title: Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia.
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 diasporas. 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.
authors.affiliation: Clinical Investigation Center in Biotherapy, Groupe Hospitalier Universitaire Ouest, Inserm/Assistance Publique-Hôpitaux de Paris, Paris 75015, France.
authors.forename: Marina
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authors.lastname: Cavazzana-Calvo
authors.forename: Emmanuel
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authors.lastname: Payen
authors.forename: Olivier
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authors.lastname: Negre
authors.forename: Gary
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authors.lastname: Wang
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authors.lastname: Denaro
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authors.lastname: Caccavelli
authors.forename: Riccardo
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authors.lastname: Sgarra
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authors.lastname: Maouche-Chrétien
authors.forename: Françoise
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authors.lastname: Bernaudin
authors.forename: Robert
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authors.lastname: Girot
authors.forename: Ronald
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authors.lastname: Dorazio
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Mulder
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authors.lastname: Polack
authors.forename: Arthur
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authors.lastname: Bank
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.forename: Nabil
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authors.lastname: Kabbara
authors.forename: Bruno
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authors.lastname: Dalle
authors.forename: Bernard
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authors.lastname: Gourmel
authors.forename: Gérard
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authors.lastname: Socie
authors.forename: Stany
authors.initials: S
authors.lastname: Chrétien
authors.forename: Nathalie
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authors.lastname: Cartier
authors.forename: Patrick
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authors.lastname: Aubourg
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Kenneth
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authors.lastname: Cornetta
authors.forename: Frédéric
authors.initials: F
authors.lastname: Galacteros
authors.forename: Yves
authors.initials: Y
authors.lastname: Beuzard
authors.forename: Eliane
authors.initials: E
authors.lastname: Gluckman
authors.forename: Frederick
authors.initials: F
authors.lastname: Bushman
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey-Abina
authors.forename: Philippe
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authors.lastname: Leboulch
mesh_terms: D000293:Adolescent; D001773:Blood Cells / Q000166:cytology / Q000378:metabolism; D001803:Blood Transfusion; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002675:Child, Preschool; D002999:Clone Cells / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D009928:Organ Specificity; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D013997:Time Factors; D015533:Transcriptional Activation; D055815:Young Adult; D055544:beta-Globins / Q000235:genetics* / Q000378:metabolism*; D017086:beta-Thalassemia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*
chemical_list: D025743:HMGA2 Protein; D035683:MicroRNAs; D012333:RNA, Messenger; D055544:beta-Globins; C487931:mirnlet7 microRNA, human