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

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, Grober Baltazar, Adrian Westhaus, Jessica Merjane, Michael Crawford, Geoffrey W. McCaughan, Carmen Unzu, Gloria González-Aseguinolaza, Ian E. Alexander, Carlo Pulitano and Leszek Lisowski ()
Additional contact information
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
Mark Ly: 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
Geoffrey W. McCaughan: The University of Sydney
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
Carlo Pulitano: The University of Sydney
Leszek Lisowski: The University of Sydney

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-024-46194-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46194-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-46194-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().