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

M Cavazzana-Calvo, E Payen, O Negre, G Wang… - Nature, 2010 - nature.com
M Cavazzana-Calvo, E Payen, O Negre, G Wang, K Hehir, F Fusil, J Down, M Denaro…
Nature, 2010nature.com
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 βE/β0-thalassaemia is the most
common form of severe thalassaemia in southeast Asian countries and their diasporas,. The
βE-globin allele bears a point mutation that causes alternative splicing. The abnormally …
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 βE0-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas,. The βE-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 βE-globin with partial instability,. When this is compounded with a non-functional β0 allele, a profound decrease in β-globin synthesis results, and approximately half of βE0-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 βE0-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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