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. SilvaViviana Gradinaru, Katherine W Ferrara

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number2102
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Seo, J. W., Ingham, E. S., Mahakian, L., Tumbale, S., Wu, B., Aghevlian, S., Shams, S., Baikoghli, M., Jain, P., Ding, X., Goeden, N., Dobreva, T., Flytzanis, N. C., Chavez, M., Singhal, K., Leib, R., James, M. L., Segal, D. J., Cheng, R. H., ... Ferrara, K. W. (2020). Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation. Nature communications, 11(1), [2102]. https://doi.org/10.1038/s41467-020-15818-4