Our research interest is in identifying therapeutic targets in neurodegenerative diseases and delivering protective factors via viral-mediated gene therapy to stop or slow the progression of disease. The most common retinal degenerative diseases – trauma, glaucoma, age-related macular degeneration, and diabetic retinopathy – are not due to a single, identified, genetic mutation. They are complex conditions. In addition, they are not acute, but rather require long-term therapy. Therefore, we are interested in developing therapies that preserve neurons, their axons, and visual function regardless of the underlying etiology of the disease. We use gene therapy to provide long-term treatment.
An estimated 300,000 service members were exposed to improvised explosive devices in the recent wars in Iraq, resulting in traumatic brain injury (http://veterans.rand.org). Recently, 43% of Veterans with mild traumatic brain injury due to blast exposure, who retained closed globes, were shown to have ocular pathologies including corneal abrasions, hyphemas, cataracts, corneal edema, angle recession, hemorrhage, retinal tears or detachments, macular holes, choroidal rupture, commotio retinae, and optic neuropathy (Blanch and Scott, 2009; Cockerham et al., 2011). Unfortunately, most service members and Veterans do not receive this level of examination so the prevalence of vision impairing damage is unknown. Further, since the realization that blast exposure without the presence of perforating or penetrating injury may cause permanent vision loss due to damage to the retina is new, there is a lack of animal models. Ocular trauma is also responsible for 500,000 US citizens losing vision every year.
One goal of our laboratory is to use our new mouse model of ocular trauma to study the molecular and cellular effects of this injury on the retina and to develop treatments. We are assessing cell death pathways, genetic controls, and biomarkers, and are testing therapeutic interventions.
Glaucoma and Neuroprotection
Our previous work has identified an IOP-independent, therapeutic agent, 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 glaucomatous DBA/2J mouse. We are now investigating the mechanism of action of EPO in glaucoma and testing the efficacy of delayed therapy.
Hines-Beard J, Marchetta, J, Gordon S, Chaum E, Geisert EE, Rex TS (2012) A novel mouse model of ocular blast injury. Exp Eye Res. Epub.
Sullivan TA, Geisert EE, Templeton JP, Rex TS. (2012) Dose-dependent treatment of optic nerve crush by exogenous mutant erythropoietin. Exp Eye Res. 96: 36-41.
Sullivan TA, Geisert EE, Hines-Beard J, Rex TS. (2011) Systemic AAV-mediated gene therapy preserves retinal ganglion cells and visual function in DBA/2J glaucomatous mice. J Hum Gene Ther. 22: 1191-1200.
Sullivan T, Rex TS. (2011). Systemic gene delivery protects the photoreceptors in the retinal degeneration slow mouse. J Neurochem Res. 36:613-618.
Rex TS, Wong Y, Kodali K, Merry S. (2009). Neuroprotection of photoreceptors by direct delivery of erythropoietin to the retina of the retinal degeneration slow mouse. Exp Eye Res. 89: 735-740.