論文 - 詳細
| RRC ID | 77302 |
|---|---|
| 著者 | Nualkaew T, Sii-Felice K, Giorgi M, McColl B, Gouzil J, Glaser A, Voon HPJ, Tee HY, Grigoriadis G, Svasti S, Fucharoen S, Hongeng S, Leboulch P, Payen E, Vadolas J. |
| タイトル | Coordinated β-globin expression and α2-globin reduction in a multiplex lentiviral gene therapy vector for β-thalassemia. |
| ジャーナル | Mol Ther |
| Abstract |
A primary challenge in lentiviral gene therapy of β-hemoglobinopathies is to maintain low vector copy numbers to avoid genotoxicity while being reliably therapeutic for all genotypes. We designed a high-titer lentiviral vector, LVβ-shα2, that allows coordinated expression of the therapeutic βA-T87Q-globin gene and of an intron-embedded miR-30-based short hairpin RNA (shRNA) selectively targeting the α2-globin mRNA. Our approach was guided by the knowledge that moderate reduction of α-globin chain synthesis ameliorates disease severity in β-thalassemia. We demonstrate that LVβ-shα2 reduces α2-globin mRNA expression in erythroid cells while keeping α1-globin mRNA levels unchanged and βA-T87Q-globin gene expression identical to the parent vector. Compared with the first βA-T87Q-globin lentiviral vector that has received conditional marketing authorization, BB305, LVβ-shα2 shows 1.7-fold greater potency to improve α/β ratios. It may thus result in greater therapeutic efficacy and reliability for the most severe types of β-thalassemia and provide an improved benefit/risk ratio regardless of the β-thalassemia genotype. |
| 巻・号 | 29(9) |
| ページ | 2841-2853 |
| 公開日 | 2021-9-1 |
| DOI | 10.1016/j.ymthe.2021.04.037 |
| PII | S1525-0016(21)00251-3 |
| PMID | 33940155 |
| PMC | PMC8417505 |
| MeSH | Cell Line Cells, Cultured Down-Regulation Erythroid Cells / cytology Erythroid Cells / metabolism Genetic Vectors / administration & dosage* Genotype Humans K562 Cells Lentivirus / genetics Lentivirus / physiology MicroRNAs / antagonists & inhibitors Primary Cell Culture RNA, Small Interfering / genetics* Viral Load alpha-Globins / genetics* beta-Globins / genetics* beta-Thalassemia / genetics* beta-Thalassemia / therapy |
| IF | 8.986 |
| リソース情報 | |
| ヒト・動物細胞 | HUDEP-2(RCB4557) |