論文 - 詳細
| RRC ID | 77341 |
|---|---|
| 著者 | Psatha N, Georgakopoulou A, Li C, Nandakumar V, Georgolopoulos G, Acosta R, Paschoudi K, Nelson J, Chee D, Athanasiadou A, Kouvatsi A, Funnell APW, Lieber A, Yannaki E, Papayannopoulou T. |
| タイトル | Enhanced HbF reactivation by multiplex mutagenesis of thalassemic CD34+ cells in vitro and in vivo. |
| ジャーナル | Blood |
| Abstract |
Thalassemia or sickle cell patients with hereditary persistence of fetal hemoglobin (HbF) have an ameliorated clinical phenotype and, in some cases, can achieve transfusion independence. Inactivation via genome editing of γ-globin developmental suppressors, such as BCL11A or LRF/ZBTB7A, or of their binding sites, have been shown to significantly increase expression of endogenous HbF. To broaden the therapeutic window beyond a single-editing approach, we have explored combinations of cis- and trans-editing targets to enhance HbF reactivation. Multiplex mutagenesis in adult CD34+ cells was well tolerated and did not lead to any detectable defect in the cells' proliferation and differentiation, either in vitro or in vivo. The combination of 1 trans and 1 cis mutation resulted in high editing retention in vivo, coupled with almost pancellular HbF expression in NBSGW mice. The greater in vivo performance of this combination was also recapitulated using a novel helper-dependent adenoviral-CRISPR vector (HD-Ad-dualCRISPR) in CD34+ cells from β-thalassemia patients transplanted to NBSGW mice. A pronounced increase in HbF expression was observed in human red blood cells in mice with established predominant β0/β0-thalassemic hemopoiesis after in vivo injection of the HD-Ad-dualCRISPR vector. Collectively, our data suggest that the combination of cis and trans fetal globin reactivation mutations has the potential to significantly increase HbF both totally and on a per cell basis over single editing and could thus provide significant clinical benefit to patients with severe β-globin phenotype. |
| 巻・号 | 138(17) |
| ページ | 1540-1553 |
| 公開日 | 2021-10-28 |
| DOI | 10.1182/blood.2020010020 |
| PII | S0006-4971(21)01163-0 |
| PMID | 34086867 |
| PMC | PMC8554647 |
| MeSH | Adult Animals Antigens, CD34 / genetics* CRISPR-Cas Systems Cells, Cultured Fetal Hemoglobin / genetics* Gene Editing Genetic Therapy Humans Mice Mutagenesis* beta-Thalassemia / genetics* beta-Thalassemia / therapy gamma-Globins / genetics |
| IF | 17.794 |
| 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 | 2 |
| 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) |