title: Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema.
abstract: Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 autophosphorylation and downstream signaling. Activated Tie2 increases endothelial cell survival, adhesion, and cell junction integrity, thereby stabilizing the vasculature. Angiopoietin-2 (Angpt2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are negative regulators increased by hypoxia; they inactivate Tie2, destabilizing the vasculature and increasing responsiveness to vascular endothelial growth factor (VEGF) and other inflammatory cytokines that stimulate vascular leakage and neovascularization. AKB-9778 is a small-molecule antagonist of VE-PTP which increases phosphorylation of Tie2 even in the presence of high Angpt2 levels. In preclinical studies, AKB-9778 reduced VEGF-induced leakage and ocular neovascularization (NV) and showed additive benefit when combined with VEGF suppression. In two clinical trials in diabetic macular edema (DME) patients, subcutaneous injections of AKB-9778 were safe and provided added benefit to VEGF suppression. Preliminary data suggest that AKB-9778 monotherapy improves diabetic retinopathy. These data suggest that Tie2 activation may be a valuable strategy to treat or prevent diabetic retinopathy.
authors: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. pcampo@jhmi.edu.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. pcampo@jhmi.edu.|The Wilmer Eye Institute, The Johns Hopkins School of Medicine, 815 Maumenee, 600 N. Wolfe Street, Baltimore, MD, 21287-9277, USA. pcampo@jhmi.edu.
authors: Peter A
authors: PA
authors: Campochiaro
authors: Aerpio Therapeutics, 9987 Carver Road, Cincinnati, OH, USA.
authors: Kevin G
authors: KG
authors: Peters
mesh_terms: D042683:Angiopoietin-1 / Q000502:physiology; D042702:Angiopoietin-2 / Q000502:physiology; D000814:Aniline Compounds / Q000627:therapeutic use*; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D006801:Humans; D008269:Macular Edema / Q000188:drug therapy*; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000502:physiology; D015398:Signal Transduction; D013451:Sulfonic Acids / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C000598564:AKB-9778; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000814:Aniline Compounds; D013451:Sulfonic Acids; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3
keywords: Angiopoietins; Hypoxia; Neovascularization; Vascular endothelial growth factor; Vascular endothelial-protein tyrosine phosphatase; Vascular leakage