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

Science. 2022 Feb 18;375(6582):eabm4459. doi: 10.1126/science.abm4459. Epub 2022 Feb 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / physiology*
  • Brain / metabolism
  • Endothelial Cells / metabolism
  • Frizzled Receptors / metabolism
  • GPI-Linked Proteins / agonists*
  • Glioblastoma / metabolism
  • Glioblastoma / therapy*
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Mutagenesis
  • Nervous System / embryology
  • Protein Engineering
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Stroke / metabolism
  • Stroke / therapy*
  • Wnt Proteins / chemistry
  • Wnt Proteins / genetics*
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway*
  • Xenopus laevis
  • Zebrafish


  • Frizzled Receptors
  • GPI-Linked Proteins
  • GPR124 protein, mouse
  • Ligands
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • Reck protein, mouse
  • Wnt Proteins
  • Wnt7a protein, mouse
  • Wnt7b protein, mouse

Grant support