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Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy

Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we present an unplanned exploratory analysis evaluating the hematopoietic reconstitution kinetics, engraftment and clonality in 13 pedi...

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Autores principales: Scala, Serena, Ferrua, Francesca, Basso-Ricci, Luca, Dionisio, Francesca, Omrani, Maryam, Quaranta, Pamela, Jofra Hernandez, Raisa, Del Core, Luca, Benedicenti, Fabrizio, Monti, Ilaria, Giannelli, Stefania, Fraschetta, Federico, Darin, Silvia, Albertazzi, Elena, Galimberti, Stefania, Montini, Eugenio, Calabria, Andrea, Cicalese, Maria Pia, Aiuti, Alessandro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10224916/
https://www.ncbi.nlm.nih.gov/pubmed/37244942
http://dx.doi.org/10.1038/s41467-023-38448-y
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author Scala, Serena
Ferrua, Francesca
Basso-Ricci, Luca
Dionisio, Francesca
Omrani, Maryam
Quaranta, Pamela
Jofra Hernandez, Raisa
Del Core, Luca
Benedicenti, Fabrizio
Monti, Ilaria
Giannelli, Stefania
Fraschetta, Federico
Darin, Silvia
Albertazzi, Elena
Galimberti, Stefania
Montini, Eugenio
Calabria, Andrea
Cicalese, Maria Pia
Aiuti, Alessandro
author_facet Scala, Serena
Ferrua, Francesca
Basso-Ricci, Luca
Dionisio, Francesca
Omrani, Maryam
Quaranta, Pamela
Jofra Hernandez, Raisa
Del Core, Luca
Benedicenti, Fabrizio
Monti, Ilaria
Giannelli, Stefania
Fraschetta, Federico
Darin, Silvia
Albertazzi, Elena
Galimberti, Stefania
Montini, Eugenio
Calabria, Andrea
Cicalese, Maria Pia
Aiuti, Alessandro
author_sort Scala, Serena
collection PubMed
description Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we present an unplanned exploratory analysis evaluating the hematopoietic reconstitution kinetics, engraftment and clonality in 13 pediatric Wiskott-Aldrich syndrome patients treated with autologous lentiviral-vector transduced hematopoietic stem/progenitor cells derived from mobilized peripheral blood (n = 7), bone marrow (n = 5) or the combination of the two sources (n = 1). 8 out of 13 gene therapy patients were enrolled in an open-label, non-randomized, phase 1/2 clinical study (NCT01515462) and the remaining 5 patients were treated under expanded access programs. Although mobilized peripheral blood- and bone marrow- hematopoietic stem/progenitor cells display similar capability of being gene-corrected, maintaining the engineered grafts up to 3 years after gene therapy, mobilized peripheral blood-gene therapy group shows faster neutrophil and platelet recovery, higher number of engrafted clones and increased gene correction in the myeloid lineage which correlate with higher amount of primitive and myeloid progenitors contained in hematopoietic stem/progenitor cells derived from mobilized peripheral blood. In vitro differentiation and transplantation studies in mice confirm that primitive hematopoietic stem/progenitor cells from both sources have comparable engraftment and multilineage differentiation potential. Altogether, our analyses reveal that the differential behavior after gene therapy of hematopoietic stem/progenitor cells derived from either bone marrow or mobilized peripheral blood is mainly due to the distinct cell composition rather than functional differences of the infused cell products, providing new frames of references for clinical interpretation of hematopoietic stem/progenitor cell transplantation outcome.
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spelling pubmed-102249162023-05-29 Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy Scala, Serena Ferrua, Francesca Basso-Ricci, Luca Dionisio, Francesca Omrani, Maryam Quaranta, Pamela Jofra Hernandez, Raisa Del Core, Luca Benedicenti, Fabrizio Monti, Ilaria Giannelli, Stefania Fraschetta, Federico Darin, Silvia Albertazzi, Elena Galimberti, Stefania Montini, Eugenio Calabria, Andrea Cicalese, Maria Pia Aiuti, Alessandro Nat Commun Article Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we present an unplanned exploratory analysis evaluating the hematopoietic reconstitution kinetics, engraftment and clonality in 13 pediatric Wiskott-Aldrich syndrome patients treated with autologous lentiviral-vector transduced hematopoietic stem/progenitor cells derived from mobilized peripheral blood (n = 7), bone marrow (n = 5) or the combination of the two sources (n = 1). 8 out of 13 gene therapy patients were enrolled in an open-label, non-randomized, phase 1/2 clinical study (NCT01515462) and the remaining 5 patients were treated under expanded access programs. Although mobilized peripheral blood- and bone marrow- hematopoietic stem/progenitor cells display similar capability of being gene-corrected, maintaining the engineered grafts up to 3 years after gene therapy, mobilized peripheral blood-gene therapy group shows faster neutrophil and platelet recovery, higher number of engrafted clones and increased gene correction in the myeloid lineage which correlate with higher amount of primitive and myeloid progenitors contained in hematopoietic stem/progenitor cells derived from mobilized peripheral blood. In vitro differentiation and transplantation studies in mice confirm that primitive hematopoietic stem/progenitor cells from both sources have comparable engraftment and multilineage differentiation potential. Altogether, our analyses reveal that the differential behavior after gene therapy of hematopoietic stem/progenitor cells derived from either bone marrow or mobilized peripheral blood is mainly due to the distinct cell composition rather than functional differences of the infused cell products, providing new frames of references for clinical interpretation of hematopoietic stem/progenitor cell transplantation outcome. Nature Publishing Group UK 2023-05-27 /pmc/articles/PMC10224916/ /pubmed/37244942 http://dx.doi.org/10.1038/s41467-023-38448-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Scala, Serena
Ferrua, Francesca
Basso-Ricci, Luca
Dionisio, Francesca
Omrani, Maryam
Quaranta, Pamela
Jofra Hernandez, Raisa
Del Core, Luca
Benedicenti, Fabrizio
Monti, Ilaria
Giannelli, Stefania
Fraschetta, Federico
Darin, Silvia
Albertazzi, Elena
Galimberti, Stefania
Montini, Eugenio
Calabria, Andrea
Cicalese, Maria Pia
Aiuti, Alessandro
Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy
title Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy
title_full Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy
title_fullStr Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy
title_full_unstemmed Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy
title_short Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy
title_sort hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10224916/
https://www.ncbi.nlm.nih.gov/pubmed/37244942
http://dx.doi.org/10.1038/s41467-023-38448-y
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