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 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.
Transfusion independence and HMGA2 activation after gene therapy of human ß-thalassaemia / 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, Riccardo; Maouche Chrétien, L.; Bernaudin, F.; Girot, R.; Dorazio, R.; Mulder, G. J.; Polack, A.; Bank, A.; Soulier, J.; Larghero, J.; Kabbara, N.; Dalle, B.; Gourmel, B.; Socie, G.; Chrétien, S.; Cartier, N.; Aubourg, P.; Fischer, A.; Cornetta, K.; Galacteros, F.; Beuzard, Y.; Gluckman, E.; Bushman, F.; Hacein Bey Abina, S.; Leboulch, P.. - In: NATURE. - ISSN 0028-0836. - STAMPA. - 467:(2010), pp. 318-322. [10.1038/nature09328]
Transfusion independence and HMGA2 activation after gene therapy of human ß-thalassaemia.
SGARRA, RICCARDO;
2010-01-01
Abstract
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 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.Pubblicazioni consigliate
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