Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes

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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Publication Details

Journal
Nature Communications
Published
2025-05-23
DOI
https://doi.org/10.1038/s41467-025-60073-0
Citations
10
Primary Topic
Virus-based gene therapy research
Type
article
Field-Weighted Citation Impact
18.17

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article

Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes

Chiara Brombin, Francesco Starinieri, Mauro Biffi, Francesca Sanvito et al.
10 citations
Nature Communications
Virus-based gene therapy research
18.17
article

Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes

Chiara Brombin, Francesco Starinieri, Mauro Biffi, Francesca Sanvito, Federica Cugnata, Cesare Canepari, Fabio Russo, Rossana Norata, Alessio Cantore, Markus Grompe, Eugenio Montini, Michela Milani, Monica Volpin, Anna Fabiano, Martina Rocchi, Chiara Simoni
article en
10 citations

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.

Nature CommunicationsVol. 16(1)
Vita-Salute San Raffaele University (IT), Oregon Health & Science University (US), The San Raffaele Telethon Institute for Gene Therapy (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
Sanofi, Fondazione Telethon
Zero hunger
Openalex Percentile: Top 1%
Virus-based gene therapy research
18.17
DOIOpen Access PDFOpenAlex
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