Open AccessA Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy
Author(s) -
Chidiac Rony,
Abedin Md.,
Macleod Graham,
Yang Andy,
Thibeault Pierre E,
Blazer Levi L,
Adams Jarrett J,
Zhang Lingling,
Roehrich Heidi,
Jo HaNeul,
Seshagiri Somasekar,
Sidhu Sachdev S,
Junge Harald J,
Angers Stephane
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202113977
Subject(s) - wnt signaling pathway , endothelial stem cell , cancer research , surrogate endpoint , antibody , microbiology and biotechnology , function (biology) , chemistry , immunology , medicine , biology , signal transduction , biochemistry , in vitro
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.