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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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
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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| Summary: | 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. |
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| ISSN: | 2041-1723 |