Therapeutic potential of a monoclonal antibody blocking the Wnt pathway in diabetic retinopathy.
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.
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Kyungwon
K
Lee
Yang
Y
Hu
Lexi
L
Ding
Ying
Y
Chen
Yusuke
Y
Takahashi
Robert
R
Mott
Jian-Xing
JX
Ma
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017930:Genes, Reporter / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D058449:Intravitreal Injections; D018921:Leukostasis / Q000517:prevention & control; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D051381:Rats; D011914:Rats, Inbred BN; D060490:Receptors, Wnt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D060490:Receptors, Wnt; D011994:Recombinant Proteins; D051176:beta Catenin