Mettananda, S.Fisher, C.A.Hay, D.Badat, M.Quek, L.Clark, K.Hublitz, P.Downes, D.Kerry, J.Gosden, M.Telenius, J.Sloane-Stanley, J.A.Faustino, P.Coelho, A.Doondeea, J.Usukhbayar, B.Sopp, P.Sharpe, J.A.Hughes, J.R.Vyas, P.Gibbons, R.J.Higgs, D.R.2017-10-032017-10-032017Nature Communications.2017;8(1):4242041-1723 (Electronic)2041-1723 (Linking)http://repository.kln.ac.lk/handle/123456789/17708Indexed In MEDLINEβ-Thalassemia is one of the most common inherited anemias, with no effective cure for most patients. The pathophysiology reflects an imbalance between α- and β-globin chains with an excess of free α-globin chains causing ineffective erythropoiesis and hemolysis. When α-thalassemia is co-inherited with β-thalassemia, excess free α-globin chains are reduced significantly ameliorating the clinical severity. Here we demonstrate the use of CRISPR/Cas9 genome editing of primary human hematopoietic stem/progenitor (CD34+) cells to emulate a natural mutation, which deletes the MCS-R2 α-globin enhancer and causes α-thalassemia. When edited CD34+ cells are differentiated into erythroid cells, we observe the expected reduction in α-globin expression and a correction of the pathologic globin chain imbalance in cells from patients with β-thalassemia. Xenograft assays show that a proportion of the edited CD34+ cells are long-term repopulating hematopoietic stem cells, demonstrating the potential of this approach for translation into a therapy for β-thalassemia.β-thalassemia is characterised by the presence of an excess of α-globin chains, which contribute to erythrocyte pathology. Here the authors use CRISP/Cas9 to reduce α-globin expression in hematopoietic precursors, and show effectiveness in xenograft assays in mice.en-USβ-ThalassemiaArticle