Translational Research in Retinopathy of Prematurity: From Bedside to Bench and Back Again

Abstract

Retinopathy of prematurity (ROP), a vascular proliferative disease affecting preterm infants, is a leading cause of childhood blindness. Various studies have investigated the pathogenesis of ROP. Clinical experience indicates that oxygen levels are strongly correlated with ROP development, which led to the development of oxygen-induced retinopathy (OIR) as an animal model of ROP. OIR has been used extensively to investigate the molecular mechanisms underlying ROP and to evaluate the efficacy of new drug candidates. Large clinical trials have demonstrated the efficacy of anti-vascular endothelial growth factor (VEGF) agents to treat ROP, and anti-VEGF therapy is presently becoming the first-line treatment worldwide. Anti-VEGF therapy has advantages over conventional treatments, including being minimally invasive with a low risk of refractive error. However, long-term safety concerns and the risk of late recurrence limit this treatment. There is an unmet medical need for novel ROP therapies, which need to be addressed by safe and minimally invasive therapies. The recent progress in biotechnology has contributed greatly to translational research. In this review, we outline how basic ROP research has evolved with clinical experience and the subsequent emergence of new drugs. We discuss previous and ongoing trials and present the candidate molecules expected to become novel targets.

Keywords: clinical trial; oxygen-induced retinopathy; retinopathy of prematurity; translational research.

Figure 1

Phases of retinopathy of prematurity (ROP) and the action mechanisms of drugs with confirmed therapeutic effects in the treatment of ROP in previous clinical trials and meta-analysis. (A). Relative hyperoxia in phase 1 arrests vascular growth (left). Relative hypoxia in phase 2 causes pathological neovascularization (right). (B). Molecular mechanisms of neovascularization. The various points at which anti-vascular endothelial growth factor therapy (Section 3.3), vitamin E (Section 4.1), vitamin A (Section 4.2), insulin-like growth factor-1 (Section 4.5), ω3-polyunsaturated fatty acids (Section 4.7), and β-blockers (Section 4.8) act are shown in red.

Figure 2

Vascular endothelial growth factor/vascular endothelial growth factor (VEGF) receptor pathways involved in angiogenesis and the targets of VEGF (anti-VEGF agents): bevacizumab, ranibizumab, and aflibercept.