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

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 21months. Blood haemoglobin is maintained between 9 and 10gdl 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.