Reference - Detail
| RRC ID | 77337 |
|---|---|
| Author | Li C, Psatha N, Sova P, Gil S, Wang H, Kim J, Kulkarni C, Valensisi C, Hawkins RD, Stamatoyannopoulos G, Lieber A. |
| Title | Reactivation of γ-globin in adult β-YAC mice after ex vivo and in vivo hematopoietic stem cell genome editing. |
| Journal | Blood |
| Abstract |
Disorders involving β-globin gene mutations, primarily β-thalassemia and sickle cell disease, represent a major target for hematopoietic stem/progenitor cell (HSPC) gene therapy. This includes CRISPR/Cas9-mediated genome editing approaches in adult CD34+ cells aimed toward the reactivation of fetal γ-globin expression in red blood cells. Because models involving erythroid differentiation of CD34+ cells have limitations in assessing γ-globin reactivation, we focused on human β-globin locus-transgenic (β-YAC) mice. We used a helper-dependent human CD46-targeting adenovirus vector expressing CRISPR/Cas9 (HDAd-HBG-CRISPR) to disrupt a repressor binding region within the γ-globin promoter. We transduced HSPCs from β-YAC/human CD46-transgenic mice ex vivo and subsequently transplanted them into irradiated recipients. Furthermore, we used an in vivo HSPC transduction approach that involves HSPC mobilization and the intravenous injection of HDAd-HBG-CRISPR into β-YAC/CD46-transgenic mice. In both models, we demonstrated efficient target site disruption, resulting in a pronounced switch from human β- to γ-globin expression in red blood cells of adult mice that was maintained after secondary transplantation of HSPCs. In long-term follow-up studies, we did not detect hematological abnormalities, indicating that HBG promoter editing does not negatively affect hematopoiesis. This is the first study that shows successful in vivo HSPC genome editing by CRISPR/Cas9. |
| Volume | 131(26) |
| Pages | 2915-2928 |
| Published | 2018-6-28 |
| DOI | 10.1182/blood-2018-03-838540 |
| PII | S0006-4971(20)32118-2 |
| PMID | 29789357 |
| PMC | PMC6024639 |
| MeSH | Animals CRISPR-Cas Systems* Erythrocytes / metabolism Female Gene Editing / methods* Gene Expression* Hematopoietic Stem Cell Mobilization Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells / metabolism* Humans Mice Mice, Inbred C57BL Mice, Transgenic Promoter Regions, Genetic beta-Globins / genetics* gamma-Globins / genetics* |
| IF | 17.794 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 12 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | HUDEP-2(RCB4557) |