The FZD4:LRP5:TSPAN12 receptor complex is activated by the secreted protein Norrin in retinal endothelial cells and leads to βcatenin-dependent formation of the blood–retina–barrier during development and its homeostasis in adults. Mutations disrupting Norrin signaling have been identified in several congenital diseases leading to hypovascularization of the retina and blindness. Here, we developed F4L5.13, a tetravalent antibody designed to induce FZD4 and LRP5 proximity in such a way as to trigger βcatenin signaling. Treatment of cultured endothelial cells with F4L5.13 rescued permeability induced by VEGF in part by promoting surface expression of junction proteins. Treatment of Tspan12−/− mice with F4L5.13 restored retinal angiogenesis and barrier function. F4L5.13 treatment also significantly normalized neovascularization in an oxygen-induced retinopathy model revealing a novel therapeutic strategy for diseases characterized by abnormal angiogenesis and/or barrier dysfunction.
Bibliographical noteFunding Information:
We are grateful to members of the Sidhu, Junge, and Angers laboratories for helpful discussions and to the Vanderbilt Ophthalmic Contract Research Organization for work on the OIR experiment. This work was supported by grants from the Canadian Institutes of Health Research (MOP‐84273 and PJT‐175160) to SA, the Ontario Ministry of Research and Innovation (RE07‐043) to SSS and SA, the Canadian Institutes of Health Research (MOP‐136944) to SSS, the CFREF Medicine by Design (MBDC2‐2019‐03) to SA and SSS, and the National Institutes of Health (R01 EY024261) to HJJ. HR was supported by NIH P30 EY011374.
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
- Wnt signaling
- blood–retina barrier
- endothelial cells