Journal
NATURE MEDICINE
Volume 22, Issue 9, Pages 987-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4170
Keywords
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Funding
- US National Institutes of Health [4R01HL119479, 2R56DK0658, P30CA021765-37, F30DK102291]
- American Lebanese Syrian Associated Charities
- Assisi Foundation of Memphis
- Wellcome Strategic Award
- MRC [MC_UU_12009/15] Funding Source: UKRI
- Medical Research Council [MC_UU_12009/15] Funding Source: researchfish
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Disorders resulting from mutations in the hemoglobin subunit beta gene (HBB; which encodes beta-globin), mainly sickle cell disease (SCD) and beta-thalassemia, become symptomatic postnatally as fetal gamma-globin expression from two paralogous genes, hemoglobin subunit gamma 1 (HBG1) and HBG2, decreases and adult beta-globin expression increases, thereby shifting red blood cell (RBC) hemoglobin from the fetal (referred to as HbF or alpha 2 gamma 2) to adult (referred to as HbA or alpha 2 beta 2) form. These disorders are alleviated when postnatal expression of fetal gamma-globin is maintained. For example, in hereditary persistence of fetal hemoglobin (HPFH), a benign genetic condition, mutations attenuate gamma-globin-to-beta-globin switching, causing high-level HbF expression throughout life. Co-inheritance of HPFH with beta-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 beta-hemoglobinopathies.
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