Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD(4)-selective WNT surrogate in mice.
Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD(4)-selective WNT surrogate in mice.
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DOI：
10.1038/s41467-023-37689-1
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发表时间：
2023-06-02
影响因子：
16.6
通讯作者：
Kuo, Calvin J.
中科院分区：
文献类型：
--
作者：
Ding, Jie;Lee, Sung-Jin;Vlahos, Lukas;Yuki, Kanako;Rada, Cara C.;van Unen, Vincent;Vuppalapaty, Meghah;Chen, Hui;Sura, Asmiti;McCormick, Aaron K.;Tomaske, Madeline;Alwahabi, Samira;Nguyen, Huy;Nowatzke, William;Kim, Lily;Kelly, Lisa;Vollrath, Douglas;Califano, Andrea;Yeh, Wen-Chen;Li, Yang;Kuo, Calvin J.
血脑屏障（BBB）或血视网膜屏障（BRB）的紊乱发生在中风、癌症、糖尿病视网膜病变和阿尔茨海默病等疾病中。Norrin/FZD4/TSPAN12通路激活WNT/β-catenin信号，这对BBB和BRB功能至关重要。然而，FZD4的系统性药理学刺激受到专性棕榈酰化和天然WNTs的不溶性以及FZD4选择性配体Norrin的次优性质的阻碍。在这里，我们开发了L6-F4-2，一种非脂化的fzd4特异性替代物，与天然Norrin相比，它显著提高了亚皮摩尔亲和力。在Norrin敲除（NdpKO）小鼠中，L6-F4-2不仅能有效逆转新生儿视网膜血管生成缺陷，还能恢复BRB和血脑屏障功能。在成年C57Bl/6J小鼠中，脑卒中后全身给药L6-F4-2可显著降低血脑屏障通透性、梗死和水肿，同时改善神经评分和毛细血管周细胞覆盖。我们的研究结果揭示了生物工程fzd4选择性WNT替代物在缺血性血脑屏障功能障碍期间的全身功效，可能适用于以异常血脑屏障为特征的成人中枢神经系统疾病。WNT/b-catenin通路对血脑屏障（BBB）和血视网膜屏障（BRB）功能至关重要。生物工程fzd4选择性WNT替代物在小鼠BRB和缺血性脑卒中血脑屏障功能障碍中显示出全身功效。
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. The WNT/b-catenin pathway is essential for bloodbrain barrier (BBB) and blood-retina barrier (BRB) function. A bioengineered FZD4-selective WNT surrogate demonstrated systemic efficacy during BRB and ischemic stroke BBB dysfunction in mice.
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