Our long-term goal is to treat glaucoma using systemic neuroprotective gene therapy. Nearly 3 million people have been diagnosed with glaucoma, a leading cause of blindness in the United States. Current therapies are directed at lowering the intraocular pressure (IOP), the most significant risk factor for the development of glaucoma. The need for daily treatment can lead to poor patient compliance. We offer an alternative IOP-independent neuroprotective therapy, a modified form of erythropoietin (EPO). EPO is already FDA approved for the treatment of anemia. We modified EPO to diminish the erythropoietic activity while preserving its neuroprotective activity, and packaged it into an adeno-associated viral vector (rAAV) to provide sustained, systemic delivery. Transduction of peripheral muscle by a single injection protects 70% of RGC somata and axons, and preserves visual function in the DBA/2J mouse. We have preliminary data that treatment with our novel gene therapy vector, rAAV.EpoR76E, decreases levels of C1Q and glial fibrillary acidic protein in the retina of 10 month old DBA/2J mice. There is also evidence that EPO can decrease the levels of Aquaporin 4 (AQP4), a water channel that induces astrocyte hypertrophy in the brain. Further, we have preliminary data that all of these proteins interact based on correlation analysis of microarray data. The proposed study will test two conceptual hypotheses. Our first conceptual hypothesis is that EPO-R76E, blocks astrocyte hypertrophy and the resulting mechanical injury to the axons and secondary RGC death by downregulation of the water channel, AQP4. Our second conceptual hypothesis predicts that synapse targeting by the immune system initiates the cascade of RGC death in glaucoma. We propose that treatment with rAAV.EpoR76E blocks synapse targeting by C1Q, thus preserving normal synaptic connections and visual function. These hypotheses will be tested in the DBA/2J, and additional novel mouse models of glaucoma.
We developed a novel gene therapy treatment for glaucoma that is intraocular pressure (IOP)-independent, protects 70% of RGC somata and axons, and preserves visual function in the DBA/2J mouse. We will test this therapy in novel mouse models of glaucoma. We will also test two hypotheses on the mechanism of action of our therapeutic, a modified form of erythropoietin, EPO-R76E: 1) EPO-R76E blocks astrocyte hypertrophy and the resulting mechanical injury to the axons by downregulation of the water channel, Aquaporin 4;and 2) EPO-R76E blocks synapse targeting by C1Q, thus preserving normal synaptic connections and visual function.
|Bricker-Anthony, Courtney; D'Surney, Lauren; Lunn, Brendan et al. (2017) Erythropoietin either Prevents or Exacerbates Retinal Damage from Eye Trauma Depending on Treatment Timing. Optom Vis Sci 94:20-32|
|Bond, Wesley S; Hines-Beard, Jessica; GoldenMerry, YPaul L et al. (2016) Virus-mediated EpoR76E Therapy Slows Optic Nerve Axonopathy in Experimental Glaucoma. Mol Ther 24:230-239|
|Rex, Tonia S; Boyd, Kelli; Apple, Troy et al. (2016) Effects of Repeated Anesthesia Containing Urethane on Tumor Formation and Health Scores in Male C57BL/6J Mice. J Am Assoc Lab Anim Sci 55:295-9|
|Hines-Beard, Jessica; Bond, Wesley S; Backstrom, Jon R et al. (2016) Virus-mediated EpoR76E gene therapy preserves vision in a glaucoma model by modulating neuroinflammation and decreasing oxidative stress. J Neuroinflammation 13:39|
|Guley, Natalie H; Rogers, Joshua T; Del Mar, Nobel A et al. (2016) A Novel Closed-Head Model of Mild Traumatic Brain Injury Using Focal Primary Overpressure Blast to the Cranium in Mice. J Neurotrauma 33:403-22|
|de Lucas Cerrillo, A M; Bond, W S; Rex, T S (2015) Safety and angiogenic effects of systemic gene delivery of a modified erythropoietin. Gene Ther 22:365-73|
|Rex, Tonia S; Reilly, Matthew A; Sponsel, William Eric (2015) Elucidating the effects of primary blast on the eye. Clin Exp Ophthalmol 43:197-9|
|Bricker-Anthony, Courtney; Rex, Tonia S (2015) Neurodegeneration and Vision Loss after Mild Blunt Trauma in the C57Bl/6 and DBA/2J Mouse. PLoS One 10:e0131921|
|Bricker-Anthony, Courtney; Hines-Beard, Jessica; Rex, Tonia S (2014) Molecular changes and vision loss in a mouse model of closed-globe blast trauma. Invest Ophthalmol Vis Sci 55:4853-62|
|Bond, Wesley S; Rex, Tonia S (2014) Evidence That Erythropoietin Modulates Neuroinflammation through Differential Action on Neurons, Astrocytes, and Microglia. Front Immunol 5:523|
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