In vivo haemopoietic stem cell gene therapy enabled by postnatal trafficking
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 diseases<sup>1</sup>. 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.
Authors
- Juan A. Bueren (ORCID: https://orcid.org/0000-0002-3228-7013)
- Chiara Brombin (ORCID: https://orcid.org/0000-0002-8215-6206)
- Pamela Quaranta (ORCID: https://orcid.org/0009-0009-2988-5387)
- Mauro Biffi (ORCID: https://orcid.org/0000-0002-6914-2854)
- Filippo Carlucci (ORCID: https://orcid.org/0000-0002-9592-8025)
- Valentina Capo (ORCID: https://orcid.org/0000-0002-1851-1429)
- Luca Basso‐Ricci (ORCID: https://orcid.org/0000-0002-5907-005X)
- Antonella Forlino (ORCID: https://orcid.org/0000-0002-6385-1182)
- Marta Filibian (ORCID: https://orcid.org/0000-0003-0939-7879)
- Fabio Russo (ORCID: https://orcid.org/0000-0001-5280-5677)
- Raisa Jofra Hernández (ORCID: https://orcid.org/0000-0002-9812-9042)
- Alessandro Aiuti (ORCID: https://orcid.org/0000-0002-5398-1717)
- Serena Scala (ORCID: https://orcid.org/0000-0002-8579-3809)
- Alessio Cantore (ORCID: https://orcid.org/0000-0002-9741-997X)
- Paula Rı́o (ORCID: https://orcid.org/0000-0002-5424-5543)
- Erika Zonari (ORCID: https://orcid.org/0000-0002-7915-3995)
- Alessandra Zecchillo (ORCID: https://orcid.org/0000-0003-4142-1162)
- Eugenio Montini (ORCID: https://orcid.org/0000-0003-1771-6067)
- Michela Milani (ORCID: https://orcid.org/0000-0002-0363-678X)
- Luigi Naldini (ORCID: https://orcid.org/0000-0002-7835-527X)
- Monica Volpin (ORCID: https://orcid.org/0000-0002-0794-9900)
- Anna Villa (ORCID: https://orcid.org/0000-0003-4428-9013)
- Cesare Canepari
- Anna Fabiano (ORCID: https://orcid.org/0000-0002-7604-6967)
- Simone Ottonello (ORCID: https://orcid.org/0000-0001-5837-0942)
- Luca Seffin (ORCID: https://orcid.org/0009-0005-7028-6125)
- Valeria Iannello
- Leonardo Ormoli
- Marta Perez-Rodriguez (ORCID: https://orcid.org/0009-0007-8115-4093)
Institutions
- University of Siena (IT)
- Vita-Salute San Raffaele University (IT)
- University of Pavia (IT)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Institute of Genetic and Biomedical Research (IT)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- Center for Innovation (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)
- University of Milano-Bicocca (IT)
Publication Details
- Journal
- Nature
- Published
- 2025-05-28
- DOI
- https://doi.org/10.1038/s41586-025-09070-3
- Citations
- 9
- Primary Topic
- Virus-based gene therapy research
- Type
- article
- Field-Weighted Citation Impact
- 16.36