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Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation

Author

Listed:
  • Jai Woong Seo

    (Stanford University
    University of California)

  • Elizabeth S. Ingham

    (University of California)

  • Lisa Mahakian

    (University of California)

  • Spencer Tumbale

    (Stanford University)

  • Bo Wu

    (Stanford University)

  • Sadaf Aghevlian

    (Stanford University)

  • Shahin Shams

    (University of California)

  • Mo Baikoghli

    (University of California)

  • Poorva Jain

    (Stanford University)

  • Xiaozhe Ding

    (California Institute of Technology)

  • Nick Goeden

    (California Institute of Technology)

  • Tatyana Dobreva

    (California Institute of Technology)

  • Nicholas C. Flytzanis

    (California Institute of Technology)

  • Michael Chavez

    (Stanford University)

  • Kratika Singhal

    (Stanford University Mass Spectrometry)

  • Ryan Leib

    (Stanford University Mass Spectrometry)

  • Michelle L. James

    (Stanford University)

  • David J. Segal

    (University of California)

  • R. Holland Cheng

    (University of California)

  • Eduardo A. Silva

    (University of California)

  • Viviana Gradinaru

    (California Institute of Technology)

  • Katherine W. Ferrara

    (Stanford University)

Abstract

Adeno-associated viruses (AAVs) are typically single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids. Recently, tissue-specific AAV capsids (e.g. PHP.eB) have been shown to enhance brain delivery in rodents via the LY6A receptor on brain endothelial cells. Here, we create a non-invasive positron emission tomography (PET) methodology to track viruses. To provide the sensitivity required to track AAVs injected at picomolar levels, a unique multichelator construct labeled with a positron emitter (Cu-64, t1/2 = 12.7 h) is coupled to the viral capsid. We find that brain accumulation of the PHP.eB capsid 1) exceeds that reported in any previous PET study of brain uptake of targeted therapies and 2) is correlated with optical reporter gene transduction of the brain. The PHP.eB capsid brain endothelial receptor affinity is nearly 20-fold greater than that of AAV9. The results suggest that novel PET imaging techniques can be applied to inform and optimize capsid design.

Suggested Citation

  • Jai Woong Seo & Elizabeth S. Ingham & Lisa Mahakian & Spencer Tumbale & Bo Wu & Sadaf Aghevlian & Shahin Shams & Mo Baikoghli & Poorva Jain & Xiaozhe Ding & Nick Goeden & Tatyana Dobreva & Nicholas C., 2020. "Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15818-4
    DOI: 10.1038/s41467-020-15818-4
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    Cited by:

    1. 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 , 2024. "Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Shuixiu Li & Yajing Zhao & Yishan Zhang & Yanli Zhang & Zhanpeng Zhang & Chuanyan Tang & Luobei Weng & Xiaohong Chen & Gehua Zhang & Hong Zhang, 2021. "The δ subunit of F1Fo-ATP synthase is required for pathogenicity of Candida albicans," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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