Abstract
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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Acknowledgements
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.
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P.L. is the scientific director of the overall project, conceived the strategy and supervised the studies. M.C.-C. and E.G. are the principal clinical investigators. F.Be., R.G., G.S. and E.G. conducted clinical work. E.P., K.W., R.C., Y.B. and P.L. initiated the studies. M.C.-C., E.P., O.N., G.W., K.H., F.F., J.D., M.D., T.B., B.G.-L., L.C., R.S., L.M.-C., J.S., J.L., N.K., B.G., K.C., Y.B., F.Bu., S.H.-B.-A. and P.L. designed or performed experiments. E.P., O.N., G.W., K.H., J.D., M.D., B.D., F.Bu. and P.L. analysed the data. All authors discussed results and conclusions. P.L. wrote the paper.
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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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This file contains Supplementary Figures 1-3 with legends, Supplementary Tables 1-2, Supplementary Notes 1-3 and additional references. (PDF 330 kb)
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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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DOI: https://doi.org/10.1038/nature09328
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