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

Marina Cavazzana-Calvo, Emmanuel Payen, Olivier Negre, Gary Wang, Kathleen Hehir, Floriane Fusil, Julian Down, Maria Denaro, Troy Brady, Karen Westerman, Resy Cavallesco, Beatrix Gillet-Legrand, Laure Caccavelli, Riccardo Sgarra, Leila Maouche-Chrétien, Françoise Bernaudin, Robert Girot, Ronald Dorazio, Geert Jan Mulder, Axel PolackArthur Bank, Jean Soulier, Jérôme Larghero, Nabil Kabbara, Bruno Dalle, Bernard Gourmel, Gérard Socie, Stany Chrétien, Nathalie Cartier, Patrick Aubourg, Alain Fischer, Kenneth Cornetta, Frédéric Galacteros, Yves Beuzard, Eliane Gluckman, Frederick Bushman, Salima Hacein-Bey-Abina, Philippe Leboulch

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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 E0 -thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas. 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 E0 -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 E0 -thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21months. Blood haemoglobin is maintained between 9 and 10gdl 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.

Original languageEnglish (US)
Pages (from-to)318-322
Number of pages5
Issue number7313
StatePublished - Sep 2010
Externally publishedYes

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    Cavazzana-Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., Down, J., Denaro, M., Brady, T., Westerman, K., Cavallesco, R., Gillet-Legrand, B., Caccavelli, L., Sgarra, R., Maouche-Chrétien, L., Bernaudin, F., Girot, R., Dorazio, R., Mulder, G. J., ... Leboulch, P. (2010). Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature, 467(7313), 318-322.