Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes
Abstract In vivo gene therapy to the liver using lentiviral vectors (LV) may represent a one-and-done therapeutic approach for monogenic diseases. Increasing LV gene therapy potency is crucial for reducing the effective doses, thus alleviating dose-dependent toxicities and facilitating manufacturing...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60073-0 |
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| author | Cesare Canepari Michela Milani Chiara Simoni Francesco Starinieri Monica Volpin Anna Fabiano Mauro Biffi Fabio Russo Rossana Norata Martina Rocchi Chiara Brombin Federica Cugnata Eugenio Montini Francesca Sanvito Markus Grompe Alessio Cantore |
| author_facet | Cesare Canepari Michela Milani Chiara Simoni Francesco Starinieri Monica Volpin Anna Fabiano Mauro Biffi Fabio Russo Rossana Norata Martina Rocchi Chiara Brombin Federica Cugnata Eugenio Montini Francesca Sanvito Markus Grompe Alessio Cantore |
| author_sort | Cesare Canepari |
| collection | DOAJ |
| description | Abstract In vivo gene therapy to the liver using lentiviral vectors (LV) may represent a one-and-done therapeutic approach for monogenic diseases. Increasing LV gene therapy potency is crucial for reducing the effective doses, thus alleviating dose-dependent toxicities and facilitating manufacturing. LV-mediated liver transduction may be enhanced by positively selecting LV-transduced hepatocytes after treatment (a posteriori) or by augmenting the initial fraction of LV-targeted hepatocytes (a priori). We show here that the a posteriori enhancement increased transgene output without expansion of hepatocytes bearing LV genomic integrations near cancer genes, in mouse models of hemophilia, an inherited coagulation disorder. Furthermore, we enhanced hepatocyte transduction a priori in mice by transiently inhibiting antiviral pathways and/or through a fasting regimen. The most promising transduction-enhancer combination synergized with phagocytosis-shielded LV, resulting in a remarkable 40-fold increase in transgene output. Overall, our work highlights the potential of minimally invasive, cost-effective treatments capable of improving the potency of in vivo LV gene therapy to hepatocytes, in order to expand its applicability and ease clinical translation. |
| format | Article |
| id | doaj-art-946de42e6b274abcb189442f7cc2f5a5 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-946de42e6b274abcb189442f7cc2f5a52025-08-20T03:08:43ZengNature PortfolioNature Communications2041-17232025-05-0116111710.1038/s41467-025-60073-0Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytesCesare Canepari0Michela Milani1Chiara Simoni2Francesco Starinieri3Monica Volpin4Anna Fabiano5Mauro Biffi6Fabio Russo7Rossana Norata8Martina Rocchi9Chiara Brombin10Federica Cugnata11Eugenio Montini12Francesca Sanvito13Markus Grompe14Alessio Cantore15San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteSan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteIRCCS San Raffaele Scientific InstituteCenter for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele UniversityCenter for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele UniversitySan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteIRCCS San Raffaele Scientific InstituteOregon Health and Science UniversitySan Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteAbstract In vivo gene therapy to the liver using lentiviral vectors (LV) may represent a one-and-done therapeutic approach for monogenic diseases. Increasing LV gene therapy potency is crucial for reducing the effective doses, thus alleviating dose-dependent toxicities and facilitating manufacturing. LV-mediated liver transduction may be enhanced by positively selecting LV-transduced hepatocytes after treatment (a posteriori) or by augmenting the initial fraction of LV-targeted hepatocytes (a priori). We show here that the a posteriori enhancement increased transgene output without expansion of hepatocytes bearing LV genomic integrations near cancer genes, in mouse models of hemophilia, an inherited coagulation disorder. Furthermore, we enhanced hepatocyte transduction a priori in mice by transiently inhibiting antiviral pathways and/or through a fasting regimen. The most promising transduction-enhancer combination synergized with phagocytosis-shielded LV, resulting in a remarkable 40-fold increase in transgene output. Overall, our work highlights the potential of minimally invasive, cost-effective treatments capable of improving the potency of in vivo LV gene therapy to hepatocytes, in order to expand its applicability and ease clinical translation.https://doi.org/10.1038/s41467-025-60073-0 |
| spellingShingle | Cesare Canepari Michela Milani Chiara Simoni Francesco Starinieri Monica Volpin Anna Fabiano Mauro Biffi Fabio Russo Rossana Norata Martina Rocchi Chiara Brombin Federica Cugnata Eugenio Montini Francesca Sanvito Markus Grompe Alessio Cantore Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes Nature Communications |
| title | Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes |
| title_full | Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes |
| title_fullStr | Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes |
| title_full_unstemmed | Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes |
| title_short | Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes |
| title_sort | enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes |
| url | https://doi.org/10.1038/s41467-025-60073-0 |
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