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

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 and Alessio Cantore ()
Additional contact information
Cesare Canepari: IRCCS San Raffaele Scientific Institute
Michela Milani: IRCCS San Raffaele Scientific Institute
Chiara Simoni: IRCCS San Raffaele Scientific Institute
Francesco Starinieri: IRCCS San Raffaele Scientific Institute
Monica Volpin: IRCCS San Raffaele Scientific Institute
Anna Fabiano: IRCCS San Raffaele Scientific Institute
Mauro Biffi: IRCCS San Raffaele Scientific Institute
Fabio Russo: IRCCS San Raffaele Scientific Institute
Rossana Norata: IRCCS San Raffaele Scientific Institute
Martina Rocchi: IRCCS San Raffaele Scientific Institute
Chiara Brombin: Vita-Salute San Raffaele University
Federica Cugnata: Vita-Salute San Raffaele University
Eugenio Montini: IRCCS San Raffaele Scientific Institute
Francesca Sanvito: IRCCS San Raffaele Scientific Institute
Markus Grompe: Oregon Health and Science University
Alessio Cantore: IRCCS San Raffaele Scientific Institute

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60073-0

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