Harnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation
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, w...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46194-y |
| _version_ | 1797259236959322112 |
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| author | 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 Leszek Lisowski |
| author_facet | 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 Leszek Lisowski |
| author_sort | Marti Cabanes-Creus |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T23:06:14Z |
| format | Article |
| id | doaj.art-adfc0f2727d740ed8d6f7bc8f0977ed6 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T23:06:14Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-adfc0f2727d740ed8d6f7bc8f0977ed62024-03-17T12:30:13ZengNature PortfolioNature Communications2041-17232024-03-0115111510.1038/s41467-024-46194-yHarnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluationMarti Cabanes-Creus0Sophia H. Y. Liao1Renina Gale Navarro2Maddison Knight3Deborah Nazareth4Ngee-Soon Lau5Mark Ly6Erhua Zhu7Ramon Roca-Pinilla8Ricardo Bugallo Delgado9Ana F. Vicente10Grober Baltazar11Adrian Westhaus12Jessica Merjane13Michael Crawford14Geoffrey W. McCaughan15Carmen Unzu16Gloria González-Aseguinolaza17Ian E. Alexander18Carlo Pulitano19Leszek Lisowski20Translational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyTranslational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyTranslational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyTranslational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyTranslational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyAustralian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Faculty of Medicine and Health, The University of SydneyAustralian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Faculty of Medicine and Health, The University of SydneyGene Therapy Research Unit, Children’s Medical Research Institute and The Children’s Hospital at Westmead, Faculty of Medicine and Health, The University of Sydney, and Sydney Children’s Hospitals NetworkTranslational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyGene Therapy and Regulation of Gene Expression Department, IdiSNA, Instituto de Investigación Sanitaria de Navarra, Universidad de Navarra, CIMAGene Therapy and Regulation of Gene Expression Department, IdiSNA, Instituto de Investigación Sanitaria de Navarra, Universidad de Navarra, CIMATranslational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyTranslational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyTranslational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyAustralian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Faculty of Medicine and Health, The University of SydneyAustralian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Faculty of Medicine and Health, The University of SydneyGene Therapy and Regulation of Gene Expression Department, IdiSNA, Instituto de Investigación Sanitaria de Navarra, Universidad de Navarra, CIMAGene Therapy and Regulation of Gene Expression Department, IdiSNA, Instituto de Investigación Sanitaria de Navarra, Universidad de Navarra, CIMAGene Therapy Research Unit, Children’s Medical Research Institute and The Children’s Hospital at Westmead, Faculty of Medicine and Health, The University of Sydney, and Sydney Children’s Hospitals NetworkAustralian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Faculty of Medicine and Health, The University of SydneyTranslational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of SydneyAbstract 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.https://doi.org/10.1038/s41467-024-46194-y |
| spellingShingle | 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 Leszek Lisowski Harnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation Nature Communications |
| title | Harnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation |
| title_full | Harnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation |
| title_fullStr | Harnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation |
| title_full_unstemmed | Harnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation |
| title_short | Harnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation |
| title_sort | harnessing whole human liver ex situ normothermic perfusion for preclinical aav vector evaluation |
| url | https://doi.org/10.1038/s41467-024-46194-y |
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