| First Author | Liu B | Year | 2022 |
| Journal | Mol Ther | Volume | 30 |
| Issue | 8 | Pages | 2693-2708 |
| PubMed ID | 35526095 | Mgi Jnum | J:354926 |
| Mgi Id | MGI:7736860 | Doi | 10.1016/j.ymthe.2022.05.002 |
| Citation | Liu B, et al. (2022) Development of a double shmiR lentivirus effectively targeting both BCL11A and ZNF410 for enhanced induction of fetal hemoglobin to treat beta-hemoglobinopathies. Mol Ther 30(8):2693-2708 |
| abstractText | A promising treatment for beta-hemoglobinopathies is the de-repression of gamma-globin expression leading to increased fetal hemoglobin (HbF) by targeting BCL11A. Here, we aim to improve a lentivirus vector (LV) containing a single BCL11A shmiR (SS) to further increase gamma-globin induction. We engineered a novel LV to express two shmiRs simultaneously targeting BCL11A and the gamma-globin repressor ZNF410. Erythroid cells derived from human HSCs transduced with the double shmiR (DS) showed up to a 70% reduction of both BCL11A and ZNF410 proteins. There was a consistent and significant additional 10% increase in HbF compared to targeting BCL11A alone in erythroid cells. Erythrocytes differentiated from SCD HSCs transduced with the DS demonstrated significantly reduced in vitro sickling phenotype compared to the SS. Erythrocytes differentiated from transduced HSCs from beta-thalassemia major patients demonstrated improved globin chain balance by increased gamma-globin with reduced microcytosis. Reconstitution of DS-transduced cells from Berkeley SCD mice was associated with a statistically larger reduction in peripheral blood hemolysis markers compared with the SS vector. Overall, these results indicate that the DS LV targeting BCL11A and ZNF410 can enhance HbF induction for treating beta-hemoglobinopathies and could be used as a model to simultaneously and efficiently target multiple gene products. |
