Muscle-Directed Delivery of an AAV1 Vector Leads to Capsid-Specific T Cell Exhaustion in Nonhuman Primates and Humans
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Authors
Gernoux, GwladysGruntman, Alisha M.
Blackwood, Meghan
Zieger, Marina
Flotte, Terence R.
Mueller, Christian
Document Type
Journal ArticlePublication Date
2020-03-04Keywords
AAVTregs
adeno-associated virus
exhausted T cells
exhaustion
gene therapy
gene transfer
immunity
regulatory T cells
tolerance
Analytical, Diagnostic and Therapeutic Techniques and Equipment
Genetics and Genomics
Molecular Biology
Viruses
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With the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals for Zolgensma, Luxturna, and Glybera, recombinant adeno-associated viruses (rAAVs) are considered efficient tools for gene transfer. However, studies in animals and humans demonstrate that intramuscular (IM) AAV delivery can trigger immune responses to AAV capsids and/or transgenes. IM delivery of rAAV1 in humans has also been described to induce tolerance to rAAV characterized by the presence of capsid-specific regulatory T cells (Tregs) in periphery. To understand mechanisms responsible for tolerance and parameters involved, we tested 3 muscle-directed administration routes in rhesus monkeys: IM delivery, venous limb perfusion, and the intra-arterial push and dwell method. These 3 methods were well tolerated and led to transgene expression. Interestingly, gene transfer in muscle led to Tregs and exhausted T cell infiltrates in situ at both day 21 and day 60 post-injection. In human samples, an in-depth analysis of the functionality of these cells demonstrates that capsid-specific exhausted T cells are detected after at least 5 years post-vector delivery and that the exhaustion can be reversed by blocking the checkpoint pathway. Overall, our study shows that persisting transgene expression after gene transfer in muscle is mediated by Tregs and exhausted T cells.Source
Gernoux G, Gruntman AM, Blackwood M, Zieger M, Flotte TR, Mueller C. Muscle-Directed Delivery of an AAV1 Vector Leads to Capsid-Specific T Cell Exhaustion in Nonhuman Primates and Humans. Mol Ther. 2020 Jan 13:S1525-0016(20)30010-1. doi: 10.1016/j.ymthe.2020.01.004. Epub ahead of print. PMID: 31982038. Link to article on publisher's site
DOI
10.1016/j.ymthe.2020.01.004Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41350PubMed ID
31982038Related Resources
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Copyright 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.ymthe.2020.01.004
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Except where otherwise noted, this item's license is described as Copyright 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).