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

By M. Cavazzana‐Calvo, E. Payen, O. Nègre, Gary Wang, K. Hehir, F. Fusil, J. Down, M. Denaro, Troy L. Brady, Karen Westerman and 28 more. Nature, 2010

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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 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 βE/β0-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 βE/β0-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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e5286f9769609fd89188225b5edae87a1a30983a

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Citations in the corpus

Gene therapy clinical trials worldwide to 2012 – an update (2013, background): “appeared to be mediated by a dominant clone containing an integration site within the HMGA2 gene [47].”
State-of-the-art gene-based therapies: the road ahead (2011, background): “In a recent study, the transduction of haematopoietic progenitor cells with a lentiviral vector expressing a β-globin cDNA successfully reversed the transfusion dependency of one patient with β-thalassaemia-based anaemi”
Clinical use of lentiviral vectors (2018, background): “patient with β/β-thalassemia achieved independence from transfusion [67].”
Gene therapy comes of age (2018, positive): “Lentiviral vectors harboring multiple regulatory elements to direct high-level, erythroid-specific hemoglobin expression have been developed (26) and in case reports have shown promise in patients with b-thalassemia or sickle cell disease (120, 121), with larger multicenter clinical trials ongoing (”
Decade-Long Safety and Function of Retroviral-Modified Chimeric Antigen Receptor T-cells (2012, methodology): “The durable persistence of the CD4ζ T-cells provided a unique opportunity to interrogate selection for preferred gammaretroviral integration sites over time in T cells, resulting from modulation of cellular growth control genes as a result of integration-mediated events such as distal effects from t”