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.
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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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