In this section, you can access to the latest technical information related to the FUTURE project topic.

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) 1) reporter genes and 2) capsid tagging 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 of 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 noninvasive 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.

» Author: Jai Woong Seo, Javier Ajenjo, Bo Wu, Elise Robinson, Marina Nura Raie, James Wang, Spencer K. Tumbale, Pablo Buccino, David Alexander Anders, Bin Shen, Frezghi G. Habte, Corinne Beinat, Michelle L. James, Samantha Taylor Reyes, Ravindra Kumar Sripriya, T

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