PUBLICATION
Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders
- Authors
- Martin, M., Vermeiren, S., Bostaille, N., Eubelen, M., Spitzer, D., Vermeersch, M., Profaci, C.P., Pozuelo, E., Toussay, X., Raman-Nair, J., Tebabi, P., America, M., De Groote, A., Sanderson, L.E., Cabochette, P., Germano, R.F.V., Torres, D., Boutry, S., de Kerchove d'Exaerde, A., Bellefroid, E.J., Phoenix, T.N., Devraj, K., Lacoste, B., Daneman, R., Liebner, S., Vanhollebeke, B.
- ID
- ZDB-PUB-220304-2
- Date
- 2022
- Source
- Science (New York, N.Y.) 375: eabm4459 (Journal)
- Registered Authors
- Sanderson, Leslie, Vanhollebeke, Benoit
- Keywords
- none
- 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
- PubMed
- 35175798 Full text @ Science
Citation
Martin, M., Vermeiren, S., Bostaille, N., Eubelen, M., Spitzer, D., Vermeersch, M., Profaci, C.P., Pozuelo, E., Toussay, X., Raman-Nair, J., Tebabi, P., America, M., De Groote, A., Sanderson, L.E., Cabochette, P., Germano, R.F.V., Torres, D., Boutry, S., de Kerchove d'Exaerde, A., Bellefroid, E.J., Phoenix, T.N., Devraj, K., Lacoste, B., Daneman, R., Liebner, S., Vanhollebeke, B. (2022) Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders. Science (New York, N.Y.). 375:eabm4459.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping