Therapeutic Potential of Arginase 1 for Trauma-Induced Vision Loss

Rationale: This proposal addresses a major clinical problem: the lack of effective therapies to limit neurovascular injury and promote repair after potentially blinding traumatic injury to the brain or eye. Vision loss is a common complication of traumatic brain or ocular injury during military combat. Many of these combatants suffer from traumatic optic neuropathy (TON) due to direct ocular injury or as an indirect result of traumatic brain injury (TBI). Such injury is frequently associated with degeneration of retinal ganglion cells (RGC) due to primary trauma to their axons or injury-related glaucoma and may involve degeneration of other retinal neurons secondary to oxidative stress, inflammation, vascular dysfunction, and ischemia. Compromised vision can negatively affect healthy behavior, social functioning, and quality of life, and has also been linked to increased mortality. Excellent visual function is required in military personnel for a variety of tasks ranging from effective weapons use to aircraft flight operations. Ocular injuries are a significant problem for service members and their care providers and are associated with substantial costs for resources, rehabilitation, and training. So far, there is no effective treatment. The lack of understanding of the mechanisms by which trauma damages retinal neurons represents a critical knowledge gap in developing effective therapies. Our group is studying the role of an enzyme called arginase 1 in this pathological process. Our National Institutes of Health and Department of Veterans Affairs Merit Review-funded research has shown that arginase 1 protects against injury and promotes repair in models of acute glaucoma and traumatic ocular nerve injury. Our studies using a stable, long-acting form of human recombinant arginase 1 (PEGArg1) have shown that PEGArg1 protects against retinal neuronal injury by decreasing inflammation and increasing repair functions by resident retinal immune cells. Pharmaceutical forms of PEGArg1 are currently under development as cancer therapy. Thus, this treatment is safe for use in patients and can be readily adapted for treating trauma to the retina or brain. Our proposed research will expand this work to further elucidate the underlying mechanisms of the PEGArg1-mediated neuroprotection by examining its downstream targets and determine whether this treatment can also limit neuronal injury and promote repair in models of TON and glaucoma. Arginase converts the amino acid L-arginine to form L-ornithine and urea. L-ornithine is metabolized by another enzyme called ornithine decarboxylase 1 (ODC) to form the polyamine putrescine, which is further metabolized to form spermidine and spermine. Activation of the L-ornithine/polyamine pathway can limit injury by several mechanisms, including suppression of inflammatory cytokines, reduction in oxidative stress, and production of a reparative immune cell phenotype. Previous studies have shown that dietary supplement with the polyamine spermidine limits inflammatory neuronal injury in models of TBI, optic nerve crush (ONC), and glaucoma. In addition, arginase competes with the nitric oxide synthase (NOS) enzymes for their common substrate L-arginine. High levels of NO produced by upregulation of the inducible NOS (NOS2) enzyme during inflammation induces neuronal injury via increasing nitrative/oxidative stress. The depletion of the L-arginine supply for NOS2 via the arginase/ODC activity will reduce its expression/activity, which will reduce oxidative and nitrative stress. Our studies in mouse models of ischemic retinopathy have shown that PEGArg1 treatment increases arginase activity, promotes retinal microvascular repair, reduces neurovascular injury, and limits vision loss. These observations strongly suggest that increasing Arg1 activity is a novel therapeutic strategy to promote repair and improve vision after retinal or brain injury. We have further tested this co