Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice

Jie Ding, Sung-Jin Lee, Lukas Vlahos, Kanako Yuki, Cara C. Rada, Vincent 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 and Calvin J. Kuo ()
Additional contact information
Jie Ding: Stanford University School of Medicine
Sung-Jin Lee: Surrozen, Inc. South San Francisco
Lukas Vlahos: Columbia University
Kanako Yuki: Stanford University School of Medicine
Cara C. Rada: Stanford University School of Medicine
Vincent Unen: Stanford University School of Medicine
Meghah Vuppalapaty: Surrozen, Inc. South San Francisco
Hui Chen: Surrozen, Inc. South San Francisco
Asmiti Sura: Surrozen, Inc. South San Francisco
Aaron K. McCormick: Stanford University School of Medicine
Madeline Tomaske: Stanford University School of Medicine
Samira Alwahabi: Stanford University School of Medicine
Huy Nguyen: Surrozen, Inc. South San Francisco
William Nowatzke: Surrozen, Inc. South San Francisco
Lily Kim: Stanford University School of Medicine
Lisa Kelly: Stanford University School of Medicine
Douglas Vollrath: Stanford University School of Medicine
Andrea Califano: Columbia University
Wen-Chen Yeh: Surrozen, Inc. South San Francisco
Yang Li: Surrozen, Inc. South San Francisco
Calvin J. Kuo: Stanford University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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/FZD4/TSPAN12 pathway activates WNT/β-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD4-selective ligand Norrin. Here, we develop L6-F4-2, a non-lipidated, FZD4-specific surrogate which significantly improves subpicomolar affinity versus native Norrin. In Norrin knockout (NdpKO) 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 FZD4-selective WNT surrogate during ischemic BBB dysfunction, with potential applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.

Date: 2023
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DOI: 10.1038/s41467-023-37689-1

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