Author:
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 J.,Yeh Wen-Chen,Li Yang,Kuo Calvin J.
Abstract
AbstractDerangements 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 FZD4stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD4-selective ligand Norrin. Here, we developed L6-F4-2, a non-lipidated, FZD4-specific surrogate with significantly improved sub-picomolar affinity versus native Norrin. In Norrin knockout (NdpKO) mice, L6-F4-2 not only potently reversed neonatal retinal angiogenesis deficits, but also restored BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduced 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 general applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.
Publisher
Cold Spring Harbor Laboratory