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Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia

Marina Cavazzana-Calvo 1, 2 Emmanuel Payen 3, 4 Olivier Negre 3, 4, 5 Gary Wang 6 Kathleen Hehir 7 Floriane Fusil 3, 4 Julian Down 7 Maria Denaro 7 Troy Brady 6 Karen Westerman 7 Resy Cavallesco 8 Beatrix Gillet-Legrand 5 Laure Caccavelli 1, 2 Riccardo Sgarra 9 Leila Maouche-Chrétien 3, 4 Françoise Bernaudin 10 Robert Girot 11 Ronald Dorazio 7 Geert-Jan Mulder 7 Axel Polack 7 Arthur Bank 12 Jean Soulier 13, 14 Jérôme Larghero 13, 14 Nabil Kabbara 13, 14 Bruno Dalle 13, 14 Bernard Gourmel 13, 14 Gérard Socie 15 Stany Chrétien 3, 4 Nathalie Cartier 16 Patrick Aubourg 16 Alain Fischer 1, 2 Kenneth Cornetta 17 Frédéric Galacteros 18 Yves Beuzard 3, 4 Eliane Gluckman 13 Frederick Bushman 6 Salima Hacein-Bey-Abina 1, 2 Philippe Leboulch 3, 4, * 
Abstract : 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 β$^E$/β$^0$-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1, 2. The β$^E$-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 β$^E$-globin with partial instability. When this is compounded with a non-functional β$^0$ allele, a profound decrease in β-globin synthesis results, and approximately half of β$^E$/β$^0$-thalassaemia patients are transfusion-dependent. 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 β$^E$/β$^0$-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
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Submitted on : Monday, November 18, 2013 - 9:51:11 AM
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Marina Cavazzana-Calvo, Emmanuel Payen, Olivier Negre, Gary Wang, Kathleen Hehir, et al.. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature, Nature Publishing Group, 2010, 467 (7313), pp.318-322. ⟨10.1038/nature09328⟩. ⟨cea-00905288⟩



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