Retinopathy of prematurity (ROP) is present in up to 70-85% of very low birthweight premature infants (<1 kg). The more severe forms of ROP (Grades 3-5) account for more than 50% of injuries and are associated with lifelong visual impairment, including blindness. There are no pharmaceutical agents, or other measures, approved for the prevention of ROP. An effective prophylaxis of ROP would preserve vision and transform medical management of prematurity. ROP results from the abrupt increase in oxygenation at birth that produces a relative hyperoxia in the premature retina, resulting in the excessive production of superoxide anion. Hyperoxia also induces arginase-1 overexpression, which depletes L-arginine, the precursor of the endothelial nitric oxide (NO) synthase (ecNOS), thereby blocking NO synthesis and diverting the uncoupled ecNOS to synthesize superoxide. Compounding this increase in superoxide production is the ontogenic deficiency of anti-oxidant enzymes, such as superoxide dismutase. The resulting relative abundance of retinal superoxide and paucity of NO create an imbalance of these two free radical species that vasoconstricts the retinal microcirculation and induces retinal ischemia. The response to ischemia futher triggers aberrant production of vascular endothelial growth factor (VEGF), which in turn stimulates neoproliferation of retinal blood vessels. The ensuing retinal avascularity (RA) and intravitreous neovascularization (IVNV) contribute to significant visual impairment. A successful prophylactic of ROP requires the simultaneous replenishment of NO and removal of superoxide. To meet this unmet need, we are developing R-200, a novel agent formed from 2 redox-based moieties: 1) an organic nitrovasodilator moiety that releases NO, and 2) a lipoic acid moiety that acts as an SOD mimetic, a catalase mimic that detoxifies hydrogen peroxide, and a peroxynitrite decomposition catalyst. Taken together, R-200 removes superoxide and delivers NO without the confounding effect of peroxynitrite formation.
Specific Aim : Establish the efficacy of R-200 in a clinically-relevant neonatal murine model of ROP. We will carry out a dose-response study of retinal injury induced in mouse pups exposed to 70% O2 for 7 days, followed by room air for 10 days. Prophylactic administration of R-200 will be initiated at the onset of hyperoxic exposure. We expect that R-200 will: 1) attenuate morphologic injury, as manifested reductions in retinal flat-plate evaluation for RA and IVNV, and 2) reduce retinal inflammation and injury, as manifested by reductions in retinal lipid peroxidation, VEGF concentration, and formation of peroxynitrite and poly(ADP-ribose). These treatment effects are expected to translate into clinical improvement, as reflected by a decrease in RA and IVNV and an increase in visual acuity.
Retinopathy of prematurity is a major complication in the very low birthweight infant and contributes to the high prevalence of visual impairment in this population. At present, there are no approved therapies. We are developing a novel drug that targets the basic mechanisms of this condition and will test this agent in a clinically-relevant animal model.
