論文 - 詳細
| RRC ID | 77259 |
|---|---|
| 著者 | Pavani G, Fabiano A, Laurent M, Amor F, Cantelli E, Chalumeau A, Maule G, Tachtsidi A, Concordet JP, Cereseto A, Mavilio F, Ferrari G, Miccio A, Amendola M. |
| タイトル | Correction of β-thalassemia by CRISPR/Cas9 editing of the α-globin locus in human hematopoietic stem cells. |
| ジャーナル | Blood Adv |
| Abstract |
β-thalassemias (β-thal) are a group of blood disorders caused by mutations in the β-globin gene (HBB) cluster. β-globin associates with α-globin to form adult hemoglobin (HbA, α2β2), the main oxygen-carrier in erythrocytes. When β-globin chains are absent or limiting, free α-globins precipitate and damage cell membranes, causing hemolysis and ineffective erythropoiesis. Clinical data show that severity of β-thal correlates with the number of inherited α-globin genes (HBA1 and HBA2), with α-globin gene deletions having a beneficial effect for patients. Here, we describe a novel strategy to treat β-thal based on genome editing of the α-globin locus in human hematopoietic stem/progenitor cells (HSPCs). Using CRISPR/Cas9, we combined 2 therapeutic approaches: (1) α-globin downregulation, by deleting the HBA2 gene to recreate an α-thalassemia trait, and (2) β-globin expression, by targeted integration of a β-globin transgene downstream the HBA2 promoter. First, we optimized the CRISPR/Cas9 strategy and corrected the pathological phenotype in a cellular model of β-thalassemia (human erythroid progenitor cell [HUDEP-2] β0). Then, we edited healthy donor HSPCs and demonstrated that they maintained long-term repopulation capacity and multipotency in xenotransplanted mice. To assess the clinical potential of this approach, we next edited β-thal HSPCs and achieved correction of α/β globin imbalance in HSPC-derived erythroblasts. As a safer option for clinical translation, we performed editing in HSPCs using Cas9 nickase showing precise editing with no InDels. Overall, we described an innovative CRISPR/Cas9 approach to improve α/β globin imbalance in thalassemic HSPCs, paving the way for novel therapeutic strategies for β-thal. |
| 巻・号 | 5(5) |
| ページ | 1137-1153 |
| 公開日 | 2021-3-9 |
| DOI | 10.1182/bloodadvances.2020001996 |
| PII | S2473-9529(21)00140-3 |
| PMID | 33635334 |
| PMC | PMC7948300 |
| MeSH | Animals CRISPR-Cas Systems Hematopoietic Stem Cells / metabolism Humans Mice alpha-Globins / genetics beta-Globins / genetics beta-Thalassemia* / genetics beta-Thalassemia* / therapy |
| IF | 4.91 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 16 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HUDEP-2(RCB4557) |