論文 - 詳細
| RRC ID | 77335 |
|---|---|
| 著者 | Ramadier S, Chalumeau A, Felix T, Othman N, Aknoun S, Casini A, Maule G, Masson C, De Cian A, Frati G, Brusson M, Concordet JP, Cavazzana M, Cereseto A, El Nemer W, Amendola M, Wattellier B, Meneghini V, Miccio A. |
| タイトル | Combination of lentiviral and genome editing technologies for the treatment of sickle cell disease. |
| ジャーナル | Mol Ther |
| Abstract |
Sickle cell disease (SCD) is caused by a mutation in the β-globin gene leading to polymerization of the sickle hemoglobin (HbS) and deformation of red blood cells. Autologous transplantation of hematopoietic stem/progenitor cells (HSPCs) genetically modified using lentiviral vectors (LVs) to express an anti-sickling β-globin leads to some clinical benefit in SCD patients, but it requires high-level transgene expression (i.e., high vector copy number [VCN]) to counteract HbS polymerization. Here, we developed therapeutic approaches combining LV-based gene addition and CRISPR-Cas9 strategies aimed to either knock down the sickle β-globin and increase the incorporation of an anti-sickling globin (AS3) in hemoglobin tetramers, or to induce the expression of anti-sickling fetal γ-globins. HSPCs from SCD patients were transduced with LVs expressing AS3 and a guide RNA either targeting the endogenous β-globin gene or regions involved in fetal hemoglobin silencing. Transfection of transduced cells with Cas9 protein resulted in high editing efficiency, elevated levels of anti-sickling hemoglobins, and rescue of the SCD phenotype at a significantly lower VCN compared to the conventional LV-based approach. This versatile platform can improve the efficacy of current gene addition approaches by combining different therapeutic strategies, thus reducing the vector amount required to achieve a therapeutic VCN and the associated genotoxicity risk. |
| 巻・号 | 30(1) |
| ページ | 145-163 |
| 公開日 | 2022-1-5 |
| DOI | 10.1016/j.ymthe.2021.08.019 |
| PII | S1525-0016(21)00413-5 |
| PMID | 34418541 |
| PMC | PMC8753569 |
| MeSH | Anemia, Sickle Cell* / genetics Anemia, Sickle Cell* / therapy CRISPR-Associated Protein 9 / genetics Fetal Hemoglobin / genetics Gene Editing* / methods Humans beta-Globins / genetics |
| IF | 8.986 |
| 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 | 21 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 6.0 |
| リソース情報 | |
| ヒト・動物細胞 | HUDEP-2(RCB4557) |