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

Author

Listed:
  • 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
    Institute for Immunity, Transplantation and Infection, 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)

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.

Suggested Citation

  • 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 , 2023. "Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37689-1
    DOI: 10.1038/s41467-023-37689-1
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    References listed on IDEAS

    as
    1. Ayal Ben-Zvi & Baptiste Lacoste & Esther Kur & Benjamin J. Andreone & Yoav Mayshar & Han Yan & Chenghua Gu, 2014. "Mfsd2a is critical for the formation and function of the blood–brain barrier," Nature, Nature, vol. 509(7501), pages 507-511, May.
    2. Annika Armulik & Guillem Genové & Maarja Mäe & Maya H. Nisancioglu & Elisabet Wallgard & Colin Niaudet & Liqun He & Jenny Norlin & Per Lindblom & Karin Strittmatter & Bengt R. Johansson & Christer Bet, 2010. "Pericytes regulate the blood–brain barrier," Nature, Nature, vol. 468(7323), pages 557-561, November.
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    4. Kelley S. Yan & Claudia Y. Janda & Junlei Chang & Grace X. Y. Zheng & Kathryn A. Larkin & Vincent C. Luca & Luis A. Chia & Amanda T. Mah & Arnold Han & Jessica M. Terry & Akifumi Ootani & Kelly Roelf , 2017. "Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal," Nature, Nature, vol. 545(7653), pages 238-242, May.
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