Targeting Scleral Stiffness as a Novel Therapeutic Approach in Glaucoma

针对巩膜僵硬作为青光眼治疗的新方法

基本信息

批准号：
9248387
负责人：
C ROSS ETHIER
金额：
$ 50.42万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9248387
关键词：
Adenoviruses Adult Affect Axon Axonal Transport Biological Biology Biomechanics Blindness Cell physiology Cells Cellular biology Clinical Trials Complement Computer Simulation Control Groups Crosslinker Cytoprotection Data Ensure Environment Experimental Designs Experimental Models Eye Fibroblasts Formulation Functional disorder Future Gene Expression Glaucoma Health Human Image Injection of therapeutic agent Light Measures Methodology Methods Modeling Modification Morphology Mus Ocular Hypertension Optic Disk Optics Outcome Measure Partner in relationship Patients Pattern Performance Physiologic Intraocular Pressure Physiological Play Primates Property Rattus Research Resistance Retina Retinal Retinal Ganglion Cells Risk Factors Role Saline Sclera Symptoms Techniques Technology Testing Therapeutic Tissues Toxic effect Work base bone morphogenetic protein 2 cell injury clinical translation design efficacy testing in vivo innovation new technology normotensive novel novel strategies novel therapeutic intervention novel therapeutics predictive modeling prevent public health relevance response tool

项目摘要

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.

描述（由适用提供）：青光眼是失明的主要原因，当前治疗不足。在这里，我们建议基于僵硬的外围巩膜测试一种新的疗法，这代表了治疗青光眼的全新范式。我们的中心假设是，增加的外围巩膜僵硬度将减少眼内压力引起的柔软，精致的视神经头（ONH）组织（“屏蔽”）的变形，从而通过对ONH细胞及其周围矩阵的生物力学受伤来降低残留神经节细胞（RGC）功能。如果成功的话，这种疗法将独立于眼内压（IOP）降低和协同作用。我们提出了3个特定目标（SA）来检验这一假设。在SA1中，我们将优化并表征巩膜加强剂（交联和BMP-2）如何影响巩膜，视网膜和IOP传递给ONH的生物力学“侮辱”。在SA2中，我们将评估增加后巩膜刚度增加对青光眼实验模型中RGC功能和生存能力的影响。最后，在SA3中，我们将巩膜僵硬的稳固耐硬化巩膜的作用进行定位，从而优化了期货理论方法在青光眼患者中巩固巩膜僵硬的有效性。除了上面概述的新颖范式外，该项目具有创新性，原因有几个。我们将在生物学上使用适当的代理（BMP-2）使巩膜加强，而不是Harmser交联。它将开发出新颖的技术，以将僵硬的代理传递给活眼睛，并控制它们在何处执行其效果。它将使用最先进的生物力学，生物学和物理技术来表征眼睛健康和功能的特征。我们将首先表征正常感染大鼠眼睛中僵硬剂（能够使巩膜僵硬而耐毒性的能力）的性能。我们还将量化不断变化的硬化性质如何影响大鼠的ONH生物力学环境。然后，我们将通过既定的大鼠高血压大鼠模型（Morrison Hypertonic Salines盐水注入模型）中的BMP-2和几个硬化交叉链链接器来评估RGC保护。最后，我们将使用甲状腺上的递送和光诱导的凝胶来精确地将BMP-2和交联链链链接在同一Morrison模型中。通过这种方式，我们可以全面检验我们的假设，并确定哪种代理和交付方法在实践中最有效。如我们的初步数据所示，我们期望BMP-2向外围巩膜递送是神经保护眼高血压。加上调节内源性BMP-2活性的新型策略，这将激发这种治疗方法的临床翻译。