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

Marina Cavazzana-Calvo; Emmanuel Payen; Olivier Negre; Gary Wang; Kathleen Hehir; Floriane Fusil; Julian Down; Maria Denaro; Troy Brady; Karen Westerman; Resy Cavallesco; Beatrix Gillet-Legrand; Laure Caccavelli; Riccardo Sgarra; Leila Maouche-Chrétien; Françoise Bernaudin; Robert Girot; Ronald Dorazio; Geert-Jan Mulder; Axel Polack; Arthur Bank; Jean Soulier; Jérôme Larghero; Nabil Kabbara; Bruno Dalle; Bernard Gourmel; Gérard Socie; Stany Chrétien; Nathalie Cartier; Patrick Aubourg; Alain Fischer; Kenneth Cornetta; Frédéric Galacteros; Yves Beuzard; Eliane Gluckman; Frederick Bushman; Salima Hacein-Bey-Abina; Philippe Leboulch

doi:10.1038/nature09328

Journal articles

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

Marina Cavazzana-Calvo ^{1, 2} Emmanuel Payen ^{3, 4} Olivier Negre ^{3, 4, 5} Gary Wang ⁶ Kathleen Hehir ⁷ Floriane Fusil ^{3, 4} Julian Down ⁷ Maria Denaro ⁷ Troy Brady ⁶ Karen Westerman ⁷ Resy Cavallesco ⁸ Beatrix Gillet-Legrand ⁵ Laure Caccavelli ^{1, 2} Riccardo Sgarra ⁹ Leila Maouche-Chrétien ^{3, 4} Françoise Bernaudin ¹⁰ Robert Girot ¹¹ Ronald Dorazio ⁷ Geert-Jan Mulder ⁷ Axel Polack ⁷ Arthur Bank ¹² Jean Soulier ^{13, 14} Jérôme Larghero ^{13, 14} Nabil Kabbara ^{13, 14} Bruno Dalle ^{13, 14} Bernard Gourmel ^{13, 14} Gérard Socie ¹⁵ Stany Chrétien ^{3, 4} Nathalie Cartier ¹⁶ Patrick Aubourg ¹⁶ Alain Fischer ^{1, 2} Kenneth Cornetta ¹⁷ Frédéric Galacteros ¹⁸ Yves Beuzard ^{3, 4} Eliane Gluckman ¹³ Frederick Bushman ⁶ Salima Hacein-Bey-Abina ^{1, 2} Philippe Leboulch ^{3, 4, *}

* Corresponding author

1 Developpement Normal et Pathologique du Système Immunitaire

2 Clinical Investigation Center in Biotherapy

3 IMETI - Institut des Maladies Emergentes et des Thérapies Innovantes

4 UMR E007 - Thérapie génique et contrôle de l'expansion cellulaire

5 Genetix-France

6 Department of Microbiology

7 Genetix Pharmaceuticals

8 Genetics Division, Boston

9 Department of Life Sciences, Trieste

10 Service d'hématologie pédiatrique

11 CHU Tenon [APHP]

12 Department of Medicine and Department of Genetics and Development

13 Departments of Hematology

14 Institute of Hematology

15 Service d'hématologie greffe [Saint-Louis]

16 Inserm U745 - Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux

17 Department of Medical and Molecular Genetics

18 IMRB - Institut Mondor de Recherche Biomédicale

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 β$^E$/β$^0$-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1, 2. The β$^E$-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 β$^E$-globin with partial instability. When this is compounded with a non-functional β$^0$ allele, a profound decrease in β-globin synthesis results, and approximately half of β$^E$/β$^0$-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 β-globin gene transfer, an adult patient with severe β$^E$/β$^0$-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 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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Journal articles

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Life Sciences [q-bio] / Cellular Biology

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Submitted on : Monday, November 18, 2013 - 9:51:11 AM
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Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia

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

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