Long-term lineage commitment in hematopoietic stem cell gene therapy.

Autor: Calabria A; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy. calabria.andrea@hsr.it., Spinozzi G; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Cesana D; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Buscaroli E; Department of Mathematics, Informatics and Geosciences, University of Trieste, Triste, Italy., Benedicenti F; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Pais G; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Gazzo F; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy., Scala S; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Lidonnici MR; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Scaramuzza S; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Albertini A; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Esposito S; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Tucci F; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Pediatric Immunohematology and BMT, San Raffaele Hospital, Milan, Italy., Canarutto D; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Pediatric Immunohematology and BMT, San Raffaele Hospital, Milan, Italy.; Vita Salute San Raffaele University, Milan, Italy., Omrani M; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., De Mattia F; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Dionisio F; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Giannelli S; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Marktel S; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Pediatric Immunohematology and BMT, San Raffaele Hospital, Milan, Italy., Fumagalli F; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Pediatric Immunohematology and BMT, San Raffaele Hospital, Milan, Italy., Calbi V; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Pediatric Immunohematology and BMT, San Raffaele Hospital, Milan, Italy., Cenciarelli S; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Pediatric Immunohematology and BMT, San Raffaele Hospital, Milan, Italy., Ferrua F; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Pediatric Immunohematology and BMT, San Raffaele Hospital, Milan, Italy., Gentner B; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy., Caravagna G; Department of Mathematics, Informatics and Geosciences, University of Trieste, Triste, Italy., Ciceri F; Pediatric Immunohematology and BMT, San Raffaele Hospital, Milan, Italy., Naldini L; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Vita Salute San Raffaele University, Milan, Italy., Ferrari G; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Vita Salute San Raffaele University, Milan, Italy., Aiuti A; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Pediatric Immunohematology and BMT, San Raffaele Hospital, Milan, Italy.; Vita Salute San Raffaele University, Milan, Italy., Montini E; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy. montini.eugenio@hsr.it.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Oct 23. Date of Electronic Publication: 2024 Oct 23.
DOI: 10.1038/s41586-024-08250-x
Abstrakt: Hematopoietic Stem Cell (HSC) gene therapy (GT) may provide lifelong reconstitution of the hematopoietic system with gene-corrected cells 1 . However, the effects of underlying genetic diseases, replication stress, and aging on hematopoietic reconstitution and lineage specification remain unclear. In this study, we analyzed hematopoietic reconstitution in 53 patients treated with lentiviral-HSC-GT for diverse conditions such as metachromatic leukodystrophy 2,3 (MLD), Wiskott-Aldrich syndrome 4,5 (WAS), and β-thalassemia 6 (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 hematopoietic reconstitution was supported by 770 to 35,000 active HSCs. While 50% of transplanted clones demonstrated multilineage potential across all conditions, the remaining clones exhibited 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 hematopoietic stress imposed by the inherited disease. This suggests that HSCs adapt to the pathological condition during hematopoietic reconstitution.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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