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.
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We thank S. Cross, C. Ballas and L. Duffy for cGMP vector manufacturing and QC testing; T. Andrieux, D. Bachir, C. Courne, A. Henri, A. Janin, A. Moindrot, M.-E. Noguera and F. Pinto for their experimental or medical contributions; F. Calvo, C. Eaves, K. Humphries, G. Manfioletti, R. Nagel, K. Sii Felice and A. Slanetz for discussions; and C. Berry for statistical analysis. This work was supported by NIH grants HL090921 to P.L. and AI52845 and AI082020 to F.B., and l’Association française contre les myopathies.
E.P., A.B., G.-J.M., A.P., Y.B. and P.L. have a financial interest in Genetix Pharmaceuticals.
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Cavazzana-Calvo, M., Payen, E., Negre, O. et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature 467, 318–322 (2010). https://doi.org/10.1038/nature09328
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