Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders
Maud Martin, Simon Vermeiren, Naguissa Bostaille, Marie Eubelen, Daniel Spitzer, Marjorie Vermeersch, Caterina P. Profaci, Elisa Pozuelo, Xavier Toussay, Joanna Raman‐Nair, Patricia Tebabi, Michelle America, Aurélie De Groote, Leslie E. Sanderson, Pauline Cabochette, Raoul F. V. Germano, David Torres, Sébastien Boutry, Alban de Kerchove d’Exaerde, Eric Bellefroid, Timothy N. Phoenix, Kavi Devraj, Baptiste Lacoste, Richard Daneman, Stefan Liebner, Benoît Vanhollebeke
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.