Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders-Reference-Cited by-同舟云学术

Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders

Published:2022-02-18 Issue:6582 Volume:375 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Martin Maud¹^ORCID,Vermeiren Simon¹,Bostaille Naguissa¹^ORCID,Eubelen Marie¹^ORCID,Spitzer Daniel²,Vermeersch Marjorie³,Profaci Caterina P.⁴^ORCID,Pozuelo Elisa⁵,Toussay Xavier⁶^ORCID,Raman-Nair Joanna⁶,Tebabi Patricia¹,America Michelle¹,De Groote Aurélie⁵,Sanderson Leslie E.¹^ORCID,Cabochette Pauline¹^ORCID,Germano Raoul F. V.¹^ORCID,Torres David⁷^ORCID,Boutry Sébastien³^ORCID,de Kerchove d’Exaerde Alban⁵^ORCID,Bellefroid Eric J.⁸^ORCID,Phoenix Timothy N.⁹^ORCID,Devraj Kavi²^ORCID,Lacoste Baptiste⁶^ORCID,Daneman Richard⁴^ORCID,Liebner Stefan²^ORCID,Vanhollebeke Benoit¹¹⁰^ORCID

Affiliation:

1. Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium.

2. Institute of Neurology (Edinger Institute), University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.

3. Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Université de Mons, Gosselies B-6041, Belgium.

4. Departments of Pharmacology and Neurosciences, University of California, San Diego, La Jolla, CA, USA.

5. Laboratory of Neurophysiology, ULB Neuroscience Institute, Université libre de Bruxelles, Brussels B-1070, Belgium.

6. Ottawa Hospital Research Institute, Neuroscience Program, Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Faculty of Medicine, Ottawa, Ontario, Canada.

7. Institut d’Immunologie Médicale, Université libre de Bruxelles, Gosselies, Belgium.

8. Laboratory of Developmental Genetics, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium.

9. Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.

10. Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wavre, Belgium.

Abstract

The blood-brain barrier (BBB) protects the central nervous system (CNS) from harmful blood-borne factors. Although BBB dysfunction is a hallmark of several neurological disorders, therapies to restore BBB function are lacking. An attractive strategy is to repurpose developmental BBB regulators, such as Wnt7a, into BBB-protective agents. However, safe therapeutic use of Wnt ligands is complicated by their pleiotropic Frizzled signaling activities. Taking advantage of the Wnt7a/b-specific Gpr124/Reck co-receptor complex, we genetically engineered Wnt7a ligands into BBB-specific Wnt activators. In a “hit-and-run” adeno-associated virus–assisted CNS gene delivery setting, these new Gpr124/Reck-specific agonists protected BBB function, thereby mitigating glioblastoma expansion and ischemic stroke infarction. This work reveals that the signaling specificity of Wnt ligands is adjustable and defines a modality to treat CNS disorders by normalizing the BBB.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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