Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia

β-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 wi...

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Published in:Nature communications Vol. 8; no. 1; pp. 424 - 11
Main Authors: Mettananda, Sachith, Fisher, Chris A., Hay, Deborah, Badat, Mohsin, Quek, Lynn, Clark, Kevin, Hublitz, Philip, Downes, Damien, Kerry, Jon, Gosden, Matthew, Telenius, Jelena, Sloane-Stanley, Jackie A., Faustino, Paula, Coelho, Andreia, Doondeea, Jessica, Usukhbayar, Batchimeg, Sopp, Paul, Sharpe, Jacqueline A., Hughes, Jim R., Vyas, Paresh, Gibbons, Richard J., Higgs, Douglas R.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 04.09.2017
Nature Publishing Group
Nature Portfolio
Subjects:
631/337/4041/3196
631/532/1542
692/699/1541/13
alpha-Globins - genetics
Animals
Antigens, CD34 - metabolism
Base Sequence
beta-Thalassemia - genetics
beta-Thalassemia - therapy
Cells, Cultured
CRISPR-Cas Systems
Enhancer Elements, Genetic - genetics
Female
Gene Editing
Gene Knockdown Techniques
Genome editing
Genome, Human
Hematopoietic Stem Cells - metabolism
Heterografts
Humanities and Social Sciences
Humans
Mice
multidisciplinary
Science
Science (multidisciplinary)
Sequence Deletion - genetics
Single-Cell Analysis
Stem cell transplantation
Stem cells
Thalassemia
Xenografts
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:β-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.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-017-00479-7