Iron as therapeutic target in retinopathy of prematurity – FeROP

This project aims to determine the potential therapeutic benefit of the iron- binding proteins, transferrin and lactoferrin, in the prevention of early stage of retinopathy of prematurity (ROP). ROP, one of the leading causes of blindness in children, is secondary to excessive oxygen delivery and oxidative stress but also oxygen-independent factors, such as lower concentration of placental growth factors: IGF-1/IGFBP-3. Recently, a shift in clinical practices favoring higher oxygen saturation targets for preterm infants have led to an increased incidence of ROP. As hyperoxia favors oxygen radical formation, identification of strategies attempting to mitigate oxidative stress are getting interesting again to prevent ROP. Preterm infants required iron supplementation and red blood cell transfusions, that are a major source of iron overload. Since, excess iron worsens oxidative stress, we hypothesize that the oxidative stress involved in ROP could result not only from oxygen therapy but also from iron overload, that could be prevented by iron-binding protein administration. We have shown that transferrin has anti-oxidant, anti-inflammatory and anti-apoptotic effects in several retinal disease, both by iron chelation and oxidative stress reduction but also by activation of neuroprotectives pathways such as IGFBP3 pathway, which is a major contributor to ROP pathogenesis. Lactoferrin (that has similar structure to transferrin and is well tolerated in preterm newborns) has the advantage that could be orally administered. By using oxygen-induced retinopathy rat model, iron supplementation neonatal model, in vivo retinal anatomical and functional exploration and ex vivo gold standard methods for retinal vascular and neural quantification, we aim to determine: whether iron supplementation aggravates ROP (AIM1), whether transferrin (locally or systemically administrated) and/or oral lactoferrin prevent ROP (AIM 2 and 3), and the involved mechanisms and pathways (AIM 4).