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

• Published in: Nature communications Vol. 11; no. 1; pp. 2102 - 13
• Main Authors: Seo, Jai Woong, Ingham, Elizabeth S., Mahakian, Lisa, Tumbale, Spencer, Wu, Bo, Aghevlian, Sadaf, Shams, Shahin, Baikoghli, Mo, Jain, Poorva, Ding, Xiaozhe, Goeden, Nick, Dobreva, Tatyana, Flytzanis, Nicholas C., Chavez, Michael, Singhal, Kratika, Leib, Ryan, James, Michelle L., Segal, David J., Cheng, R. Holland, Silva, Eduardo A., Gradinaru, Viviana, Ferrara, Katherine W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-04-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 42/44; 59; 59/78; 631/1647/245/2092; 631/1647/245/2160; 631/1647/245/2227; Accumulation; Animals; Bioaccumulation; Brain; Brain - diagnostic imaging; Brain mapping; Capsid; Capsids; Chelating Agents - pharmacokinetics; Copper Radioisotopes - pharmacokinetics; Deoxyribonucleic acid; Dependovirus - isolation & purification; Design optimization; DNA; Emissions; Emitters; Endothelial cells; Female; Gene mapping; Genetic Vectors; HEK293 Cells; Humanities and Social Sciences; Humans; Imaging techniques; Medical imaging; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Neuroimaging; Positron emission; Positron emission tomography; Receptors; Reporter gene; Science; Science (multidisciplinary); Tomography; Transduction, Genetic; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15818-4

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, t
1/2
 = 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.
Adeno-associated viruses (AAVs) can be targeted in a tissue-specific manner, but their tissue accumulation cannot be assessed in a non-invasive manner. Here the authors conjugate a multivalent chelator labelled with Cu-64 to the surface of AAVs and image the brain accumulation of the PHB.eB capsid by PET.