Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD(4)-selective WNT surrogate in mice.

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Publication Year:
2023
Authors:
Jie Ding, Sung-Jin Lee, Lukas Vlahos, Kanako Yuki, Cara C Rada, Vincent van Unen, Meghah Vuppalapaty, Hui Chen, Asmiti Sura, Aaron K McCormick, Madeline Tomaske, Samira Alwahabi, Huy Nguyen, William Nowatzke, Lily Kim, Lisa Kelly, Douglas Vollrath, Andrea Califano, Wen-Chen Yeh, Yang Li, Calvin J Kuo
PubMed ID:
37268690
Funding Grants:
Public Summary:
Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer's disease. The Norrin/FZD(4)/TSPAN12 pathway activates WNT/beta-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD(4) stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD(4)-selective ligand Norrin. Here, we develop L6-F4-2, a non-lipidated, FZD(4)-specific surrogate which significantly improves subpicomolar affinity versus native Norrin. In Norrin knockout (Ndp(KO)) mice, L6-F4-2 not only potently reverses neonatal retinal angiogenesis deficits, but also restores BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduces BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD(4)-selective WNT surrogate during ischemic BBB dysfunction, with potential applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.
Scientific Abstract:
Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer's disease. The Norrin/FZD(4)/TSPAN12 pathway activates WNT/beta-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD(4) stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD(4)-selective ligand Norrin. Here, we develop L6-F4-2, a non-lipidated, FZD(4)-specific surrogate which significantly improves subpicomolar affinity versus native Norrin. In Norrin knockout (Ndp(KO)) mice, L6-F4-2 not only potently reverses neonatal retinal angiogenesis deficits, but also restores BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduces BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD(4)-selective WNT surrogate during ischemic BBB dysfunction, with potential applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.