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Nat Med. 2016 Sep;22(9):987-90. doi: 10.1038/nm.4170. Epub 2016 Aug 15.

A genome-editing strategy to treat β-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition.

Author information

1
Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
2
Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
3
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
4
Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Japan.
5
Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
6
Medical Research Council, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK.
7
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
8
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
9
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Abstract

Disorders resulting from mutations in the hemoglobin subunit beta gene (HBB; which encodes β-globin), mainly sickle cell disease (SCD) and β-thalassemia, become symptomatic postnatally as fetal γ-globin expression from two paralogous genes, hemoglobin subunit gamma 1 (HBG1) and HBG2, decreases and adult β-globin expression increases, thereby shifting red blood cell (RBC) hemoglobin from the fetal (referred to as HbF or α2γ2) to adult (referred to as HbA or α2β2) form. These disorders are alleviated when postnatal expression of fetal γ-globin is maintained. For example, in hereditary persistence of fetal hemoglobin (HPFH), a benign genetic condition, mutations attenuate γ-globin-to-β-globin switching, causing high-level HbF expression throughout life. Co-inheritance of HPFH with β-thalassemia- or SCD-associated gene mutations alleviates their clinical manifestations. Here we performed CRISPR-Cas9-mediated genome editing of human blood progenitors to mutate a 13-nt sequence that is present in the promoters of the HBG1 and HBG2 genes, thereby recapitulating a naturally occurring HPFH-associated mutation. Edited progenitors produced RBCs with increased HbF levels that were sufficient to inhibit the pathological hypoxia-induced RBC morphology found in SCD. Our findings identify a potential DNA target for genome-editing-mediated therapy of β-hemoglobinopathies.

PMID:
27525524
PMCID:
PMC5706766
DOI:
10.1038/nm.4170
[Indexed for MEDLINE]
Free PMC Article

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