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

Published: 14 July 2023| Version 1 | DOI: 10.17632/25v78pp9pg.1
, Serena Scala


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. Data supporting the current study are part of a registered clinical trial (NCT01515462). These data are available under restricted access for the sensitive nature of the clinical data, access can be obtained by request to the corresponding author (Prof. Alessandro Aiuti, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, 20132 Italy.). We intend to reply to any requests within two weeks and we will share the deposited data only for research purposes. The non-clinical data generated in this study are also provided as the Source Data file associated to the published work.

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Please refer to: doi:10.1038/s41467-023-38448-y.


San Raffaele Telethon Institute for Gene Therapy, Ospedale San Raffaele, Universita Vita Salute San Raffaele


Gene Therapy, Bone Marrow Stem Cell, Hematopoietic Stem Cell, Stem Cell Mobilization


Else Kröner-Fresenius-Stiftung

Prize to Alessandro Aiuti

Fondazione Telethon

TIGET Core Grant B2

Ministero della Salute


European Commission