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Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia
Marina Cavazzana-Calvo1,2,17, Emmanuel Payen3,4,5,17, Olivier Negre3,4,5,6, Gary Wang7, Kathleen Hehir8, Floriane Fusil3,4,5, Julian Down8, Maria Denaro8, Troy Brady7, Karen Westerman8,9, Resy Cavallesco9, Beatrix Gillet-Legrand6, Laure Caccavelli1,2, Riccardo Sgarra10, Leila Maouche-Chrétien3,4, Fran?oise Bernaudin11, Robert Girot12, Ronald Dorazio8, Geert-Jan Mulder8, Axel Polack8, Arthur Bank13, Jean Soulier5, Jér?me Larghero5, Nabil Kabbara5, Bruno Dalle5, Bernard Gourmel5, Gérard Socie5, Stany Chrétien3,4,9, Nathalie Cartier14, Patrick Aubourg14, Alain Fischer1,2, Kenneth Cornetta15, Frédéric Galacteros16, Yves Beuzard3,4,5, Eliane Gluckman5, Frederick Bushman7, Salima Hacein-Bey-Abina1,2,17 & Philippe Leboulch3,4,9,17
The β-haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. Compound βE/β0-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1, 2. The βE-globin allele bears a point mutation that causes alternative splicing. The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated βE-globin with partial instability1, 2. When this is compounded with a non-functional β0 allele, a profound decrease in β-globin synthesis results, and approximately half of βE/β0-thalassaemia patients are transfusion-dependent1, 2. The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease. Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe βE/β0-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21?months. Blood haemoglobin is maintained between 9 and 10?g?dl?1, of which one-third contains vector-encoded β-globin. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells.
