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

• Published in: Nature (London) Vol. 467; no. 7313; pp. 318 - 322
• Main Authors: Leboulch, Philippe, Cavazzana-Calvo, Marina, Payen, Emmanuel, Negre, Olivier, Wang, Gary, Hehir, Kathleen, Fusil, Floriane, Down, Julian, Denaro, Maria, Brady, Troy, Westerman, Karen, Cavallesco, Resy, Gillet-Legrand, Beatrix, Caccavelli, Laure, Sgarra, Riccardo, Maouche-Chrétien, Leila, Bernaudin, Françoise, Girot, Robert, Dorazio, Ronald, Mulder, Geert-Jan, Polack, Axel, Bank, Arthur, Soulier, Jean, Larghero, Jérôme, Kabbara, Nabil, Dalle, Bruno, Gourmel, Bernard, Socie, Gérard, Chrétien, Stany, Cartier, Nathalie, Aubourg, Patrick, Fischer, Alain, Cornetta, Kenneth, Galacteros, Frédéric, Beuzard, Yves, Gluckman, Eliane, Bushman, Frederick, Hacein-Bey-Abina, Salima
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 16.09.2010
• Subjects: Bone marrow; Gene expression; Gene therapy; Stem cells; Transfusion
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature09328

The -haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of -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 E/ 0-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas. The 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 E-globin with partial instability. When this is compounded with a non-functional 0 allele, a profound decrease in -globin synthesis results, and approximately half of E/ 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 -globin gene transfer, an adult patient with severe E/ 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 -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.