Bile Acids and Complications of Prematurity

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The studies here presented are relevant to the treatment of retinopathy of prematurity (ROP) a leading cause of blindness in infants. ROP is a developmental vascular disorder characterized by abnormal growth of retinal blood vessels in the incompletely vascularized retina of extremely low gestational age neonates (<1250 g, <28 weeks gestation). ROP occurs in premature babies as consequence of perinatal care due to toxicity of oxygen therapy on the developing retinal vasculature. To date, therapies for ROP are applied in the most advanced stages and essentially involve potentially harmful side effects, including significant loss of visual field, glaucoma and others. Herein we present a novel strategy to ameliorate ROP by systemic administration of a therapeutically active secondary bile acid, ursodeoxycholic acid (UDCA) and its derivative taurine-UDCA (TUDCA) and glycine-UDCA (GUDCA). Based on the foundation of solid preliminary results, this proposal will evaluate in-depth dosing strategy and mechanism of action for UDCA, TUDCA and GUDCA to reduce ROP in an experimental model of oxygen-induced retinopathy (OIR). In this mouse model recapitulating the two main phases of ROP we will assess the best therapeutic window/application of the three bile acids and evaluate their mode of action. Our study aims are: 1)) To investigate the effects of UDCA, TUDCA and GUDCA on pathological retinal neovascularization; 2)) To assess the effects of UDCA, TUDCA and GUDCA on retinal endothelial cells angiogenic and barrier function. The potential outcomes of the proposed studies could have immediate clinical application, as UDCA containing US-FDA approved formulations are already available in the market and could be rapidly re-purposed for this new important and much needed therapeutic application.