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Prevention of Retinopathy of Prematurity with a Novel Bifunctional Redox Reagent

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43EY021379-01
Agency Tracking Number: R43EY021379
Amount: $220,613.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: NEI
Solicitation Number: PA10-050
Solicitation Year: 2011
Award Year: 2011
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
WEST TISBURY, MA 02575-1626
United States
DUNS: 833130045
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (978) 232-9660
Business Contact
Phone: (866) 925-2871
Research Institution

DESCRIPTION (provided by applicant): Retinopathy of prematurity (ROP) is present in up to 70-85% of very low birthweight premature infants (lt 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. PUBLIC HEALTH RELEVANCE: 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.

* Information listed above is at the time of submission. *

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