新性还有几个原因。我们将使用生物学上的 适当的药剂（BMP-2），而不是苛刻的交联剂。它将开发新技术，将硬化剂输送到活体眼睛，并控制它们发挥作用的位置。它将使用最先进的生物力学、生物学和生理学技术来表征接受治疗的眼睛的眼部健康和功能。我们将首先在正常眼压大鼠眼中表征硬化剂的性能（在避免毒性的同时使巩膜硬化的能力）。我们还将量化巩膜特性的变化如何影响大鼠ONH生物力学环境。然后，我们将在已建立的高眼压大鼠模型（莫里森高渗盐水注射模型）中评价通过结膜下递送BMP-2和几种巩膜交联剂的RGC保护作用。最后，我们将在同一莫里森模型中使用脉络膜上递送和光诱导凝胶化来精确地将BMP-2和交联剂递送到视乳头周围巩膜。通过这种方式，我们可以全面测试我们的假设，并确定哪些代理和交付方法在实践中最有效。正如我们的初步数据所示，我们期望显示BMP-2递送到视乳头周围巩膜在视网膜病变中具有神经保护作用。 高眼压与调节内源性BMP-2活性的新策略一起，这将激励这种治疗方法的临床转化。

 DESCRIPTION (provided by applicant): Glaucoma is a major cause of blindness and current treatments are insufficient. Here we propose to test a novel therapy based on stiffening the peripapillary sclera, which represents an entirely new paradigm to treat glaucoma. Our central hypothesis is that increasing peripapillary scleral stiffness will reduce intraocular pressure- induced deformation of soft, delicate optic nerve head (ONH) tissues ("shielding"), which will in turn protect retinal ganglion cell (RGC) function by decreasing the biomechanical insult to ONH cells and their surrounding matrix. This therapy, if successful, would be independent of, and synergistic with, intraocular pressure (IOP) lowering. We propose 3 specific aims (SA's) to test this hypothesis. In SA1, we will optimize and characterize how scleral stiffening agents (crosslinkers and BMP-2) affect sclera, retina, and the biomechanical "insult" delivered to ONH by IOP. In SA2, we will evaluate the effects of increased posterior scleral stiffness on the function and viability of RGCs in an experimental model of glaucoma. Finally, in SA3 we will localize effects of scleral stiffening to the peripapillary sclera, optimizing the efficacy of futue therapeutic approaches to scleral stiffening in glaucoma patients. In addition to the novel paradigm outlined above, this project is innovative for several reasons. We will use a biologically appropriate agent (BMP-2) to stiffen sclera, rather than harsher crosslinkers. It will develop novel technologies to deliver stiffening agents to the living eye, and to control where they exert their effect. It will use state-of-the-art biomechanical, biological and physiological techniques t characterize ocular health and function in treated eyes. We will first characterize the performance of stiffening agents (ability to stiffen sclera while avoiding toxicity) in normotensiv rat eyes. We will also quantify how changing scleral properties affects the ONH biomechanical environment in the rat. We will then evaluate RGC protection by subconjunctival delivery of BMP-2 and several scleral crosslinkers in an established rat model of ocular hypertension (the Morrison hypertonic saline injection model). Finally, we will use suprachoroidal delivery and light-induced gelation to precisely deliver BMP-2 and crosslinkers to the peripapillary sclera in the same Morrison model. In this way we can comprehensively test our hypothesis, and determine which agents and delivery method work best in practice. We expect, as indicated by our preliminary data, to show that BMP-2 delivery to the peripapillary sclera is neuroprotective in ocular hypertension. Together with novel strategies for modulating endogenous BMP-2 activity, this would motivate clinical translation of this therapeutic approach.