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 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.

Palavras-chave

Steam Cells Beta-thalassemia Alpha-thalassemia Therapy for β-thalassemia Doenças Genéticas Doenças Raras Regulação Génica Edição do Genoma CRISPR/Cas9 Tratamento beta-talassémia Globinas Terapia Génica Hemoglobinopatias Talassémias

URI

http://hdl.handle.net/10400.18/4791

Citação

Nat Commun. 2017 Sep 4;8(1):424. doi: 10.1038/s41467-017-00479-7

Editora

Nature Publishing Group

DOI

10.1038/s41467-017-00479-7

Coleções

DGH - Artigos em revistas internacionais

Licença CC

cclicense-by

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