In vivo haemopoietic stem cell gene therapy enabled by postnatal trafficking

Michela Milani (), Anna Fabiano, Marta Perez-Rodriguez, Raisa Jofra Hernandez, Alessandra Zecchillo, Erika Zonari, Sofia Ottonello, Luca Basso-Ricci, Cesare Canepari, Monica Volpin, Valeria Iannello, Valentina Capo, Pamela Quaranta, Luca Seffin, Fabio Russo, Mauro Biffi, Leonardo Ormoli, Chiara Brombin, Filippo Carlucci, Antonella Forlino, Marta Filibian, Eugenio Montini, Serena Scala, Anna Villa, Juan Antonio Bueren, Paula Rio, Alessandro Aiuti, Alessio Cantore and Luigi Naldini ()
Additional contact information
Michela Milani: IRCCS San Raffaele Scientific Institute
Anna Fabiano: IRCCS San Raffaele Scientific Institute
Marta Perez-Rodriguez: Center for Research on Energy, Environment and Technology (CIEMAT)
Raisa Jofra Hernandez: IRCCS San Raffaele Scientific Institute
Alessandra Zecchillo: IRCCS San Raffaele Scientific Institute
Erika Zonari: IRCCS San Raffaele Scientific Institute
Sofia Ottonello: IRCCS San Raffaele Scientific Institute
Luca Basso-Ricci: IRCCS San Raffaele Scientific Institute
Cesare Canepari: IRCCS San Raffaele Scientific Institute
Monica Volpin: IRCCS San Raffaele Scientific Institute
Valeria Iannello: IRCCS San Raffaele Scientific Institute
Valentina Capo: IRCCS San Raffaele Scientific Institute
Pamela Quaranta: IRCCS San Raffaele Scientific Institute
Luca Seffin: IRCCS San Raffaele Scientific Institute
Fabio Russo: IRCCS San Raffaele Scientific Institute
Mauro Biffi: IRCCS San Raffaele Scientific Institute
Leonardo Ormoli: IRCCS San Raffaele Scientific Institute
Chiara Brombin: Vita-Salute San Raffaele University
Filippo Carlucci: University of Siena
Antonella Forlino: University of Pavia
Marta Filibian: University of Pavia
Eugenio Montini: IRCCS San Raffaele Scientific Institute
Serena Scala: IRCCS San Raffaele Scientific Institute
Anna Villa: IRCCS San Raffaele Scientific Institute
Juan Antonio Bueren: Center for Research on Energy, Environment and Technology (CIEMAT)
Paula Rio: Center for Research on Energy, Environment and Technology (CIEMAT)
Alessandro Aiuti: IRCCS San Raffaele Scientific Institute
Alessio Cantore: IRCCS San Raffaele Scientific Institute
Luigi Naldini: IRCCS San Raffaele Scientific Institute

Nature, 2025, vol. 643, issue 8073, 1097-1106

Abstract: Abstract Lentiviral vector (LV)-mediated ex vivo gene therapy for haematopoietic stem and progenitor cells (HSPCs) has delivered on the promise of a ‘one-and-done’ treatment for several genetic diseases1. However, ex vivo manipulation and patient conditioning before transplantation are major hurdles that could be overcome by an in vivo approach. Here we demonstrate that in vivo gene delivery to HSPCs after systemic LV administration is enabled by the substantial trafficking of these cells from the liver to the bone marrow in newborn mice. We improved gene-transfer efficiency using a phagocytosis-shielded LV, successfully reaching bona fide HSPCs capable of long-term multilineage output and engraftment after serial transplantation, as confirmed by clonal tracking. HSPC mobilization further increased gene transfer, extending the window of intervention, although permissiveness to LV transduction declined with age. We successfully tested this in vivo strategy in mouse models of adenosine deaminase deficiency, autosomal recessive osteopetrosis and Fanconi anaemia. Interestingly, in vivo gene transfer provided a selective advantage to corrected HSPCs in Fanconi anaemia, leading to near-complete haematopoietic reconstitution and prevention of bone marrow failure. Given that circulating HSPCs in humans are also most abundant shortly after birth, in vivo HSPC gene transfer holds strong translational potential across multiple diseases.

Date: 2025
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DOI: 10.1038/s41586-025-09070-3

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