在这里，研究人员利用Wnt7a/b 特异性Gpr124/Reck共受体复合物，将Wnt7a配体基因工程改造为BBB特异性Wnt激活子。 在“打了就跑”的腺病毒辅助中枢神经系统基因传递环境中，这些新的Gpr124/Reck特异性激动剂保护BBB功能，从而减轻胶质母细胞瘤扩张和缺血性中风梗塞。这项工作揭示了Wnt配体的信号特异性是可调节的，并定义了一种通过使 BBB 正常化来治疗中枢神经系统疾病的模式。
据介绍，血脑屏障 (blood-brain barrier, BBB) 保护中枢神经系统 (central nervous system, CNS) 免受有害的血源性因素的影响。尽管BBB功能障碍是几种神经系统疾病的标志，但目前尚缺乏恢复BBB功能的治疗方法。 一个值得考虑的策略是重新利用发育性BBB调节器，如Wnt7a，成为BBB保护剂。然而，Wnt 配体的安全治疗用途因其多效性Frizzled 信号活性而变得复杂。
附：英文原文
Title: Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders
Author: Maud Martin, Simon Vermeiren, Naguissa Bostaille, Marie Eubelen, Daniel Spitzer, Marjorie Vermeersch, Caterina P. Profaci, Elisa Pozuelo, Xavier Toussay, Joanna Raman-Nair, Patricia Tebabi, Michelle America, Aurélie De Groote, Leslie E. Sanderson, Pauline Cabochette, Raoul F. V. Germano, David Torres, Sébastien Boutry, Alban de Kerchove d’Exaerde, Eric J. Bellefroid, Timothy N. Phoenix, Kavi Devraj, Baptiste Lacoste, Richard Daneman, Stefan Liebner, Benoit Vanhollebeke
Issue&Volume: 2022-02-18
Abstract: 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.
DOI: abm4459
Source: https://www.science.org/doi/10.1126/science.abm4459