| First Author | Li C | Year | 2022 |
| Journal | JCI Insight | Volume | 7 |
| Issue | 19 | PubMed ID | 36006707 |
| Mgi Jnum | J:331794 | Mgi Id | MGI:7387615 |
| Doi | 10.1172/jci.insight.162939 | Citation | Li C, et al. (2022) In vivo base editing by a single i.v. vector injection for treatment of hemoglobinopathies. JCI Insight 7(19) |
| abstractText | Individuals with beta-thalassemia or sickle cell disease and hereditary persistence of fetal hemoglobin (HPFH) possessing 30% fetal hemoglobin (HbF) appear to be symptom free. Here, we used a nonintegrating HDAd5/35++ vector expressing a highly efficient and accurate version of an adenine base editor (ABE8e) to install, in vivo, a -113 A>G HPFH mutation in the gamma-globin promoters in healthy CD46/beta-YAC mice carrying the human beta-globin locus. Our in vivo hematopoietic stem cell (HSC) editing/selection strategy involves only s.c. and i.v. injections and does not require myeloablation and HSC transplantation. In vivo HSC base editing in CD46/beta-YAC mice resulted in > 60% -113 A>G conversion, with 30% gamma-globin of beta-globin expressed in 70% of erythrocytes. Importantly, no off-target editing at sites predicted by CIRCLE-Seq or in silico was detected. Furthermore, no critical alterations in the transcriptome of in vivo edited mice were found by RNA-Seq. In vitro, in HSCs from beta-thalassemia and patients with sickle cell disease, transduction with the base editor vector mediated efficient -113 A>G conversion and reactivation of gamma-globin expression with subsequent phenotypic correction of erythroid cells. Because our in vivo base editing strategy is safe and technically simple, it has the potential for clinical application in developing countries where hemoglobinopathies are prevalent. |
