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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-09

AUTHORS

Elizabeth A Traxler, Yu Yao, Yong-Dong Wang, Kaitly J Woodard, Ryo Kurita, Yukio Nakamura, Jim R Hughes, Ross C Hardison, Gerd A Blobel, Chunliang Li, Mitchell J Weiss

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. More... »

PAGES

987-990

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nm.4170

DOI

http://dx.doi.org/10.1038/nm.4170

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1027882655

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27525524


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