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

par Martin, Maud ;Vermeiren, Simon ;Bostaille, Naguissa ;Eubelen, Marie ;Spitzer, Daniel;Vermeersch, Marjorie ;Profaci, Caterina CP;Pozuelo Fernandez, Elisa ;Toussay, Xavier;Raman-Nair, Joanna;Tebabi, Patricia ;America, Michelle ;De Groote, Aurélie ;Sanderson, Leslie ;Cabochette, Pauline ;Freitas Vale Germano, Raoul ;Torres, David ;Boutry, Sébastien ;de Kerchove d'Exaerde, Alban ;Bellefroid, Eric ;Phoenix, Timothy N;Devraj, Kavi;Lacoste, Baptiste;Daneman, Richard;Liebner, Stefan;Vanhollebeke, Benoît
Référence Science, 375(6582):eabm4459
Publication Publié, 2022-02-18

Article révisé par les pairs

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Résumé :

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.