Mettananda, SachithFisher, Chris A.Hay, DeborahBadat, MohsinQuek, LynnClark, KevinHublitz, PhilipDownes, DamienKerry, JonGosden, MatthewTelenius, JelenaSloane-Stanley, Jackie A.Faustino, PaulaCoelho, AndreiaDoondeea, JessicaUsukhbayar, BatchimegSopp, PaulSharpe, Jacqueline A.Hughes, Jim R.Vyas, PareshGibbons, Richard J.Higgs, Douglas R.2017-09-152017-09-152017-09-04Nat Commun. 2017 Sep 4;8(1):424. doi: 10.1038/s41467-017-00479-72041-1723http://hdl.handle.net/10400.18/4791β-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.engSteam CellsBeta-thalassemiaAlpha-thalassemiaTherapy for β-thalassemiaDoenças GenéticasDoenças RarasRegulação GénicaEdição do GenomaCRISPR/Cas9Tratamento beta-talassémiaGlobinasTerapia GénicaHemoglobinopatiasTalassémiasjournal article10.1038/s41467-017-00479-7