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

2010; Nature Portfolio; Volume: 467; Issue: 7313 Linguagem: Inglês

10.1038/nature09328

1476-4687

Marina Cavazzana, Emmanuel Payen, Olivier Nègre, Gary Wang, Kathleen Hehir, Floriane Fusil, Julian D. Down, Maria Denaro, Troy Brady, Karen A. Westerman, Resy Cavallesco, Béatrix Gillet-Legrand, Laure Caccavelli, Riccardo Sgarra, Stany Chrétien, Françoise Bernaudin, Robert Girot, Ronald Dorazio, Geert-Jan Mulder, Axel Polack, Arthur Bank, Jean Soulier, Jérôme Larghero, Nabil Kabbara, B Dalle, B. Gourmel, Gèrard Socié, Stany Chrétien, Nathalie Cartier, Patrick Aubourg, Alain Fischer, Kenneth Cornetta, F. Galactéros, Yves Beuzard, Éliane Gluckman, Frederic D. Bushman, Salima Hacein‐Bey‐Abina, Philippe Leboulch,

Hemoglobinopathies and Related Disorders

Blood disorders caused by abnormal β-globin — β-thalassaemia and sickle cell disease — are the most prevalent inherited disorders worldwide, with patients often remaining dependent on blood transfusions throughout their lives. So a report of the successful use of gene therapy in a case of severe β-thalassaemia — using a lentiviral vector expressing the β-globin gene — is an eagerly awaited event. More than two years after gene transfer, the adult male patient has been transfusion-independent for 21 months. The therapeutic benefit seems to result from a dominant, myeloid-biased cell clone that may remain benign, although it could yet develop into leukaemia — a reminder that gene therapy is still at an early stage. Disorders caused by abnormal β-globin, such as β-thalassaemia, are the most prevalent inherited disorders worldwide. For treatment, many patients are dependent on blood transfusions; thus far the only cure has involved matched transplantation of haematopoietic stem cells. Here it is shown that lentiviral β-globin gene transfer can be an effective substitute for regular transfusions in a patient with severe β-thalassaemia. 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.