 Long-term lineage commitment in haematopoietic stem cell gene therapyAndrea Calabria (),
Giulio Spinozzi,
Daniela Cesana,
Elena Buscaroli,
Fabrizio Benedicenti,
Giulia Pais,
Francesco Gazzo,
Serena Scala,
Maria Rosa Lidonnici,
Samantha Scaramuzza,
Alessandra Albertini,
Simona Esposito,
Francesca Tucci,
Daniele Canarutto,
Maryam Omrani,
Fabiola De Mattia,
Francesca Dionisio,
Stefania Giannelli,
Sarah Marktel,
Francesca Fumagalli,
Valeria Calbi,
Sabina Cenciarelli,
Francesca Ferrua,
Bernhard Gentner,
Giulio Caravagna,
Fabio Ciceri,
Luigi Naldini,
Giuliana Ferrari,
Alessandro Aiuti and
Eugenio Montini ()
Nature, 2024, vol. 636, issue 8041, 162-171 Abstract: Abstract Haematopoietic stem cell (HSC) gene therapy (GT) may provide lifelong reconstitution of the haematopoietic system with gene-corrected cells1. However, the effects of underlying genetic diseases, replication stress and ageing on haematopoietic reconstitution and lineage specification remain unclear. In this study, we analysed haematopoietic reconstitution in 53 patients treated with lentiviral-HSC-GT for diverse conditions such as metachromatic leukodystrophy2,3 (MLD), Wiskott–Aldrich syndrome4,5 (WAS) and β-thalassaemia6 (β-Thal) over a follow-up period of up to 8 years, using vector integration sites as markers of clonal identity. We found that long-term haematopoietic reconstitution was supported by 770 to 35,000 active HSCs. Whereas 50% of transplanted clones demonstrated multi-lineage potential across all conditions, the remaining clones showed a disease-specific preferential lineage output and long-term commitment: myeloid for MLD, lymphoid for WAS and erythroid for β-Thal, particularly in adult patients. Our results indicate that HSC clonogenic activity, lineage output, long-term lineage commitment and rates of somatic mutations are influenced by the underlying disease, patient age at the time of therapy, the extent of genetic defect correction and the haematopoietic stress imposed by the inherited disease. This suggests that HSCs adapt to the pathological condition during haematopoietic reconstitution. Date: 2024 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:636:y:2024:i:8041:d:10.1038_s41586-024-08250-x Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-024-08250-x Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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