Characterization and treatment of a novel model of radiation optic neuropathy using the tree shrew

PROJECT SUMMARY/ABSTRACT Uveal melanoma (UM) is the most common primary intraocular tumor of adulthood, and radiation-based therapies are the mainstay treatment for most small, medium, and some large UM. Despite high rates of local tumor control, over two-thirds of patients are left with functional blindness in the treated eye due to radiation- induced side effects. Radiation optic neuropathy (RON) is particularly devastating due to its strong association with profound visual deficits and lack of effective treatment options. We recently identified a potential novel opportunity for intervention based on a retrospective study identifying risk factors for RON. In our clinical practice, we observed that some patients with RON manifested with concurrent neuroretinal rim thinning (NRT). Based on this observation, we analyzed a number of potential risk factors for RON in patients treated with plaque radiotherapy for UM and found that higher baseline intraocular pressure (IOP) was associated an increased risk of RON. These data supported a hypothesis previously proposed in glaucomatous optic neuropathies: Specifically, there is a pressure sensitive component to optic nerve injury, which is associated with connective tissue stress and strain at the lamina cribrosa, that results in a cupping or NRT. Few animal models accurately replicate this aspect of human anatomy due to a lack of a well-developed lamina cribrosa. However, the tree shrew has a similar distinct, load-bearing lamina cribrosa, and is rapidly becoming an animal model for studies in conditions including glaucoma and other optic neuropathies. Given our clinical observation and growing use of the tree shrew as a model for optic nerve pathology, our Central Hypothesis is that a novel model of RON can be developed using the tree shrew based on its load-bearing lamina cribrosa, which will replicate characteristic features of human pathology and allow testing of novel therapeutics, specifically those related to IOP reduction. Establishing a representative animal model will have potential to accelerate new treatment approaches for patients with RON. We will evaluate our central hypothesis via two specific aims. Aim 1 will validate the use of the tree shrew as a model for RON by performing a rigorous assessment of the structural and functional phenotype of the tree shrew model of RON. Aim 2 will examine the role of IOP regulation in the severity of RON. Based on strong clinical data with which to form this hypothesis, these aims will support our long-term goal of developing novel treatment approaches including IOP reduction to reduce the risk RON and prevent blindness in patients requiring exposure to radiation.