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Harnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation

Author

Listed:
  • Marti Cabanes-Creus

    (The University of Sydney)

  • Sophia H. Y. Liao

    (The University of Sydney)

  • Renina Gale Navarro

    (The University of Sydney)

  • Maddison Knight

    (The University of Sydney)

  • Deborah Nazareth

    (The University of Sydney)

  • Ngee-Soon Lau

    (The University of Sydney
    The University of Sydney)

  • Mark Ly

    (The University of Sydney
    The University of Sydney)

  • Erhua Zhu

    (The University of Sydney, and Sydney Children’s Hospitals Network)

  • Ramon Roca-Pinilla

    (The University of Sydney)

  • Ricardo Bugallo Delgado

    (IdiSNA, Instituto de Investigación Sanitaria de Navarra, Universidad de Navarra, CIMA)

  • Ana F. Vicente

    (IdiSNA, Instituto de Investigación Sanitaria de Navarra, Universidad de Navarra, CIMA)

  • Grober Baltazar

    (The University of Sydney)

  • Adrian Westhaus

    (The University of Sydney)

  • Jessica Merjane

    (The University of Sydney)

  • Michael Crawford

    (The University of Sydney
    The University of Sydney)

  • Geoffrey W. McCaughan

    (The University of Sydney
    A.W Morrow Gastroenterology and Liver Centre)

  • Carmen Unzu

    (IdiSNA, Instituto de Investigación Sanitaria de Navarra, Universidad de Navarra, CIMA)

  • Gloria González-Aseguinolaza

    (IdiSNA, Instituto de Investigación Sanitaria de Navarra, Universidad de Navarra, CIMA)

  • Ian E. Alexander

    (The University of Sydney, and Sydney Children’s Hospitals Network
    The University of Sydney, Sydney Medical School, Faculty of Medicine and Health
    Children’s Medical Research Institute and Sydney Children’s Hospitals Network)

  • Carlo Pulitano

    (The University of Sydney
    The University of Sydney)

  • Leszek Lisowski

    (The University of Sydney
    Children’s Medical Research Institute and Sydney Children’s Hospitals Network
    Laboratory of Molecular Oncology and Innovative Therapies)

Abstract

Developing clinically predictive model systems for evaluating gene transfer and gene editing technologies has become increasingly important in the era of personalized medicine. Liver-directed gene therapies present a unique challenge due to the complexity of the human liver. In this work, we describe the application of whole human liver explants in an ex situ normothermic perfusion system to evaluate a set of fourteen natural and bioengineered adeno-associated viral (AAV) vectors directly in human liver, in the presence and absence of neutralizing human sera. Under non-neutralizing conditions, the recently developed AAV variants, AAV-SYD12 and AAV-LK03, emerged as the most functional variants in terms of cellular uptake and transgene expression. However, when assessed in the presence of human plasma containing anti-AAV neutralizing antibodies (NAbs), vectors of human origin, specifically those derived from AAV2/AAV3b, were extensively neutralized, whereas AAV8- derived variants performed efficiently. This study demonstrates the potential of using normothermic liver perfusion as a model for early-stage testing of liver-focused gene therapies. The results offer preliminary insights that could help inform the development of more effective translational strategies.

Suggested Citation

  • Marti Cabanes-Creus & Sophia H. Y. Liao & Renina Gale Navarro & Maddison Knight & Deborah Nazareth & Ngee-Soon Lau & Mark Ly & Erhua Zhu & Ramon Roca-Pinilla & Ricardo Bugallo Delgado & Ana F. Vicente, 2024. "Harnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46194-y
    DOI: 10.1038/s41467-024-46194-y
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    References listed on IDEAS

    as
    1. Hynek Mergental & Richard W. Laing & Amanda J. Kirkham & M. Thamara P. R. Perera & Yuri L. Boteon & Joseph Attard & Darren Barton & Stuart Curbishley & Manpreet Wilkhu & Desley A. H. Neil & Stefan G. , 2020. "Transplantation of discarded livers following viability testing with normothermic machine perfusion," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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