Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia

Sarah Marktel, Samantha Scaramuzza, Maria Pia Cicalese, Fabio Giglio, Stefania Galimberti, Maria Rosa Lidonnici, Valeria Calbi, Andrea Assanelli, Maria Ester Bernardo, Claudia Rossi, Andrea Calabria, Raffaella Milani, Salvatore Gattillo, Fabrizio Benedicenti, Giulio Spinozzi, Annamaria Aprile, Alessandra Bergami, Miriam Casiraghi, Giulia Consiglieri, Nicoletta MaseraEmanuela D’Angelo, Nadia Mirra, Raffaella Origa, Immacolata Tartaglione, Silverio Perrotta, Robert Winter, Milena Coppola, Gianluca Viarengo, Luca Santoleri, Giovanna Graziadei, Michela Gabaldo, Maria Grazia Valsecchi, Eugenio Montini, Luigi Naldini, Maria Domenica Cappellini, Fabio Ciceri, Alessandro Aiuti, Giuliana Ferrari

Research output: Contribution to journalArticlepeer-review


ß-thalassemia is caused by ß-globin gene mutations resulting in reduced (β+) or absent (β0) hemoglobin production. Patient life expectancy has recently increased, but the need for chronic transfusions in transfusion-dependent thalassemia (TDT) and iron chelation impairs quality of life1. Allogeneic hematopoietic stem cell (HSC) transplantation represents the curative treatment, with thalassemia-free survival exceeding 80%. However, it is available to a minority of patients and is associated with morbidity, rejection and graft-versus-host disease2. Gene therapy with autologous HSCs modified to express ß-globin represents a potential therapeutic option. We treated three adults and six children with ß0 or severe ß+ mutations in a phase 1/2 trial (NCT02453477) with an intrabone administration of HSCs transduced with the lentiviral vector GLOBE. Rapid hematopoietic recovery with polyclonal multilineage engraftment of vector-marked cells was achieved, with a median of 37.5% (range 12.6–76.4%) in hematopoietic progenitors and a vector copy number per cell (VCN) of 0.58 (range 0.10–1.97) in erythroid precursors at 1 year, in absence of clonal dominance. Transfusion requirement was reduced in the adults. Three out of four evaluable pediatric participants discontinued transfusions after gene therapy and were transfusion independent at the last follow-up. Younger age and persistence of higher VCN in the repopulating hematopoietic cells are associated with better outcome.

Original languageEnglish
JournalNature Medicine
Publication statusAccepted/In press - Jan 1 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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