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Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8

Cabanes-Creus, M; Navarro, RG; Zhu, E; Baltazar, G; Liao, SHY; Drouyer, M; Amaya, AK; ... Lisowski, L; + view all (2022) Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8. Molecular Therapy - Methods and Clinical Development , 24 pp. 88-101. 10.1016/j.omtm.2021.11.011. Green open access

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Abstract

Recent clinical successes have intensified interest in using adeno-associated virus (AAV) vectors for therapeutic gene delivery. The liver is a key clinical target, given its critical physiological functions and involvement in a wide range of genetic diseases. Here, we report the bioengineering of a set of next-generation AAV vectors, named AAV-SYDs (where “SYD” stands for Sydney, Australia), with increased human hepato-tropism in a liver xenograft mouse model repopulated with primary human hepatocytes. We followed a two-step process that staggered directed evolution and domain-swapping approaches. Using DNA-family shuffling, we first mapped key AAV capsid regions responsible for efficient human hepatocyte transduction in vivo. Focusing on these regions, we next applied domain-swapping strategies to identify and study key capsid residues that enhance primary human hepatocyte uptake and transgene expression. Our findings underscore the potential of AAV-SYDs as liver gene therapy vectors and provide insights into the mechanism responsible for their enhanced transduction profile.

Type: Article
Title: Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.omtm.2021.11.011
Publisher version: https://doi.org/10.1016/j.omtm.2021.11.011
Language: English
Additional information: © 2021 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: AAV, adeno-associated vectors, bioengineered vectors, bioengineering, gene therapy, liver-tropic, preclinical liver model, recombinant vectors, xenograft model
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10146501
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