Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder

Timothy F. Shay (), Seongmin Jang, Tyler J. Brittain, Xinhong Chen, Beth Walker, Claire Tebbutt, Yujie Fan, Damien A. Wolfe, Cynthia M. Arokiaraj, Erin E. Sullivan, Xiaozhe Ding, Ting-Yu Wang, Yaping Lei, Miguel R. Chuapoco, Tsui-Fen Chou and Viviana Gradinaru ()
Additional contact information
Timothy F. Shay: California Institute of Technology
Seongmin Jang: California Institute of Technology
Tyler J. Brittain: California Institute of Technology
Xinhong Chen: California Institute of Technology
Beth Walker: Charles River Laboratories
Claire Tebbutt: Charles River Laboratories
Yujie Fan: California Institute of Technology
Damien A. Wolfe: California Institute of Technology
Cynthia M. Arokiaraj: California Institute of Technology
Erin E. Sullivan: California Institute of Technology
Xiaozhe Ding: California Institute of Technology
Ting-Yu Wang: California Institute of Technology
Yaping Lei: California Institute of Technology
Miguel R. Chuapoco: California Institute of Technology
Tsui-Fen Chou: California Institute of Technology
Viviana Gradinaru: California Institute of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Adeno-associated viruses (AAVs) are foundational gene delivery tools for basic science and clinical therapeutics. However, lack of mechanistic insight, especially for engineered vectors created by directed evolution, can hamper their application. Here, we adapt an unbiased human cell microarray platform to determine the extracellular and cell surface interactomes of natural and engineered AAVs. We identify a naturally-evolved and serotype-specific interaction between the AAV9 capsid and human interleukin 3 (IL3), with possible roles in host immune modulation, as well as lab-evolved low-density lipoprotein receptor-related protein 6 (LRP6) interactions specific to engineered capsids with enhanced blood-brain barrier crossing in non-human primates after intravenous administration. The unbiased cell microarray screening approach also allows us to identify off-target tissue binding interactions of engineered brain-enriched AAV capsids that may inform vectors’ peripheral organ tropism and side effects. Our cryo-electron tomography and AlphaFold modeling of capsid-interactor complexes reveal LRP6 and IL3 binding sites. These results allow confident application of engineered AAVs in diverse organisms and unlock future target-informed engineering of improved viral and non-viral vectors for non-invasive therapeutic delivery to the brain.

Date: 2024
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DOI: 10.1038/s41467-024-52149-0

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