1区 · 综合性期刊
Article
作者: Lacoste, Baptiste ; Vermeiren, Simon ; de Kerchove d’Exaerde, Alban ; Eubelen, Marie ; Raman-Nair, Joanna ; America, Michelle ; De Groote, Aurélie ; Sanderson, Leslie E. ; Daneman, Richard ; Vanhollebeke, Benoit ; Tebabi, Patricia ; Bellefroid, Eric J. ; Torres, David ; Profaci, Caterina P. ; Toussay, Xavier ; Phoenix, Timothy N. ; Vermeersch, Marjorie ; Cabochette, Pauline ; Spitzer, Daniel ; Martin, Maud ; Boutry, Sébastien ; Germano, Raoul F. V. ; Pozuelo, Elisa ; Devraj, Kavi ; Bostaille, Naguissa ; Liebner, Stefan
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.
