Tine Van Bergen1, Rhyannon Spangler2, Derek Marshall2, Karolien Hollanders1, Sara Van de Veire1, Evelien Vandewalle3, Lieve Moons4, Jean Herman5, Victoria Smith2, Ingeborg Stalmans3. 1. KU Leuven - University of Leuven, Department of Neurosciences, Laboratory of Ophthalmology, Leuven, Belgium. 2. Gilead Sciences, Foster City, California, United States. 3. KU Leuven - University of Leuven, Department of Neurosciences, Laboratory of Ophthalmology, Leuven, Belgium 3University Hospitals Leuven, Department of Ophthalmology, Leuven, Belgium. 4. KU Leuven - University of Leuven, Department of Neurosciences, Laboratory of Ophthalmology, Leuven, Belgium 4KU Leuven - University of Leuven, Department of Biology, Unit Animal Physiology and Neurobiology, Leuven, Belgium. 5. KU Leuven - University of Leuven, Interface Valorization Platform (IVAP), Leuven, Belgium.
Abstract
PURPOSE: We investigated whether lysyl oxidase (LOX) and lysyl oxidase-like 2 (LOXL2) play a role in an experimental model of choroidal neovascularization (CNV). The therapeutic potential of antibodies against LOX (M64) and LOXL2 (AB0023) was evaluated in a murine laser-induced CNV model. METHODS: Expression of LOX and LOXL2 in the posterior eye cups (including retina, retinal pigment epithelium, choroid, and sclera) was studied by qRT-PCR and immunohistochemistry. In the murine model of CNV, both antibodies were administered intraperitoneally every other day until the day killed. On different time points after laser, treatment outcome was studied by immunohistochemical analysis of inflammation, angiogenesis and fibrosis, and by transcript analysis of different cytokines. RESULTS: Levels of LOX and LOXL2 in the posterior eye cups were increased after CNV-induction at different time points after laser. At day 35, their protein expression patterns appeared to correlate with retinal glial cells and endothelial cells, respectively. Both antibodies significantly inhibited fibrosis, whereas AB0023 also significantly reduced angiogenesis and inflammation. Transcript levels of α-1 type I collagen (COL1A1) in the posterior eye cups were significantly decreased in lasered mice treated with either M64 or AB0023. Vascular endothelial growth factor expression was also reduced only after AB0023 treatment, whereas activated fibroblast marker α-smooth muscle actin (αSMA) levels were not significantly changed. CONCLUSIONS: This study suggests that LOX and LOXL2 may play an important role in the pathogenesis of AMD. Targeting LOXL2 could have a broader efficacy than targeting LOX, by reducing angiogenesis and inflammation, as well as fibrosis.
PURPOSE: We investigated whether lysyl oxidase (LOX) and lysyl oxidase-like 2 (LOXL2) play a role in an experimental model of choroidal neovascularization (CNV). The therapeutic potential of antibodies against LOX (M64) and LOXL2 (AB0023) was evaluated in a murine laser-induced CNV model. METHODS: Expression of LOX and LOXL2 in the posterior eye cups (including retina, retinal pigment epithelium, choroid, and sclera) was studied by qRT-PCR and immunohistochemistry. In the murine model of CNV, both antibodies were administered intraperitoneally every other day until the day killed. On different time points after laser, treatment outcome was studied by immunohistochemical analysis of inflammation, angiogenesis and fibrosis, and by transcript analysis of different cytokines. RESULTS: Levels of LOX and LOXL2 in the posterior eye cups were increased after CNV-induction at different time points after laser. At day 35, their protein expression patterns appeared to correlate with retinal glial cells and endothelial cells, respectively. Both antibodies significantly inhibited fibrosis, whereas AB0023 also significantly reduced angiogenesis and inflammation. Transcript levels of α-1 type I collagen (COL1A1) in the posterior eye cups were significantly decreased in lasered mice treated with either M64 or AB0023. Vascular endothelial growth factor expression was also reduced only after AB0023 treatment, whereas activated fibroblast marker α-smooth muscle actin (αSMA) levels were not significantly changed. CONCLUSIONS: This study suggests that LOX and LOXL2 may play an important role in the pathogenesis of AMD. Targeting LOXL2 could have a broader efficacy than targeting LOX, by reducing angiogenesis and inflammation, as well as fibrosis.
Authors: Helena Giannakaki-Zimmermann; Despina Kokona; Sebastian Wolf; Andreas Ebneter; Martin S Zinkernagel Journal: Transl Vis Sci Technol Date: 2016-08-18 Impact factor: 3.283