Nonarteritic anterior ischemic optic neuropathy (NAION) is an optic nerve (ON) stroke and the most common cause of sudden optic nerve-related vision loss. NAION affects more than 6000 Americans every year, often bilaterally, with no currently effective treatments. Every NAION clinical treatment trial has failed. A major reason for these failures is the lack of appropriate animal models closely resembling NAION physiologically and pathologically, and that would allow testing of relevant treatments for translation to the human condition.I have now generated an old-world primate model of non-arteritic anterior ischemic optic neuropathy (pNAION). My preliminary data reveal a high degree of similarity between pNAION and human NAION. A great advantage of the current proposal is my ability to test potential optic nerve stroke treatments, using well- defined model systems, from rodents through old-world primates. This will yield improved potential for clinical success. I have assembled an incredibly capable, highly focused, integrated and dedicated team for the proposal. My preliminary data reveal that activating the Nonarteritic anterior ischemic optic neuropathy (NAION) (PGD2) metabolic pathway after rodent ON infarct reduces ON edema and improves long-term retinal ganglion cell (RGC) survival. This pathway is highly conserved from rodents to humans. Recent anecdotal studies also report improved clinical function in NAION patients following treatment with other agents that reduce tissue edema. I hypothesize that, by reducing early ON edema in pNAION, I can improve post-infarct RGC survival and optic nerve function. This translational study will determine whether PGD2 activation and ON edema reduction are likely to be effective neuroprotective treatments in NAION. There are three subaims: a. Characterize early changes in retinal and optic nerve function with ultimate neuronal loss, and tissue remodeling, to determine the appropriate intervals for early intervention and maximum recovery. b. Determine if early edema reduction improves post-stroke optic nerve function. I will activate the PGD2 pathway to reduce pNAION-induced ON edema and evaluate ON function using high-resolution optical coherence tomography (OCT), electrophysiological techniques, and magnetic resonance (MR) imaging. In vivo results will be correlated with histopathologic and immunochemical findings. c. Compare PGD2 activation with currently available VEGF-blocking drugs used to reduce clinical NAION- induced ON edema, to confirm the potential clinical effectiveness of the edema-reduction approach.

Public Health Relevance

Nonarteritic optic nerve (ON) stroke (NAION) currently affects over 6000 Americans each year. There are no effective treatments, partly because no model of the disease in a closely-related species was available for evaluating approaches that can be translated into clinical therapy. I have developed the first relevant non-human primate model of NAION, and have identified a conserved pathway effective in treating rodent ON stroke. This proposal will determine whether by activating this pathway, and additionally by reducing post-stroke ON swelling using a commercially available drug, we can improve post-ON stroke function and speed recovery after infarct.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Agarwal, Neeraj
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University of Maryland Baltimore
Schools of Medicine
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Johnson, Mary A; Miller, Neil R; Nolan, Theresa et al. (2016) Peripapillary Retinal Nerve Fiber Layer Swelling Predicts Peripapillary Atrophy in a Primate Model of Nonarteritic Anterior Ischemic Optic Neuropathy. Invest Ophthalmol Vis Sci 57:527-32
Nicholson, James D; Guo, Yan; Bernstein, Steven L (2016) SUR1-Associated Mechanisms Are Not Involved in Ischemic Optic Neuropathy 1 Day Post-Injury. PLoS One 11:e0148855
Guo, Yan; Johnson, Mary A; Mehrabian, Zara et al. (2016) Dendrimers Target the Ischemic Lesion in Rodent and Primate Models of Nonarteritic Anterior Ischemic Optic Neuropathy. PLoS One 11:e0154437
Bernstein, S L; Meister, M; Zhuo, J et al. (2016) Postnatal growth of the human optic nerve. Eye (Lond) 30:1378-1380
Miller, Neil R; Johnson, Mary A; Nolan, Theresa et al. (2015) A Single Intravitreal Injection of Ranibizumab Provides No Neuroprotection in a Nonhuman Primate Model of Moderate-to-Severe Nonarteritic Anterior Ischemic Optic Neuropathy. Invest Ophthalmol Vis Sci 56:7679-86
Bernstein, Steven L; Miller, Neil R (2015) Ischemic optic neuropathies and their models: disease comparisons, model strengths and weaknesses. Jpn J Ophthalmol 59:135-47
Ziesel, Alison; Bernstein, Steven; Wong, Paul W (2014) Generation of a foveomacular transcriptome. Mol Vis 20:947-54
Miller, Neil R; Johnson, Mary A; Nolan, Theresa et al. (2014) Sustained neuroprotection from a single intravitreal injection of PGJ? in a nonhuman primate model of nonarteritic anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci 55:7047-56
Slater, Bernard J; Vilson, Fernandino L; Guo, Yan et al. (2013) Optic nerve inflammation and demyelination in a rodent model of nonarteritic anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci 54:7952-61
Touitou, Valerie; Johnson, Mary A; Guo, Yan et al. (2013) Sustained neuroprotection from a single intravitreal injection of PGJ2 in a rodent model of anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci 54:7402-9

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