Evaluation of Neuroprotective Compounds for Glaucoma

DESCRIPTION (provided by applicant): Open-angle glaucoma is a leading cause of blindness in the United States, and its prevalence is expected to increase as the population ages Blindness in glaucoma is believed to be caused by progressive loss of retinal ganglial cells (RGCs) and degeneration of the optic nerve, precipitated by risk factors The disease is typically treated by reducing one such prevalent risk factor, elevated intraocular pressure (lOP), with appropriate medical or surgical techniques Decreasing the lOP can protect the optic nerve by preventing further pressure-induced mechanical or ischemic damage However, despite lOP reduction, patients can still manifest glaucomatous visual loss due to progressive neuronal damage Neuroprotective compounds, used in conjunction with medications to lower lOP, thus, could more comprehensively treat glaucoma. The aim of the current program is to develop and commercialize novel and safe neuroprotective drugs for the prevention of disease progression to blindness in glaucoma The applicants' strategy is to develop therapeutics that prevent retinal ganglion cell death by preserving mitochondrial function This approach is based on research demonstrating that mitochondrial dysfunction is directly implicated in RGC necrosis and apoptosis In Phase I, applicants will evaluate survival of RGCs compromised by treatment with several cytotoxic stressors, including acute calcium loading, glutamate toxicity, and oxidative stress, when treated with compounds previously shown to be cytoprotective in other neuronal cell types These compounds are from a proprietary library of novel polycyclic phenols (PPCs) know to stabilize mitochondrial function in other neuronal cell types both in vitro and in vivo The Specific Aims of this Phase I proposal are to evaluate mitochondrial energetics and cell survival in RGCs exposed to pro-apoptotic and pro-necrotic stimuli in the presence of MitoKor's proprietary PPCs. Results from Phase I will be used to prioritize the compounds, and provide information on dosing, for further testing in an lOP animal model in Phase II Further development will involve assessment for safety and efficacy of the best compound(s) in human clinical trials and, if successful, ultimately marketing.