Dark-rearing as a non-invasive treatment for Retinopathy of Prematurity: basic mechanisms and a pathway to translation

Abstract

The persistence of retinopathy of prematurity (ROP) in both the developed and the developing world remains a serious cause for concern. Some 75 years after its first clinical description, we still lack an easily applied strategy to reduce the deleterious effects of oxygen (O2) on the developing retinal vasculature. The aim of the work detailed in this thesis is to provide an early, non-invasive intervention for ROP by targeting the initiating event in the disease – hyperoxia in the retina - rather than treating the downstream effects of hyperoxia, as is presently the case. The hypothesis tested in this thesis is that dark-rearing (DR) infants at risk of ROP during supplemental O2 therapy will increase the metabolic rate of photoreceptors and increase O2 consumption in the retina, offsetting retinal hyperoxia. This thesis provides proof-of-principle that DR can normalize vascular development in the presence of supplemental O2 by maintaining ‘physiological hypoxia’ during the hyperoxic (Phase 1) of ROP, and shows that DR preserves the density and extent of retinal vessels, and reduces the severity of pre-retinal neovascularization in Phase 2 of an established rat model of ROP. In addition, the thesis presents a normative dataset for the rate of retinal vascularization in human infants under “physiological hypoxia” in utero, and provides data towards a criteria for the clinical dentification of “delayed retinal vascularization’ as a basis for initiation of laser treatment, or the application of antivascular endothelial growth factor (VEGF) therapy for infants at risk of progressing to sight-threatening stages of ROP. Finally, the thesis presents data examining the hitherto unidentified system of lymphatic vessels in the human choroid. These observations provide the foundation for further studies exploring the roles of lymphatics in posterior eye diseases, and investigations of novel therapeutic targets in these diseases, such as the lymphangiogenic factors VEGF-C & D.