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)

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 [AP-HP]
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

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

Domains: Cellular Biology

Marina Cavazzana-Calvo, Emmanuel Payen, Olivier Negre, Gary Wang, Kathleen Hehir, et al.. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature, 2010, 467 (7313), pp.318-322. ⟨10.1038/nature09328⟩. ⟨cea-00905288⟩