Preclinical Analysis of Ischemic Optic Nerve Treatment

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Abstract Nonarteritic anterior ischemic optic neuropathy (NAION) is an optic nerve (ON) stroke. It is the most common cause of sudden ON-related vision loss, occurring worldwide, and affecting more than 10,000 Americans every year; there are no clinically effective treatments. Every previous NAION clinical treatment trial has failed. We have created not only a rodent model of NAION (rNAION) but even more importantly, the first nonhuman primate model of NAION (pNAION) and have developed analytical tools to precisely and accurately measure structural and functional improvements after potential neuroprotective treatments. Our previous work demonstrated that Prostaglandin J2 (PGJ2) significantly reduces ON damage and improves function when given several hours after ischemia in nonhuman primates. This is the first drug shown to do so. However, patients with NAION often present days after symptoms begin. Thus, we must identify a treatment that will improve visual function even when begun several days after symptom onset. If PGJ2 is still effective when given several days after the development of optic nerve ischemia in this model, then it is likely to be effective in cases of human NAION. We recently found that inflammation plays a key role in NAION and hypothesize that targeted therapies are a key to effective NAION treatment. Our team includes a bioengineer who has revolutionized the use of nanoparticles in human disease treatment. We have discovered that dendrimer nanoparticles can `home in' on the ON lesion in both rNAION and pNAION and can be designed to release their compound over a prolonged time period, enabling precise, targeted, long-term drug delivery, potentially enhancing a drug's effectiveness. Our multidisciplinary team has now attached PGJ2 to dendrimer nanoparticles (D-PGJ2) and tested it in rNAION. We have found that D-PGJ2 protects retinal ganglion cells (RGCs) after ON ischemia, with a potency at least equivalent to intravitreal administration of the free drug, reducing the risks of intraocular administration. Our proposal has two specific aims. Each aim uses the pNAION model. We evaluate treatment effectiveness by in vivo imaging, electrophysiology, immunohistochemistry, and quantitative analysis of RGC and axon survival. 1. Determine the time window of opportunity for efficacy of a single intravitreal injection of PGJ2. We will administer soluble PGJ2 intravitreally at different times after pNAION induction and identify how long after NAION presents that PGJ2 is neuroprotective. 2. Determine if nanoparticle-linked PGJ2 (D-PGJ2) preserves RGCs and improves visual functional recovery after pNAION without systemic or ocular toxicity. We will determine if D-PGJ2's cell-specific targeting and sustained drug release can provide greater neuroprotection and functional recovery than an intravitreal injection of PGJ2 after pNAION induction, without the inherent potential risks of an IVT injection.