Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8
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.
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BibTeX
@article{cabanescreus2026novel,
title = {{Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8}},
author = {Marti Cabanes-Creus and Renina Gale Navarro and Erhua Zhu and Grober Baltazar and Sophia Liao and Matthieu Drouyer and Anais Amaya and Suzanne Scott and Loan Hanh Nguyen and Adrian Westhaus and Matthias Hebben and Laurence Wilson and Adrian Thrasher and Ian Alexander and Leszek Lisowski and Sophia H.Y. Liao and Laurence O.W. Wilson},
journal = {Molecular Therapy - Methods and Clinical Development},
year = {2026},
month = sep,
doi = {10.1016/j.omtm.2021.11.011},
url = {https://hal.science/hal-05771983v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8
AU - Marti Cabanes-Creus
AU - Renina Gale Navarro
AU - Erhua Zhu
AU - Grober Baltazar
AU - Sophia Liao
AU - Matthieu Drouyer
AU - Anais Amaya
AU - Suzanne Scott
AU - Loan Hanh Nguyen
AU - Adrian Westhaus
AU - Matthias Hebben
AU - Laurence Wilson
AU - Adrian Thrasher
AU - Ian Alexander
AU - Leszek Lisowski
AU - Sophia H.Y. Liao
AU - Laurence O.W. Wilson
PY - 2026
DA - 2026/09/30
JO - Molecular Therapy - Methods and Clinical Development
DO - 10.1016/j.omtm.2021.11.011
UR - https://hal.science/hal-05771983v1
AB - 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.
SN - 2329-0501
ER -