| First Author | Li C | Year | 2023 |
| Journal | Blood | Volume | 141 |
| Issue | 17 | Pages | 2085-2099 |
| PubMed ID | 36800642 | Mgi Jnum | J:354656 |
| Mgi Id | MGI:7471269 | Doi | 10.1182/blood.2022018252 |
| Citation | Li C, et al. (2023) In vivo HSC prime editing rescues sickle cell disease in a mouse model. Blood 141(17):2085-2099 |
| abstractText | Sickle cell disease (SCD) is a monogenic disease caused by a nucleotide mutation in the beta-globin gene. Current gene therapy studies are mainly focused on lentiviral vector-mediated gene addition or CRISPR/Cas9-mediated fetal globin reactivation, leaving the root cause unfixed. We developed a vectorized prime editing system that can directly repair the SCD mutation in hematopoietic stem cells (HSCs) in vivo in a SCD mouse model (CD46/Townes mice). Our approach involved a single intravenous injection of a nonintegrating, prime editor-expressing viral vector into mobilized CD46/Townes mice and low-dose drug selection in vivo. This procedure resulted in the correction of approximately 40% of betaS alleles in HSCs. On average, 43% of sickle hemoglobin was replaced by adult hemoglobin, thereby greatly mitigating the SCD phenotypes. Transplantation in secondary recipients demonstrated that long-term repopulating HSCs were edited. Highly efficient target site editing was achieved with minimal generation of insertions and deletions and no detectable off-target editing. Because of its simplicity and portability, our in vivo prime editing approach has the potential for application in resource-poor countries where SCD is prevalent. |
