Multimodal imaging of capsid and cargo reveals differential brain targeting and liver detargeting of systemically-administered AAVs

The development of gene delivery vehicles with high organ specificity when administered systemically is a critical goal for gene therapy. We combine optical and positron emission tomography (PET) imaging of 1) reporter genes and 2) capsid tags to assess the temporal and spatial distribution and tran...

Full description

Saved in:
Bibliographic Details
Published in:Biomaterials 2022-09, Vol.288, p.121701-121701, Article 121701
Main Authors: Seo, Jai Woong, Ajenjo, Javier, Wu, Bo, Robinson, Elise, Raie, Marina Nura, Wang, James, Tumbale, Spencer K., Buccino, Pablo, Anders, David Alexander, Shen, Bin, Habte, Frezghi G., Beinat, Corinne, James, Michelle L., Reyes, Samantha Taylor, Ravindra Kumar, Sripriya, Miles, Timothy F., Lee, Jason T., Gradinaru, Viviana, Ferrara, Katherine W.
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The development of gene delivery vehicles with high organ specificity when administered systemically is a critical goal for gene therapy. We combine optical and positron emission tomography (PET) imaging of 1) reporter genes and 2) capsid tags to assess the temporal and spatial distribution and transduction of adeno-associated viruses (AAVs). AAV9 and two engineered AAV vectors (PHP.eB and CAP-B10) that are noteworthy for maximizing blood-brain barrier transport were compared. CAP-B10 shares a modification in the 588 loop with PHP.eB, but also has a modification in the 455 loop, added with the goal of reducing off-target transduction. PET and optical imaging revealed that the additional modifications retained brain receptor affinity. In the liver, the accumulation of AAV9 and the engineered AAV capsids was similar (∼15% of the injected dose per cc and not significantly different between capsids at 21 h). However, the engineered capsids were primarily internalized by Kupffer cells rather than hepatocytes, and liver transduction was greatly reduced. PET reporter gene imaging after engineered AAV systemic injection provided a non-invasive method to monitor AAV-mediated protein expression over time. Through comparison with capsid tagging, differences between brain localization and transduction were revealed. In summary, AAV capsids bearing imaging tags and reporter gene payloads create a unique and powerful platform to assay the pharmacokinetics, cellular specificity and protein expression kinetics of AAV vectors in vivo, a key enabler for the field of gene therapy.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2022.121701