Pharmacologic control of neovascularization and inflammation is a promising approach for the treatment of sight threatening ocular disease such as the retinopathy of prematurity (ROP), age-related macular degeneration (AMD) and diabetic retinopathy (DR). Currently, the mainstay treatment for these diseases is based on surgical interventions and on pharmacological approaches targeting the main angiogenic factor, the vascular endothelial growth factor (VEGF). However, anti-VEGF therapies require intravitreal injections of anti- VEGF drugs and are associated with potential risks. Indeed, the high frequency of intravireal injections may lead to adverse side effects such as ocular inflammation and endophthalmitis. The urokinase receptor (uPAR) and its ligand, the urokinase (uPA) are major players in VEGF induced angiogenesis. Indeed, the uPAR-uPA system is involved in the first phase of VEGFmediated angiogenesis by triggering extracellular matrix remodeling and thus promoting endothelial cell migration. uPAR is capable of inducing cell migration by interacting with G protein-coupled receptors (GPCRs) of the formyl peptide receptor (FPR) family, which are involved in chemotaxis of the immune system. For these reasons, the uPAR-uPA system has been actively targeted for development of novel therapeutics against diseases in which angiogenesis and inflammation play a crucial role. In search for novel therapies against inflammatory/neovascular ocular pathologies, peptide analogues targeting uPAR have been developed. uPAR is an important component of the angiogenic-inflammatory response in the retina Among the series of newly synthesized analogues, the tetrapeptide Ac-L-Arg-Aib-L-Arg-LCα( Me)Phe-NH2, named UPARANT, displays strong inhibition of endothelial cell migration, longtime resistance to enzymatic digestion and high stability in blood and plasma. Using angiogenic assays both in vitro and in vivo, it has been demonstrated that UPARANT inhibits VEGF-driven angiogenesis by preventing FPR activation. Indeed, a possible clinical application of UPARANT in human ocular diseases would find a great benefit from the demonstration of its effectiveness in in vivomodels characterized by neovascularization and/or inflammation. If the antiangiogenic/anti-inflammatory activity of UPARANT will be also demonstrated in models of ROP, DR and AMD, then, the proven effectiveness in animal models will constitute a starting point, which will bring closer the likelihood of commencing preliminary studies aimed at assessing safety first and thereafter effectiveness in humans. 6 With this aim in mind, we tested the efficacy of UPARANT in different in vivo models of ocular diseases. We firstly assayed the efficacy of UPARANT in counteracting neovascularization and inflammatory in a model of oxygen induced retinopathy (OIR), an acknowledged model of ROP, in which UPARANT was found effective in counteracting retinal neovascularization. The efficacy of UPARANT was further addressed in a mouse model of laser-induced choroidal neovascularization, a model that closely mimics neovascular AMD. Moreover, in a model of early DR, mimicking type 1 diabetes, UPARANT promoted visual function recovery by restoring the blood–retinal barrier integrity and by inhibiting inflammatory and angiogenic responses. These results were also confirmed in a model of type 2 diabetes. Lastly, UPARANT was effective in mitigating rubeosis iridis in a model where neovascularization is associated with mechanisms of wound healing which are independent on VEGF signalling.
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|Titolo:||UPARANT, a novel multitarget drug for neovascular and inflammatory ocular diseases|
|Citazione:||Locri, F. (2019). UPARANT, a novel multitarget drug for neovascular and inflammatory ocular diseases.|
|Appare nelle tipologie:||8.1 Tesi Dottorato|