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Kyungwon Lee, ying chen, Yang Hu, Jian-xing Ma; Therapeutic Potential Of An Anti-lrp6 Antibody For Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5944.
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The canonical Wnt signaling pathway plays a major pathogenic role in diabetic retinopathy (DR) through mediating over-expression of angiogenic and inflammatory factors, suggesting that Wnt signaling represents a new therapeutic target for DR. The purpose of the study is to evaluate therapeutic potential of blocking LRP6, a co-receptor of Wnt signaling, using a specific monoclonal antibody.
A monoclonal antibody (mAb) specific for the first and second propeller region of LRP6 was generated. In vitro, retinal pigment epithelial (RPE) cells, rat Muller cells, and retinal capillary endothelial cells (RCECs) were treated with mAb, and then exposed to 25 mM D-glucose to evaluate the inhibitory effect of the mAb on Wnt signaling and expression of anti-angiogenic/inflammatory factors using a TOPFLASH promoter activity assay and Western blotting. In vivo, the mAb was injected into the vitreous of Streptozotocin (STZ)-induced diabetic rats and oxygen-induced retinopathy (OIR) rats. Its beneficial effects on diabetic retinopathy were evaluated by Western blotting, vascular permeability assay, and leukostasis assay.
The mAb with a high specificity for LRP6 not only inhibited LRP6 phosphorylation and β-catenin accumulation, but also down-regulated the expression of Vascular Endothelial Growth Factor (VEGF), Intracellular Adhesion Molecule-1 (ICAM-1), and Tumor Necrosis Factor-alpha (TNF-α) in RPE cells and RCEC exposed to high glucose media. In both diabetic and OIR rats, retinal vascular permeability was significantly reduced by an injection of mAb compared to control with IgG injection. In addition, intravitreal injection of the mAb resulted in significant reduction of VEGF, ICAM-1, and TNF- α in the OIR and STZ-diabetic rat retina. Leukostasis assay in STZ-diabetic rats showed that the mAb decreased the number of adherent leukocytes in the retinal vasculature, suggesting an inhibitory effect on retinal inflammation.
The mAb specific for LRP6 suppressed vascular permeability and inflammation in the retina of the OIR and STZ-diabetic rats, suggesting its therapeutic potential in diabetic retinopathy.
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