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

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

来源：Nature Medicine, 2016, 22(9): 987-+.

DOI：10.1038/nm.4170

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.

• 出版日期2016-9