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

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. Flytzanis, Michael Chavez, Kratika Singhal, Ryan Leib, Michelle L. James, David J. Segal, R. Holland Cheng, Eduardo A. Silva, Viviana Gradinaru and Katherine W. Ferrara ()
Additional contact information
Jai Woong Seo: Stanford University
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

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15818-4

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