Martin M et al. (2022), Engineered Wnt ligands enable blood-brain barri...

XB-ART-58862

Science 2022 Feb 18;3756582:eabm4459. doi: 10.1126/science.abm4459.

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

Martin M , Vermeiren S , Bostaille N , Eubelen M , Spitzer D , Vermeersch M , Profaci CP , Pozuelo E , Toussay X , Raman-Nair J , Tebabi P , America M , De Groote A , Sanderson LE , Cabochette P , Germano RFV , Torres D , Boutry S , de Kerchove d'Exaerde A , Bellefroid EJ , Phoenix TN , Devraj K , Lacoste B , Daneman R , Liebner S , Vanhollebeke B .

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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.

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Species referenced: Xenopus laevis
Genes referenced: wnt7a
GO keywords: Wnt signaling pathway [+]

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???displayArticle.omims??? STROKE, ISCHEMIC