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

EMBO Molecular Medicine
Rony ChidiacStephane Angers

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.

References

Aug 27, 2005·Investigative Ophthalmology & Visual Science·Ulrich F O LuhmannWolfgang Berger
Dec 22, 2007·Seminars in Ophthalmology·Scott M WardenShizuo Mukai
Oct 29, 2008·The Journal of Cell Biology·Stefan LiebnerElisabetta Dejana
Nov 4, 2008·Investigative Ophthalmology & Visual Science·Nikolaus F SchäferWolfgang Berger
Dec 23, 2008·Methods in Molecular Biology·Travis L Biechele, Randall T Moon
Jan 8, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Andreas OhlmannErnst R Tamm
Jul 24, 2010·PloS One·Chun-hong XiaXiaohua Gong
Jul 27, 2011·PloS One·Fran SupekTomislav Šmuc
Dec 12, 2012·Journal of Molecular Biology·Helena PerssonSachdev S Sidhu
Feb 8, 2013·Nature Medicine·Roland Baron, Michaela Kneissel
Dec 7, 2013·Nature Medicine·Birgit ObermeierRichard M Ransohoff
Aug 2, 2014·The Journal of Clinical Investigation·Yulian ZhouJeremy Nathans
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
Apr 5, 2016·Nature Biotechnology·Nicolas L BrayLior Pachter
Apr 22, 2016·Nucleic Acids Research·Jüri ReimandJaak Vilo
Jul 26, 2018·JAMA Ophthalmology·Jeffrey G GrossUNKNOWN Diabetic Retinopathy Clinical Research Network
Oct 4, 2018·Physiological Reviews·Melanie D SweeneyBerislav V Zlokovic
Oct 30, 2018·Investigative Ophthalmology & Visual Science·Luke NicholsonSobha Sivaprasad
Nov 28, 2018·Proceedings of the National Academy of Sciences of the United States of America·Yanshu WangJeremy Nathans

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.