Elucidation of novel anti-angiogenic therapies for the prevention and treatment of neovascular glaucoma

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Summary: Neovascular glaucoma (NVG) is a potentially blinding secondary glaucoma, characterized by the development of neovascularization of the iris (NVI) and angle (NVA), leading to elevated intraocular pressure (IOP) and poor visual prognosis. The underlying pathogenesis in most cases is posterior segment ischemia secondary to retinal diseases including proliferative diabetic retinopathy, central retinal vein occlusion (CRVO) and ocular ischemic syndrome, which are usually associated with an upregulated expression of angiogenic factors in the posterior segment. When these factors diffuse to the anterior segment, they promote the growth of abnormal blood vessels on the surface of the iris, causing NVI, and over the iris angle, causing NVA. Maturation of these vessels can result in the formation of a fibrovascular membrane over the trabecular meshwork that can obstruct aqueous outflow, resulting in an increase in IOP and the development of NVG. Contraction of this fibrovascular membrane can lead to secondary angle closure glaucoma (ACG) with a dramatic rise in IOP. Interestingly, the risk for NVG is directly proportional to the area of retinal ischemia, supporting a role for hypoxia-regulated gene products in its development. Prompt diagnosis and effective disease treatments in the early stages of the disease are crucial to reduce the chances of NVG and visual impairment. Unfortunately, the large-scale destruction of ischemic retinal tissue with panretinal photocoagulation (PRP) remains the preferred standard in the majority of eyes with NVG. Recently, VEGF inhibitors used for the management of ischemic retinal diseases have been incorporated for NVG clinical management, usually as adjuvants to PRP. However, these anti-VEGF agents result in only a temporary regression of new vessels in the anterior chamber angle involved in NVI/NVA. In spite of tremendous progress in the therapeutic management of NVG over the past decades, there are no effective therapies for the actively growing or established disease. This underscores the urgency to identify the molecular mechanisms that regulate NVI and NVA, to design more effective approaches for the prevention and management of NVG. Our preliminary support a role for Angiopoietin-like 4 (ANGPTL4), a pro-angiogenic and vessel hyperpermeability factor, and its novel receptor, Neuropilin 1, in the development of NVI/NVA and NVG. Our proposal intends to investigate: Aim 1) the role of ANGPTL4 and its synergism with VEGFs in the promotion of iris neovascularization in vitro and in vivo; Aim 2) the role of Neuropilin inhibitors as antiangiogenic factors in iris neovascularization in vitro and in vivo; Aim 3) how the expression of VEGF, ANGPTL4, and sNRP1 influences the development of NVG in CRVO patients.