論文 - 詳細
| RRC ID | 77350 |
|---|---|
| 著者 | Weber L, Frati G, Felix T, Hardouin G, Casini A, Wollenschlaeger C, Meneghini V, Masson C, De Cian A, Chalumeau A, Mavilio F, Amendola M, Andre-Schmutz I, Cereseto A, El Nemer W, Concordet JP, Giovannangeli C, Cavazzana M, Miccio A. |
| タイトル | Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype. |
| ジャーナル | Sci Adv |
| Abstract |
Sickle cell disease (SCD) is caused by a single amino acid change in the adult hemoglobin (Hb) β chain that causes Hb polymerization and red blood cell (RBC) sickling. The co-inheritance of mutations causing fetal γ-globin production in adult life hereditary persistence of fetal Hb (HPFH) reduces the clinical severity of SCD. HPFH mutations in the HBG γ-globin promoters disrupt binding sites for the repressors BCL11A and LRF. We used CRISPR-Cas9 to mimic HPFH mutations in the HBG promoters by generating insertions and deletions, leading to disruption of known and putative repressor binding sites. Editing of the LRF-binding site in patient-derived hematopoietic stem/progenitor cells (HSPCs) resulted in γ-globin derepression and correction of the sickling phenotype. Xenotransplantation of HSPCs treated with gRNAs targeting the LRF-binding site showed a high editing efficiency in repopulating HSPCs. This study identifies the LRF-binding site as a potent target for genome-editing treatment of SCD. |
| 巻・号 | 6(7) |
| 公開日 | 2020-2-1 |
| DOI | 10.1126/sciadv.aay9392 |
| PII | 6/7/eaay9392 |
| PMID | 32917636 |
| PMC | PMC7015694 |
| MeSH | Anemia, Sickle Cell* / genetics Anemia, Sickle Cell* / therapy Binding Sites CRISPR-Cas Systems Fetal Hemoglobin / genetics Fetal Hemoglobin / metabolism Gene Editing / methods Humans Phenotype beta-Globins / genetics beta-Globins / metabolism beta-Thalassemia* / genetics beta-Thalassemia* / metabolism beta-Thalassemia* / therapy gamma-Globins / genetics gamma-Globins / metabolism |
| IF | 13.117 |
| リソース情報 | |
| ヒト・動物細胞 | HUDEP-2(RCB4557) |