A genome-editing strategy to treat β-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition.
Elizabeth A TraxlerYu YaoYong-Dong WangKaitly J WoodardRyo KuritaYukio NakamuraJim R HughesRoss Cameron HardisonGerd A BlobelChunliang LiMitchell J WeissPublished in: Nature medicine (2016)
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.
Keyphrases
- crispr cas
- genome editing
- red blood cell
- poor prognosis
- sickle cell disease
- genome wide
- endothelial cells
- copy number
- binding protein
- dna methylation
- gene expression
- long non coding rna
- young adults
- mitochondrial dna
- stem cells
- preterm infants
- bone marrow
- amino acid
- human health
- circulating tumor
- cell therapy
- cell free
- induced pluripotent stem cells