한빛사논문
Timothy F. Shay 1,3,*, Seongmin Jang 1,3, Tyler J. Brittain 1,3, Xinhong Chen 1,3, Beth Walker 2, Claire Tebbutt 2, Yujie Fan 1, Damien A. Wolfe 1, Cynthia M. Arokiaraj 1, Erin E. Sullivan 1, Xiaozhe Ding 1, Ting-Yu Wang 1, Yaping Lei 1, Miguel R. Chuapoco 1, Tsui-Fen Chou 1 & Viviana Gradinaru 1,*
1Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
2Charles River Laboratories, High Peak Business Park, Buxton Road, Chinley SK23 6FJ, UK.
3These authors contributed equally: Timothy F. Shay, Seongmin Jang, Tyler J. Brittain, Xinhong Chen.
*Corresponding authors: correspondence to Timothy F. Shay or Viviana Gradinaru
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.
논문정보
관련 링크
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기