Targeting Scleral Stiffness as a Novel Therapeutic Approach in Glaucoma

Georgia Institute Of Technology, Atlanta GA

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Abstract

? 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.