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 βE0-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 βE0-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 βE0-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.

Author information

Author notes

    • Marina Cavazzana-Calvo
    • , Emmanuel Payen
    •  & Salima Hacein-Bey-Abina

    These authors contributed equally to this work.

Affiliations

  1. Clinical Investigation Center in Biotherapy, Groupe Hospitalier Universitaire Ouest, Inserm/Assistance Publique–Hôpitaux de Paris, Paris 75015, France

    • Marina Cavazzana-Calvo
    • , Laure Caccavelli
    • , Alain Fischer
    •  & Salima Hacein-Bey-Abina
  2. University Paris-Descartes, Paris 75005, France

    • Marina Cavazzana-Calvo
    • , Laure Caccavelli
    • , Alain Fischer
    •  & Salima Hacein-Bey-Abina
  3. CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Fontenay-aux-Roses 92265, France

    • Emmanuel Payen
    • , Olivier Negre
    • , Floriane Fusil
    • , Leila Maouche-Chrétien
    • , Stany Chrétien
    •  & Yves Beuzard
  4. Inserm U962 and University Paris XI, CEA-iMETI, Fontenay-aux-Roses 92265, France

    • Emmanuel Payen
    • , Olivier Negre
    • , Floriane Fusil
    • , Leila Maouche-Chrétien
    • , Stany Chrétien
    •  & Yves Beuzard
  5. Departments of Hematology, Bone Marrow Transplantation and Biochemistry, University Paris VII, Institute of Hematology, Hôpital Saint-Louis, AP-HP, Paris 75010, France

    • Emmanuel Payen
    • , Olivier Negre
    • , Floriane Fusil
    • , Jean Soulier
    • , Jérôme Larghero
    • , Nabil Kabbara
    • , Bruno Dalle
    • , Bernard Gourmel
    • , Gérard Socie
    • , Yves Beuzard
    •  & Eliane Gluckman
  6. Genetix-France, CEA-iMETI, Fontenay-aux-Roses 92265, France

    • Olivier Negre
    •  & Beatrix Gillet-Legrand
  7. Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

    • Gary Wang
    • , Troy Brady
    •  & Frederick Bushman
  8. Genetix Pharmaceuticals, Cambridge, Massachusetts 02139, USA

    • Kathleen Hehir
    • , Julian Down
    • , Maria Denaro
    • , Karen Westerman
    • , Ronald Dorazio
    • , Geert-Jan Mulder
    •  & Axel Polack
  9. Genetics Division, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    • Karen Westerman
    • , Resy Cavallesco
    •  & Stany Chrétien
  10. University of Trieste, Department of Life Sciences, Trieste 34127, Italy

    • Riccardo Sgarra
  11. Centre Hospitalier Intercommunal de Créteil, Créteil 94000, France

    • Françoise Bernaudin
  12. Department of Biology, Hôpital Tenon, Paris 75020, France

    • Robert Girot
  13. Department of Medicine and Department of Genetics and Development, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA

    • Arthur Bank
  14. Inserm UMR745, University Paris-Descartes, Paris 75005, France

    • Nathalie Cartier
    •  & Patrick Aubourg
  15. Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana 46202, USA

    • Kenneth Cornetta
  16. Hopital Henri Mondor, AP-HP, Créteil 94000, France

    • Frédéric Galacteros

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Contributions

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.

Competing interests

E.P., A.B., G.-J.M., A.P., Y.B. and P.L. have a financial interest in Genetix Pharmaceuticals.

Corresponding author

Correspondence to Philippe Leboulch.

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DOI

https://doi.org/10.1038/nature09328

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