Journal Article

Therapeutic Potential of a Monoclonal Antibody Blocking the Wnt Pathway in Diabetic Retinopathy

Takahashi, Yusuke, Lee, Kyungwon, Chen, Ying, Mott, Robert, Hu, Yang, Ding, Lexi, Ma, Jian-xing

2012

Overview

Dysregulation of Wnt/β-catenin signaling contributes to the development of diabetic retinopathy by inducing retinal inflammation, vascular leakage, and neovascularization. Here, we evaluated the inhibitory effect of a monoclonal antibody (Mab) specific for the E1E2 domain of Wnt coreceptor low-density lipoprotein receptor–related protein 6, Mab2F1, on canonical Wnt signaling and its therapeutic potential for diabetic retinopathy. Mab2F1 displayed robust inhibition on Wnt signaling with a half-maximal inhibitory concentration (IC50) of 20 μg/mL in retinal pigment epithelial cells. In addition, Mab2F1 also attenuated the accumulation of β-catenin and overexpression of vascular endothelial growth factor, intercellular adhesion molecule-1, and tumor necrosis factor-α induced by high-glucose medium in retinal endothelial cells. In vivo, an intravitreal injection of Mab2F1 significantly reduced retinal vascular leakage and decreased preretinal vascular cells in oxygen-induced retinopathy (OIR) rats, demonstrating its inhibitory effects on ischemia-induced retinal neovascularization. Moreover, Mab2F1 blocked the overexpression of the inflammatory/angiogenic factors, attenuated leukostasis, and reduced retinal vascular leakage in both early and late stages of streptozotocin-induced diabetes. In conclusion, Mab2F1 inhibits canonical Wnt signaling, vascular leakage, and inflammation in the retina of diabetic retinopathy models, suggesting its potential to be used as a therapeutic agent in combination with other antiangiogenic compounds.

• Publisher: American Diabetes Association
• Subject: Analysis / Angiogenesis Inhibitors - administration & dosage / Angiogenesis Inhibitors - pharmacology / Angiogenesis Inhibitors - therapeutic use / Animals / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - pharmacology / Antibodies, Monoclonal - therapeutic use / beta Catenin - metabolism / Biological and medical sciences / Capillary Permeability - drug effects / Cattle / Cells, Cultured / Complications / Diabetes / Diabetes. Impaired glucose tolerance / Diabetic retinopathy / Diabetic Retinopathy - drug therapy / Diabetic Retinopathy - immunology / Diabetic Retinopathy - metabolism / Diabetic Retinopathy - pathology / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Endothelium, Vascular - drug effects / Endothelium, Vascular - immunology / Endothelium, Vascular - metabolism / Endothelium, Vascular - pathology / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Genes, Reporter - drug effects / HEK293 Cells / Humans / Hyperglycemia / Hyperglycemia - metabolism / Inflammation / Intravitreal Injections / Kinases / Leukostasis - prevention & control / Ligands / Low Density Lipoprotein Receptor-Related Protein-6 - antagonists & inhibitors / Low Density Lipoprotein Receptor-Related Protein-6 - genetics / Low Density Lipoprotein Receptor-Related Protein-6 - metabolism / Low density lipoprotein receptors / Medical sciences / Molecular Targeted Therapy / Monoclonal antibodies / Ophthalmology / Physiological aspects / Proteins / Rats / Rats, Inbred BN / Receptors, Wnt - antagonists & inhibitors / Receptors, Wnt - genetics / Receptors, Wnt - metabolism / Recombinant Proteins - antagonists & inhibitors / Recombinant Proteins - metabolism / Retina / Retinal Pigment Epithelium - drug effects / Retinal Pigment Epithelium - immunology / Retinal Pigment Epithelium - metabolism / Retinal Pigment Epithelium - pathology / Retinopathies / Tumor necrosis factor-TNF / Vascular endothelial growth factor / Wnt Signaling Pathway - drug effects