期刊
BLOOD
卷 131, 期 17, 页码 1960-1973出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-10-811505
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资金
- AFM-Telethon [17224]
- European Research Council [ERC-2010-AdG, ERC-2015-AdG]
- Agence Nationale de la Recherche [ANR-16-CE18-0004, ANR-10-IAHU-01]
- EU Marie Curie-COFUND [PRESTIGE_2015_2_0015]
- CRISPR Therapeutics
Naturally occurring, large deletions in the beta-globin locus result in hereditary persistence of fetal hemoglobin, a condition that mitigates the clinical severity of sickle cell disease (SCD) and beta-thalassemia. We designed a clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) strategy to disrupt a 13.6-kb genomic region encompassing the delta- and beta-globin genes and a putative gamma-delta intergenic fetal hemoglobin (HbF) silencer. Disruption of just the putative HbF silencer results in a mild increase in gamma-globin expression, whereas deletion or inversion of a 13.6-kb region causes a robust reactivation of HbF synthesis in adult erythroblasts that is associated with epigenetic modifications and changes in chromatin contacts within the beta-globin locus. In primary SCD patient-derived hematopoietic stem/progenitor cells, targeting the 13.6-kb region results in a high proportion of gamma-globin expression in erythroblasts, increased HbF synthesis, and amelioration of the sickling cell phenotype. Overall, this study provides clues for a potential CRISPR/Cas9 genome editing approach to the therapy of beta-hemoglobinopathies.
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