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
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
Alain Fischer
- Function : Author
- PersonId : 832560
Philippe Leboulch
Connectez-vous pour contacter l'auteur
- Function : Correspondent author
- PersonId : 948500
Connectez-vous pour contacter l'auteur
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