Targeting Scleral Stiffness as a Novel Therapeutic Approach in Glaucoma

 描述(申请人提供)：青光眼是导致失明的主要原因，目前的治疗方法不足。在这里，我们建议测试一种基于硬化乳头周围巩膜的新疗法，这代表了一种治疗青光眼的全新范式。我们的中心假设是，增加乳头状巩膜周围的硬度将减少眼压引起的柔软、脆弱的视神经头(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)的功能。这种疗法，如果成功，将是独立的，并与降低眼压协同作用。我们提出了三个特定的目标(SA)来检验这一假设。在SA1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“侮辱”。在SA2中，我们将在青光眼实验模型中评估后巩膜硬度增加对视网膜神经节细胞功能和活性的影响。最后，在SA3中，我们将定位巩膜硬化对乳头周围巩膜的影响，优化未来治疗青光眼患者巩膜硬化的方法的疗效。除了上面概述的新范例外，这个项目具有创新性的原因有几个。我们将使用一种生物学上的 合适的巩膜硬化剂(BMP-2)，而不是更硬的交联剂。它将开发新的技术，将强化剂输送到活着的眼睛，并控制它们在哪里发挥作用。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睛健康和功能。我们将首先在正常血压的大鼠眼睛中表征硬化剂的性能(在避免毒性的同时使巩膜僵硬的能力)。我们还将量化变化的巩膜特性如何影响大鼠的ONH生物力学环境。然后，我们将评估结膜下注射BMP-2和几种巩膜交联剂对已建立的高眼压大鼠模型(Morison高渗盐水注射模型)的RGC保护作用。最后，我们将使用超脉络膜输送和光诱导凝胶将BMP-2和交联物精确地输送到相同的Morrison模型的乳头周围巩膜。通过这种方式，我们可以全面检验我们的假设，并确定哪种试剂和递送方法在实践中效果最好。我们希望，正如我们的初步数据所表明的那样，将BMP-2输送到乳头周围巩膜具有神经保护作用。 高眼压。再加上调节内源性BMP-2活性的新策略，这将推动这一治疗方法的临床翻译。

 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.