[en] 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.
Disciplines :
Médecine de laboratoire & technologie médicale
Auteur, co-auteur :
MARTIN, Maud ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Vermeiren, Simon; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Bostaille, Naguissa ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Eubelen, Marie ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Spitzer, Daniel; Institute of Neurology (Edinger Institute), University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
Vermeersch, Marjorie; Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Université de Mons, Gosselies B-6041, Belgium
Profaci, Caterina P ; Departments of Pharmacology and Neurosciences, University of California, San Diego, La Jolla, CA, USA
Pozuelo, Elisa; Laboratory of Neurophysiology, ULB Neuroscience Institute, Université libre de Bruxelles, Brussels B-1070, Belgium
Toussay, Xavier ; 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
Raman-Nair, Joanna; 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
Tebabi, Patricia; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
America, Michelle; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
De Groote, Aurélie; Laboratory of Neurophysiology, ULB Neuroscience Institute, Université libre de Bruxelles, Brussels B-1070, Belgium
Sanderson, Leslie E ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Cabochette, Pauline ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Germano, Raoul F V ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Torres, David ; Institut d'Immunologie Médicale, Université libre de Bruxelles, Gosselies, Belgium
Boutry, Sébastien ; Université de Mons - UMONS > Faculté de Médecine et de Pharmacie > Service de Chimie générale, organique et biomédicale ; Université de Mons - UMONS > Unités externes > Center for Microscopy and Molecular Imaging
De Kerchove D'exaerde, Alban ; Université libre de Bruxelles > ULB Neuroscience Institute > Laboratory of Neurophysiology
Bellefroid, Eric ; Laboratory of Developmental Genetics, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Phoenix, Timothy N ; Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA
Devraj, Kavi ; Institute of Neurology (Edinger Institute), University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
Lacoste, Baptiste ; 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
Daneman, Richard ; Departments of Pharmacology and Neurosciences, University of California, San Diego, La Jolla, CA, USA
Liebner, Stefan ; Institute of Neurology (Edinger Institute), University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
Vanhollebeke, Benoit ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium ; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wavre, Belgium
Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders.
Date de publication/diffusion :
2022
Titre du périodique :
Science
ISSN :
0036-8075
eISSN :
1095-9203
Maison d'édition :
American Association for the Advancement of Science, Etats-Unis
Volume/Tome :
375
Fascicule/Saison :
6582
Pagination :
eabm4459
Peer reviewed :
Peer reviewed vérifié par ORBi
Institut de recherche :
Biosciences R550 - Institut des Sciences et Technologies de la Santé
Subventionnement (détails) :
M.E., and N.B. are FRIA fellows, A.D.G. is FNRS-L'Oreal fellow, and S.V. and P.C. are postdoctoral researchers of the FRS-FNRS. Work in the B.V. laboratory is supported by the FNRS (MIS F.4543.15), the Concerted Research Action, the Fondation ULB, the H2020 ITN “BtRAIN,” the Queen Elisabeth Medical Foundation, the FRFSWELBIO (CR-2017S-05R), and the ERC (Ctrl-BBB 865176). Also supported by DFG grant LI 911/5-1, LI 911/7-1, the Excellence Cluster Cardio-Pulmonary Institute, the H2020 ITN “BtRAIN,” the DZHK, and the LOEWE CePTER Epilepsy Research Center of the state Hesse (S.L. and K.D.) and by Heart and Stroke Foundation of Canada grant G-17-0018290, Canadian Institute of Health Research grant 388805, and New Frontiers Research Funds-Exploration grant NFRFE-2019-00641 (B.L.). A.d.K.d'E. is research director of FRS-FNRS, supported by FRS-FNRS and the Fondation Clerdent. The Center for Microscopy and Molecular Imaging is supported by the European Regional Development Fund and the Walloon Region.
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