| First Author | McAuley GE | Year | 2023 |
| Journal | Cell | Volume | 186 |
| Issue | 7 | Pages | 1398-1416.e23 |
| PubMed ID | 36944331 | Mgi Jnum | J:352708 |
| Mgi Id | MGI:7450643 | Doi | 10.1016/j.cell.2023.02.027 |
| Citation | McAuley GE, et al. (2023) Human T cell generation is restored in CD3delta severe combined immunodeficiency through adenine base editing. Cell 186(7):1398-1416.e23 |
| abstractText | CD3delta SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3delta chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3delta in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3delta SCID patient's HSPCs resulted in a 71.2% +/- 7.85% (n = 3) correction of the pathogenic mutation. Edited HSPCs differentiated in artificial thymic organoids produced mature T cells exhibiting diverse TCR repertoires and TCR-dependent functions. Edited human HSPCs transplanted into immunodeficient mice showed 88% reversion of the CD3D defect in human CD34+ cells isolated from mouse bone marrow after 16 weeks, indicating correction of long-term repopulating HSCs. These findings demonstrate the preclinical efficacy of ABE in HSPCs for the treatment of CD3delta SCID, providing a foundation for the development of a one-time treatment for CD3delta SCID patients. |
