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Xiaodong Sun; Synergistic anti-angiogenic effect of ATN-161 and anti-VEGF antibody in a rat model of wet age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3401.
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The neovascular form of age-related macular degeneration (AMD) is characterized by abnormal vessel growth, termed choroidal neovascularization (CNV). The current standard therapy for CNV primarily inhibits vascular endothelial growth factor (VEGF), but this therapy is not effective in all patients. Considering that integrin α5β1 is involved in CNV development, inhibiting integrin α5β1 may provide a new approach for therapy targeting CNV. This study was designed to determine the role and underlying mechanisms of integrin α5β1 in angiogenesis in human choroidal endothelial cells (hCECs), and to evaluate the anti-angiogenic effects of combined therapy of ATN-161 (AC-PHSCN-NH2), an integrinα5β1 inhibitor, and anti-VEGF mAb in laser-induced CNV in experimental rats.
The antiangiogenic potential of ATN-161 was evaluated in VEFG-stimulated hCECs by MTS proliferation assays, migration assays, and synthetic matrix capillary tube formation assays. To evaluate the antiangiogenic effects of ATN-161 in vivo, CNV was induced in rats by laser photocoagulation. ATN-161 with/without AF564 anti-VEGF antibody, were injected intravitreally immediately after photocoagulation. Eyes were examined by SD-OCT and fluorescein angiography on days 1, 7, and 14 after injection, and the areas of CNV were measured by analysis of choroidal flatmounts at day 14. The signal pathway involved in the angiogenesis was tested by western blotting.
Treatment with ATN-161 and anti-VEGF antibody showed a synergistic effect in attenuating angiogenesis. Our results indicate that fibronectin (Fn) binds to integrin α5β1 and enhances VEGF-induced angiogenesis via two independent signaling pathways, FN/integrin α5β1/FAK/ERK1/2 and FN/integrin α5β1/FAK/AKT.Treatment with ATN-161 plus anti-VEGF antibody showed synergistic effects in attenuating angiogenesis.
Inhibiting Integrin α5β1 is a promising novel therapy for CNV.
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