Abstract
Purpose :
Treatment of retinal neovascular diseases by anti-VEGF based therapies has two major flaws: one third of patients respond poorly, and chronic depletion of VEGF may have neurotoxic effects. We investigated in experimental rodent models of neovascular diseases the anti-angiogenic effects of a new synthetic molecule (UPARANT) designed to inhibit endothelial cells response to a wide variety of angiogenic triggers.
Methods :
Lesions in the choroid (CNV) were induced by laser treatment in 6- to 8-week-old C57Bl6J mice (N = 54). At day 4, 8 and 12 after CNV induction, animals were treated with intravitreal injections of UPARANT at 4 and 12 mg in 1 ml, and euthanized at day 15 for analyses. Diabetes was induced in 8-week-old Sprague-Dawley rats (N=20) by a streptozotocin intraperitoneal injection. UPARANT (40 mg in 4 ml) was given by weekly intravitreal injections between weeks 6 and 9 after diabetes induction. Animals were euthanized at week 10 for analyses. Oxidative retinopathy was induced between postnatal day (P) 7 and 12 in C57Bl/6 newborn mice (N = 12) that were then treated by intravitreal injections of 15ng in 1ml UPARANT, 2 µg/ml aflibercept and 1.25 µg/ml bevacizumab at P 12 and 15. At P 17 animals were euthanized for analyses. All control animals were treated with vehicle alone. Student’s t test for unpaired data, or ANOVA with Newman-Keuls post-hoc test correction were used to evaluate the data.
Results :
UPARANT reduced CNV area in a dose-dependent manner. UPARANT at 4 mg and 12 mg progressively reduced the CNV area by about 40 % (P < 0.01) and 60% (P < 0.001). UPARANT also recovered the laser-induced up-regulation of transcription factors controlling genes involved in angiogenesis and inflammation. Accordingly, gene expression of angiogenic and inflammatory markers was also significantly reduced. UPARANT strongly decreased retinal neoangiogenesis in diabetic rats, normalizing the blood retinal barrier and recovering the ERG. In the OIR model, UPARANT normalized the blood retinal barrier more efficiently than aflibercept or bevacizumab.
Conclusions :
Our data clearly show that inhibition of the uPAR/FPR interaction at the cell surface by UPARANT is able to ameliorate neovascular pathologies in the eye most likely by controlling the production of angiogenic and inflammatory factors, thus restoring a close-to-normal barrier and retinal function.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.