DESCRIPTION: Glaucoma is a major cause of blindness, affecting over 70 million people worldwide. Glaucoma is a neurodegenerative optic neuropathy caused by the loss of retinal ganglion cells (RGC), leading to loss of vision. Current therapies are all directed at lowering intraocular pressure (IOP), and yet RGC loss still continues in many patients despite IOP lowering. The identification of an agent that complements IOP lowering by promoting RGC survival would be a significant advance toward improving the visual outcomes of patients with glaucoma. Using cultures of primary RGC, we screened more than 10,000 compounds and identified candidates with potent neuroprotective properties, including a drug that is FDA-approved for an unrelated indication. We further characterized the novel pathway through which these compounds act to protect RGC, thus identifying a novel drug/drug target combination for neuroprotection. We have also developed a microparticle ocular drug delivery system that, following intravitreal administration, allows slow release and sustained localized delivery to the eye, without causing inflammation. In this application, we are combining two of these neuroprotective drugs with our microparticle delivery system to develop a new therapeutic for the treatment of glaucoma. In Aim 1, we will formulate and characterize microparticles that release the neuroprotective drugs continuously for up to 6 months to reduce the required injection frequency to 2-3 injections per year. In Aim 2, we will test whether the drug-releasing microparticles promote RGC survival and function in the mouse optic nerve crush and bead-induced glaucoma models. A drug dose escalation study will be performed and function of the optic nerve in transmitting visual stimulation from the eye to the brain will be assessed by optokinetic responses (OKR). In Aim 3, we will evaluate the intraocular pharmacokinetics in the rabbit eye for 6 months and perform preliminary safety analyses following intravitreal administration of microparticles. Safety evaluations will include fundus exams, IOP, and retinal morphology analyses as a preliminary evaluation of the long-term effects of drug exposure in the eye. The demonstration of efficacy in rodent models of neurodegeneration, including the verification of function of the protected RGCs, along with long-term drug release and no overt toxicity in the rabbit eye, would provide evidence of the therapeutic potential of our neuroprotective drug delivery strategy for the treatment of glaucoma.