A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy

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

doi:10.15252/emmm.202113977

A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy

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

Ophthalmology & Visual Neurosciences

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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.

Original language	English (US)
Article number	e13977
Journal	EMBO Molecular Medicine
Volume	13
Issue number	7
DOIs	https://doi.org/10.15252/emmm.202113977
State	Published - Jul 7 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.

Keywords

Norrin
Wnt signaling
blood–retina barrier
endothelial cells
retinopathy

Access

10.15252/emmm.202113977

OpenUrl availability

Full text

Cite this

Chidiac, R., Abedin, M., Macleod, G., Yang, A., Thibeault, P. E., Blazer, L. L., Adams, J. J., Zhang, L., Roehrich, H., Jo, H. N., Seshagiri, S., Sidhu, S. S., Junge, H. J., & Angers, S. (2021). A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy. EMBO Molecular Medicine, 13(7), Article e13977. https://doi.org/10.15252/emmm.202113977

@article{ee12cc8bd6b94f46ab0884910e5aed20,

title = "A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy",

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.",

keywords = "Norrin, Wnt signaling, blood–retina barrier, endothelial cells, retinopathy",

author = "Rony Chidiac and Md Abedin and Graham Macleod and Andy Yang and Thibeault, {Pierre E.} and Blazer, {Levi L.} and Adams, {Jarrett J.} and Lingling Zhang and Heidi Roehrich and Jo, {Ha Neul} and Somasekar Seshagiri and Sidhu, {Sachdev S.} and Junge, {Harald J.} and Stephane Angers",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY 4.0 license.",

year = "2021",

month = jul,

day = "7",

doi = "10.15252/emmm.202113977",

language = "English (US)",

volume = "13",

journal = "EMBO Molecular Medicine",

issn = "1757-4676",

publisher = "Wiley-Blackwell",

number = "7",

}

TY - JOUR

T1 - A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy

AU - Chidiac, Rony

AU - Abedin, Md

AU - Macleod, Graham

AU - Yang, Andy

AU - Thibeault, Pierre E.

AU - Blazer, Levi L.

AU - Adams, Jarrett J.

AU - Zhang, Lingling

AU - Roehrich, Heidi

AU - Jo, Ha Neul

AU - Seshagiri, Somasekar

AU - Sidhu, Sachdev S.

AU - Junge, Harald J.

AU - Angers, Stephane

PY - 2021/7/7

Y1 - 2021/7/7

N2 - 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.

AB - 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.

KW - Norrin

KW - Wnt signaling

KW - blood–retina barrier

KW - endothelial cells

KW - retinopathy

UR - http://www.scopus.com/inward/record.url?scp=85107377994&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85107377994&partnerID=8YFLogxK

U2 - 10.15252/emmm.202113977

DO - 10.15252/emmm.202113977

M3 - Article

C2 - 34105895

AN - SCOPUS:85107377994

SN - 1757-4676

VL - 13

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 7

M1 - e13977

ER -

A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy

Abstract

Bibliographical note

Keywords

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this