iPSC-hepatocyte organoids as a novel platform to predict AAV gene therapy efficacy
Adeno-associated virus (AAV) vectors are widely used in gene therapy, particularly for liver-targeted treatments. However, predicting human-specific outcomes, such as transduction efficiency and hepatotoxicity, remains challenging. Reliable in vitro models are urgently needed to bridge the gap betwe...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050125000622 |
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| author | Estelle Berreur Giacomo Lazzaroni Cyrill Roth Marco Zihlmann Martina Stirn Ramona Matheis Rebecca Xicluna Ekaterina Breous-Nystrom Adrian B. Roth |
| author_facet | Estelle Berreur Giacomo Lazzaroni Cyrill Roth Marco Zihlmann Martina Stirn Ramona Matheis Rebecca Xicluna Ekaterina Breous-Nystrom Adrian B. Roth |
| author_sort | Estelle Berreur |
| collection | DOAJ |
| description | Adeno-associated virus (AAV) vectors are widely used in gene therapy, particularly for liver-targeted treatments. However, predicting human-specific outcomes, such as transduction efficiency and hepatotoxicity, remains challenging. Reliable in vitro models are urgently needed to bridge the gap between preclinical studies and clinical applications. This study presents the first comparative evaluation of AAV transduction across multiple induced pluripotent stem cell (iPSC)-derived hepatocyte organoid donors, offering a novel platform for assessing vector performance in human liver models. The transduction efficiency and hepatotoxicity of eight AAV serotypes (AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV8, and AAV9) were tested in iPSC-derived liver organoids and hepatic cell lines (HepG2 and HepaRG). AAV6 and AAV8 exhibited the highest transduction efficiency in organoids, while AAV4 and AAV5 were the least effective. Transduction variability was observed across different donors and cell lines. Notably, no significant hepatotoxicity, measured by AST (aspartate aminotransferase) release and viability measurements, was observed, indicating that AAVs do not induce immediate liver damage in vitro. This study introduces iPSC-derived hepatocyte organoids as a novel and effective tool for predicting AAV transduction efficiency and safety, with potential to enhance the translation of gene therapies to clinical applications. |
| format | Article |
| id | doaj-art-e2e91e27b4024ef88e8482e04dbaa44e |
| institution | DOAJ |
| issn | 2329-0501 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-e2e91e27b4024ef88e8482e04dbaa44e2025-08-20T03:14:35ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012025-06-0133210146710.1016/j.omtm.2025.101467iPSC-hepatocyte organoids as a novel platform to predict AAV gene therapy efficacyEstelle Berreur0Giacomo Lazzaroni1Cyrill Roth2Marco Zihlmann3Martina Stirn4Ramona Matheis5Rebecca Xicluna6Ekaterina Breous-Nystrom7Adrian B. Roth8Roche Pharma Research and Early Development, Roche Innovation Center Basel, CH-4070 Basel, Switzerland; Corresponding author: Estelle Berreur, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.Roche Pharma Research and Early Development, Roche Innovation Center Basel, CH-4070 Basel, SwitzerlandInstitute of Human Biology, Roche Innovation Center Basel, CH-4070 Basel, SwitzerlandRoche Pharma Research and Early Development, Roche Innovation Center Basel, CH-4070 Basel, SwitzerlandRoche Pharma Research and Early Development, Roche Innovation Center Basel, CH-4070 Basel, SwitzerlandRoche Pharma Research and Early Development, Roche Innovation Center Basel, CH-4070 Basel, SwitzerlandRoche Pharma Research and Early Development, Roche Innovation Center Basel, CH-4070 Basel, SwitzerlandRoche Pharma Research and Early Development, Roche Innovation Center Basel, CH-4070 Basel, SwitzerlandPrecision Safety, Pharma Product Development, Roche Innovation Center Basel, CH-4070 Basel, SwitzerlandAdeno-associated virus (AAV) vectors are widely used in gene therapy, particularly for liver-targeted treatments. However, predicting human-specific outcomes, such as transduction efficiency and hepatotoxicity, remains challenging. Reliable in vitro models are urgently needed to bridge the gap between preclinical studies and clinical applications. This study presents the first comparative evaluation of AAV transduction across multiple induced pluripotent stem cell (iPSC)-derived hepatocyte organoid donors, offering a novel platform for assessing vector performance in human liver models. The transduction efficiency and hepatotoxicity of eight AAV serotypes (AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV8, and AAV9) were tested in iPSC-derived liver organoids and hepatic cell lines (HepG2 and HepaRG). AAV6 and AAV8 exhibited the highest transduction efficiency in organoids, while AAV4 and AAV5 were the least effective. Transduction variability was observed across different donors and cell lines. Notably, no significant hepatotoxicity, measured by AST (aspartate aminotransferase) release and viability measurements, was observed, indicating that AAVs do not induce immediate liver damage in vitro. This study introduces iPSC-derived hepatocyte organoids as a novel and effective tool for predicting AAV transduction efficiency and safety, with potential to enhance the translation of gene therapies to clinical applications.http://www.sciencedirect.com/science/article/pii/S2329050125000622AAV vectorsliveriPSCorganoidsAAV transductionAAV serotype |
| spellingShingle | Estelle Berreur Giacomo Lazzaroni Cyrill Roth Marco Zihlmann Martina Stirn Ramona Matheis Rebecca Xicluna Ekaterina Breous-Nystrom Adrian B. Roth iPSC-hepatocyte organoids as a novel platform to predict AAV gene therapy efficacy Molecular Therapy: Methods & Clinical Development AAV vectors liver iPSC organoids AAV transduction AAV serotype |
| title | iPSC-hepatocyte organoids as a novel platform to predict AAV gene therapy efficacy |
| title_full | iPSC-hepatocyte organoids as a novel platform to predict AAV gene therapy efficacy |
| title_fullStr | iPSC-hepatocyte organoids as a novel platform to predict AAV gene therapy efficacy |
| title_full_unstemmed | iPSC-hepatocyte organoids as a novel platform to predict AAV gene therapy efficacy |
| title_short | iPSC-hepatocyte organoids as a novel platform to predict AAV gene therapy efficacy |
| title_sort | ipsc hepatocyte organoids as a novel platform to predict aav gene therapy efficacy |
| topic | AAV vectors liver iPSC organoids AAV transduction AAV serotype |
| url | http://www.sciencedirect.com/science/article/pii/S2329050125000622 |
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