Intrabone allogeneic hematopoietic stem cell (HSC) gene therapy after a reduced-toxicity myeloablative conditioning regimen may be safe and efficacious in both adult and pediatric patients with transfusion-dependent thalassemia affected by severe mutations, according to a study published in Nature Medicine.1

Researchers modified autologous HSCs to express beta-globin using the lentiviral vector GLOBE. In a phase 1/2 trial ( Identifier: NCT02453477), 3 adults (31, 34, and 35 years old) and 6 children (4, 5, 6, 13, 13, and 13 years old) with transfusion-dependent thalassemia and beta-0 or severe beta+ mutations received an intrabone administration of the modified HSCs.

There was rapid hematopoietic recovery with polyclonal multilineage engraftment of vector-marked cells. Patients were able to achieve 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.

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Transfusion requirements were reduced in the adult patients, and 3 of 4 evaluable pediatric participants discontinued transfusions after gene therapy and were transfusion-independent at the latest follow-up. Younger age and persistence of higher VCN in the repopulating hematopoietic cells were associated with better outcomes.

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The authors noted that 2 combined phase 1/2 trials reported similar results, with the majority of 22 enrolled patients achieving transfusion independence or reduced transfusion dependence.2 Taken in combination with the current study’s results, these findings may lead to “protocol improvements geared towards safety and benefit,” but studies with longer follow-up and larger patient populations are warranted to assess whether intrabone gene therapy can be curative for patients with transfusion-dependent thalassemia.


1. Marktel S, Scaramuzza S, Cicalese MP, et al. Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia [published online January 21, 2019]. Nature Medicine. doi: 10.1038/s41591-018-0301-6

2. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-dependent β-thalassemia [published online April 19, 2018]. New Engl J Med. doi: 10.1056/NEJMoa1705342