A Norrin/Wnt Surrogate Antibody Stimulates Endothelial Cell Barrier Function and Rescues Retinopathy

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2021 Jun 9

PMID 34105895

Citations 19

Authors

Rony Chidiac

Md Abedin

Graham MacLeod

Andy Yang

Pierre E Thibeault

Levi L Blazer

Jarrett J Adams

Lingling Zhang

Heidi Roehrich

Ha-Neul Jo

Somasekar Seshagiri

Sachdev S Sidhu

Harald J Junge

Stephane Angers

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Mechanistic insights into Wnt-β-catenin pathway activation and signal transduction.

Maurice M, Angers S Nat Rev Mol Cell Biol. 2025; .

PMID: 39856369 DOI: 10.1038/s41580-024-00823-y.

Selective activation of FZD2 and FZD7 reveals non-redundant function during mesoderm differentiation.

Chidiac R, Yang A, Kubarakos E, Mikolajewicz N, Han H, Almeida M Stem Cell Reports. 2025; 20(2):102391.

PMID: 39824186 PMC: 11864152. DOI: 10.1016/j.stemcr.2024.102391.

The co-receptor Tetraspanin12 directly captures Norrin to promote ligand-specific β-catenin signaling.

Bruguera E, Mahoney J, Weis W Elife. 2025; 13.

PMID: 39745873 PMC: 11695057. DOI: 10.7554/eLife.96743.

Interplay between Netrin-1 and Norrin controls arteriovenous zonation of blood-retina barrier integrity.

Furtado J, Geraldo L, Leser F, Bartkowiak B, Poulet M, Park H Proc Natl Acad Sci U S A. 2024; 121(52):e2408674121.

PMID: 39693351 PMC: 11670198. DOI: 10.1073/pnas.2408674121.

Rescue of cochlear vascular pathology prevents sensory hair cell loss in Norrie disease.

Patel A, Pauzuolyte V, Ingham N, Leong Y, Berger W, Steel K Proc Natl Acad Sci U S A. 2024; 121(49):e2322124121.

PMID: 39585982 PMC: 11626139. DOI: 10.1073/pnas.2322124121.

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