Targeting the Beta-Adrenergic System to Treat retinopathy of Prematurity: A New Therapeutic Approach?

Retinopathy of prematurity (ROP) is a hypoxia-induced neovascular retinal disease representing the major cause of blindness and visual impairment in children. Currently, surgical approaches (i.e. vitrectomy and laser photocoagulation) are the treatments of choice for ROP although they may result in a variety of complications, and new therapeutic strategies are eagerly required. In general, intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents represent the most promising form of therapy to treat neovascular retinal disorders and there is expectancy for the use of these drugs to also treat ROP. However, for the use of these substances in ROP, the optimal choice of agent and dose remain unknown, while the possibility that the treatment may interfere with serum VEGF levels, and therefore affect normal vessel growth in developing tissues, remains to be considered. The serendipitous demonstration that a non-selective β-adrenergic receptor (β-AR) antagonist, propranolol, promotes the regression of infantile hemangiomas, the most common vascular tumor of infancy, aroused an interest around the involvement of the β-adrenergic system in angiogenic processes in humans. In particular, accumulating evidence indicates that the β-adrenergic system is involved in the hypoxia-induced neo-angiogenesis that is typically observed in ROP. In this respect, animal studies carried out in the mouse model of oxygen-induced retinopathy (OIR), which replicates the main features of ROP, have shown that β-AR blockade is effective in reducing pathological angiogenesis. For instance, propranolol has been demonstrated to inhibit hypoxia-induced VEGF expression and neo-angiogenesis when administered to OIR mice. Consequent to the encouraging results obtained in the animal model, a pilot clinical trial has shown that propranolol administered orally protects newborns from ROP progression. Indeed, compared to newborns with ROP stage 2 receiving standard treatment, the newborns with ROP stage 2 treated with oral propranolol showed a reduced progression to stage 3 or stage 3 plus and no newborns progressed to stage 4. However, some serious adverse effects of oral propranolol have been also reported. Therefore, this pilot study on the one hand has established the efficacy of propranolol treatment to counteract the progression of ROP, but on the other has indicated that the safety is a concern. Recent studies performed in rabbits have reported that the administration of propranolol through eye drops induces retinal concentrations of propranolol similar to those measured after oral administration, but with significantly lower plasma concentration. In addition, propranolol eye drops have been shown to reduce VEGF levels and retinal neovascularization in the mouse OIR model. These findings have opened the perspective of possible topical treatment with propranolol in newborns with ROP, and an ongoing study is indeed exploring the possibility of administering propranolol to newborns with ROP through eye drops with the objective to significantly reduce the side effects observed after oral propranolol administrations.