The potent integrin antagonist THR‐687 is a promising next‐generation drug candidate for the treatment of multifactorial retinal diseases

Abstract

AbstractPurposeIntegrins are implicated in eye diseases such as diabetic retinopathy (DR) and wet age‐related macular degeneration (AMD). Targeting integrins can attenuate the main pathologic hallmarks like vascular leakage, inflammation, gliosis, angiogenesis and fibrosis. Previously, we showed that the integrin antagonist, THR‐687, has potent anti‐angiogenic properties in the cynomolgus choroidal neovascularization (CNV) model. The goal of this study was to further investigate the therapeutic effect of THR‐687 in the diabetic streptozotocin (STZ)‐induced rat model and the cynomolgus CNV model.MethodsIn STZ rats, 3 intravitreal (IVT) injections of THR‐687 (75 µg/eye) or vehicle were given with a weekly interval. Four weeks after diabetes onset vascular leakage, retinal inflammation and gliosis were analyzed by means of respectively FITC‐BSA perfusion, CD11b and vimentin staining. THR‐687 was investigated in the cynomolgus CNV model, by administering 3 IVT injections of THR‐687 (4.5 mg/eye, 2.25 mg/eye or 0.45 mg/eye) or vehicle with a weekly interval. Three weeks after laser induction the anti‐fibrotic and anti‐inflammatory potential of THR‐687 was studied by Sirius red and CD11b staining, respectively.ResultsIVT administration of THR‐687 in diabetic rats significantly decreased retinal permeability, inflammation and gliosis as compared to vehicle‐treated controls. In the cynomolgus CNV model, THR‐687 exhibited a dose‐dependent inhibition of collagen deposition in the laser spots, whereas only a trend towards decreased inflammation levels could be discerned with the highest dose level 3 weeks post‐laser.ConclusionTHR‐687 potently antagonizes integrins implicated in vascular leakage, inflammation, gliosis, angiogenesis and fibrosis as demonstrated in the diabetic STZ rat and cynomolgus CNV models. Given its multifaceted mode of action and broad therapeutic potential, THR‐687 is a promising drug candidate for the treatment of vision‐threatening retinal pathologies such as DR and wet AMD.