Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common cause of optic nerve-related acute loss of vision in the US;there is no effective treatment. NAION causes injury to optic nerve axons, leading to dysfunction and death of retinal ganglion cells (RGCs). Interventions to enhance RGC regeneration could be applied before RGC death, to reverse dysfunction by allowing RGCs to reconnect with their targets in the brain. Enhancement of optic nerve regeneration is a major goal for patients with NAION and other neuropathies. The lack of regeneration-promoting therapies in NAION and other diseases reflects barriers to regeneration in the injured central nervous system (CNS), including growth-inhibitory proteins associated with myelin and the glial scar. Strategies to promote regeneration by overcoming these barriers have shown efficacy in animal models, but novel strategies and translation to the clinic are needed. We have performed a phenotypic screen using a library of novel drug-like triazine compounds on primary mammalian neurons, and have identified 4 compounds capable of increasing neurite growth on a substrate of inhibitory CNS myelin. These compounds a) act on different neuronal types, including RGCs, b) are potent, c) overcome inhibition in several assays relevant to CNS injury, and d) may act by novel mechanisms. We have now shown that one compound, AA4F05, promotes regeneration in an animal model of retinal injury, as well as in a model of spinal cord injury. AA4F05 and its relatives are exciting candidates to lead to novel drugs for promoting regeneration of RGCs and other CNS neurons. Although AA4F05 has favorable chemical properties and is active both in vitro and in vivo, there has been no attempt to optimize its activity or pharmacokinetics. The present proposal will use AA4F05 as a starting point for the development of new compounds with the potential to substantially improve regeneration of damaged axons from RGCs. Derivatives will be tested in primary neurons in vitro (primary and secondary screens), and the best candidates will be tested in 2 models of optic nerve injury.

Public Health Relevance

Diseases of the optic nerve (optic neuropathies) are a leading cause of impaired vision in the US. This proposal is designed to develop and test novel therapeutic chemicals that can later be developed into drugs for treatment of optic neuropathies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZNS1-SRB-E (35))
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Cywin, Charles L
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
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Wang, Yan; Brown Jr, Dale P; Duan, Yuanli et al. (2013) A novel rodent model of posterior ischemic optic neuropathy. JAMA Ophthalmol 131:194-204
Trakhtenberg, Ephraim F; Goldberg, Jeffrey L (2011) Immunology. Neuroimmune communication. Science 334:47-8