Journal
SCIENCE
Volume 375, Issue 6582, Pages 737-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abm4459
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Funding
- FNRS [MIS F.4543.15]
- Concerted Research Action
- Fondation ULB
- H2020 ITN BtRAIN
- Queen Elisabeth Medical Foundation
- FRFSWELBIO [CR-2017S-05R]
- ERC [Ctrl-BBB 865176]
- DFG [LI 911/5-1, LI 911/7-1]
- Excellence Cluster Cardio-Pulmonary Institute
- DZHK
- LOEWE CePTER Epilepsy Research Center of the state Hesse
- Heart and Stroke Foundation of Canada [G-17-0018290]
- Canadian Institute of Health Research [388805]
- New Frontiers Research Funds-Exploration grant [NFRFE-2019-00641]
- FRS-FNRS
- Fondation Clerdent
- European Regional Development Fund
- Walloon Region
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In this study, scientists successfully engineered Wnt7a ligands into BBB-specific Wnt activators using gene engineering methods. These new Gpr124/Reck-specific agonists protected BBB function and mitigated glioblastoma expansion and ischemic stroke infarction. This study reveals the adjustable signaling specificity of Wnt ligands and provides a new modality for treating CNS disorders by normalizing the BBB.
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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