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

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.

An integrated model for Gpr124 function in Wnt7a/b signaling among vertebrates

“…Wnt7a/b discrimination by brain ECs was found to rely on an atypical receptor complex composed of the glycosylphosphatidylinositol (GPI)-anchored glycoprotein Reck and the orphan adhesion G protein-coupled receptor Gpr124 (also referred to as adhesion G protein-coupled receptor A2 or Adgra2) ( Zhou and Nathans, 2014 ; Posokhova et al., 2015 ; Vanhollebeke et al., 2015 ; Ulrich et al., 2016 ). At present, the Gpr124/Reck complex, besides being an important therapeutic target in neurological disorders ( Chang et al., 2017 ; Martin et al., 2022 ), represents the only known Wnt ligand-specific receptor complex. Its mechanism is, therefore, explored as a paradigm for how Wnt ligand-specific signaling is achieved in vertebrates.…”

Engineered Wnt7a ligands rescue blood brain barrier and neurobehavioral deficits in a mouse model of COVID-19

“…Finally, we identified Wnt/β-catenin signaling as a potential mechanistic basis relating age to severity of NeuroCOVID. Previous work has established, in human and in mouse, that Wnt7a/7b is required for CNS angiogenesis and that Wnt3/3a suppresses inflammatory T cell migration across the cerebrovasculature (Daneman et al ., 2009; Guérit et al ., 2020; Lengfeld et al ., 2017; Liebner et al ., 2008; Martin et al ., 2022; Stenman et al ., 2008; Tran et al ., 2016). Our data suggest that the resiliency of young adults to SARS-CoV-2 is related to robust canonical Wnt activity.…”

Blood–brain barrier: emerging trends on transport models and new-age strategies for therapeutics intervention against neurological disorders

“…Wnt 7a and 7b are the signals that induce the formation of the BBB and are also involved in BBB repair. The complex of Wnt 7a/b with G protein–coupled receptor (Gpr124) and the glycoprotein Reck can be well utilized for BBB repair with high specificity [ 251 ].…”