Andrea 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, Eugenio Montini
{"title":"Long-term lineage commitment in hematopoietic stem cell gene therapy","authors":"Andrea 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, Eugenio Montini","doi":"10.1038/s41586-024-08250-x","DOIUrl":null,"url":null,"abstract":"<p>Hematopoietic Stem Cell (HSC) gene therapy (GT) may provide lifelong reconstitution of the hematopoietic system with gene-corrected cells<sup>1</sup>. 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<sup>2,3</sup> (MLD), Wiskott-Aldrich syndrome<sup>4,5</sup> (WAS), and β-thalassemia<sup>6</sup> (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.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5000,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41586-024-08250-x","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Hematopoietic Stem Cell (HSC) gene therapy (GT) may provide lifelong reconstitution of the hematopoietic system with gene-corrected cells1. 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 leukodystrophy2,3 (MLD), Wiskott-Aldrich syndrome4,5 (WAS), and β-thalassemia6 (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.
期刊介绍:
Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.