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.
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The clinical trial was supported initially by Fondazione Telethon and by GlaxoSmithKline (GSK). We wish to acknowledge Fondazione Telethon for continuous support and strategic guidance. GSK has licensed the thalassemia HSC gene therapy in August 2017 and transferred to Orchard Therapeutics in April 2018. We thank the patients and families who are participating in this study; The Association of Patients with Thalassaemia and Drepanocytosis in Lombardy, Italy, for facilitating communication between patients, families and health care operators. We thank all physicians that have referred patients for participation, the clinical and laboratory staff of the Ospedale San Raffaele Stem Cell Program for patient care and data collection, the Paediatric Clinical Research Unit, S. Zancan and the personnel of SR-TIGET Clinical Trial Office for regulatory support. We thank A. Spinelli of the Ospedale San Raffaele Experimental Imaging Centre for bioluminescence acquisition and analysis. We are grateful to H. Prunty and R. Chiesa for supervision and interpretation of the treosulfan pharmacokinetics analysis (Great Ormond Street Hospital, London, UK).