Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia.
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.
Cavazzana-Calvo
Marina
M
Clinical Investigation Center in Biotherapy, Groupe Hospitalier Universitaire Ouest, Inserm/Assistance Publique-Hôpitaux de Paris, Paris 75015, France.
Payen
Emmanuel
E
Negre
Olivier
O
Wang
Gary
G
Hehir
Kathleen
K
Fusil
Floriane
F
Down
Julian
J
Denaro
Maria
M
Brady
Troy
T
Westerman
Karen
K
Cavallesco
Resy
R
Gillet-Legrand
Beatrix
B
Caccavelli
Laure
L
Sgarra
Riccardo
R
Maouche-Chrétien
Leila
L
Bernaudin
Françoise
F
Girot
Robert
R
Dorazio
Ronald
R
Mulder
Geert-Jan
GJ
Polack
Axel
A
Bank
Arthur
A
Soulier
Jean
J
Larghero
Jérôme
J
Kabbara
Nabil
N
Dalle
Bruno
B
Gourmel
Bernard
B
Socie
Gérard
G
Chrétien
Stany
S
Cartier
Nathalie
N
Aubourg
Patrick
P
Fischer
Alain
A
Cornetta
Kenneth
K
Galacteros
Frédéric
F
Beuzard
Yves
Y
Gluckman
Eliane
E
Bushman
Frederick
F
Hacein-Bey-Abina
Salima
S
Leboulch
Philippe
P
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*
D025743:HMGA2 Protein; D035683:MicroRNAs; D012333:RNA, Messenger; D055544:beta-Globins; C487931:mirnlet7 microRNA, human