Non-canonical amino acid incorporation into AAV5 capsid enhances lung transduction in mice
Student AuthorsXuntao Zhou
UMass Chan AffiliationsHorae Gene Therapy Center
Microbiology and Physiological Systems
Morningside Graduate School of Biomedical Sciences
RNA Therapeutics Institute
Document TypeJournal Article
non-canonical amino acids
MetadataShow full item record
AbstractGene therapy using recombinant adeno-associated virus (rAAV) relies on safe, efficient, and precise in vivo gene delivery that is largely dependent on the AAV capsid. The proteinaceous capsid is highly amenable to engineering using a variety of approaches, and most resulting capsids carry substitutions or insertions comprised of natural amino acids. Here, we incorporated a non-canonical amino acid (ncAA), Nε-2-azideoethyloxycarbonyl-L-lysine (also known as NAEK), into the AAV5 capsid using genetic code expansion, and serendipitously found that several NAEK-AAV5 vectors transduced various cell lines more efficiently than the parental rAAV5. Furthermore, one NAEK-AAV5 vector showed lung-specific transduction enhancement following systemic or intranasal delivery in mice. Structural modeling suggests that the long side chain of NAEK may impact on the 3-fold protrusion on the capsid surface that plays a key role in tropism, thereby modulating vector transduction. Recent advances in genetic code expansion have generated synthetic proteins carrying an increasing number of ncAAs that possess diverse biological properties. Our study suggests that ncAA incorporation into the AAV capsid may confer novel vector properties, opening a new and complementary avenue to gene therapy vector discovery.
SourceChang H, Du A, Jiang J, Ren L, Liu N, Zhou X, Liang J, Gao G, Wang D. Non-canonical amino acid incorporation into AAV5 capsid enhances lung transduction in mice. Mol Ther Methods Clin Dev. 2023 Oct 7;31:101129. doi: 10.1016/j.omtm.2023.101129. PMID: 37886602; PMCID: PMC10597788.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/52823
RightsCopyright 2023 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/); Attribution-NonCommercial-NoDerivatives 4.0 International
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Except where otherwise noted, this item's license is described as Copyright 2023 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/)