In vivo haemopoietic stem cell gene therapy enabled by postnatal trafficking

• 成果类型: Article
• 署名作者: Milani, Michela; Fabiano, Anna; Perez-Rodriguez, Marta; Hernandez, Raisa Jofra; Zecchillo, Alessandra; Zonari, Erika; Ottonello, Sofia; Basso-Ricci, Luca; Canepari, Cesare; Volpin, Monica; Iannello, Valeria; Capo, Valentina; Quaranta, Pamela; Seffin, Luca; Russo, Fabio; Biffi, Mauro; Ormoli, Leonardo; Brombin, Chiara; Carlucci, Filippo; Forlino, Antonella; Filibian, Marta; Montini, Eugenio; Scala, Serena; Villa, Anna; Bueren, Juan Antonio; Rio, Paula; Aiuti, Alessandro; Cantore, Alessio; Naldini, Luigi
• 署名单位: Fondazione Telethon; San Raffaele Telethon Institute For Gene Therapy (Sr-Tiget); Vita-Salute San Raffaele University; IRCCS Ospedale San Raffaele; Centro de Investigaciones Energeticas, Medioambientales Tecnologicas; CIBER - Centro de Investigacion Biomedica en Red; CIBERER; University of Barcelona; University of Milano-Bicocca; Vita-Salute San Raffaele University; Consiglio Nazionale delle Ricerche (CNR); Istituto di Ricerca Genetica e Biomedica (IRGB-CNR); Vita-Salute San Raffaele University; University of Siena; University of Pavia; University of Pavia
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3101
• DOI: 10.1038/s41586-025-09070-3
• 发表日期: 2025-07-24
• 关键词: mice; engraftment; proteasome; homolog; sites

摘要

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.