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

Serena Scala, Francesca Ferrua, Luca Basso-Ricci, Francesca Dionisio, Maryam Omrani, Pamela Quaranta, Raisa Jofra Hernandez, Luca Del Core, Fabrizio Benedicenti, Ilaria Monti, Stefania Giannelli, Federico Fraschetta, Silvia Darin, Elena Albertazzi, Stefania Galimberti, Eugenio Montini, Andrea Calabria, Maria Pia Cicalese and Alessandro Aiuti ()
Additional contact information
Serena Scala: IRCCS San Raffaele Scientific Institute
Francesca Ferrua: IRCCS San Raffaele Scientific Institute
Luca Basso-Ricci: IRCCS San Raffaele Scientific Institute
Francesca Dionisio: IRCCS San Raffaele Scientific Institute
Maryam Omrani: IRCCS San Raffaele Scientific Institute
Pamela Quaranta: IRCCS San Raffaele Scientific Institute
Raisa Jofra Hernandez: IRCCS San Raffaele Scientific Institute
Luca Del Core: IRCCS San Raffaele Scientific Institute
Fabrizio Benedicenti: IRCCS San Raffaele Scientific Institute
Ilaria Monti: IRCCS San Raffaele Scientific Institute
Stefania Giannelli: IRCCS San Raffaele Scientific Institute
Federico Fraschetta: IRCCS San Raffaele Scientific Institute
Silvia Darin: IRCCS San Raffaele Scientific Institute
Elena Albertazzi: IRCCS San Raffaele Scientific Institute
Stefania Galimberti: University of Milano—Bicocca
Eugenio Montini: IRCCS San Raffaele Scientific Institute
Andrea Calabria: IRCCS San Raffaele Scientific Institute
Maria Pia Cicalese: IRCCS San Raffaele Scientific Institute
Alessandro Aiuti: IRCCS San Raffaele Scientific Institute

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38448-y

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