Human T cell generation is restored in CD3 delta severe combined immunodeficiency through adenine base editing

CD3 delta SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3 delta chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3 delta in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3 delta 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 CD3 delta SCID, providing a foundation for the development of a one-time treatment for CD3 delta SCID patients.

Automated summary

CD3 delta SCID is a genetic disorder caused by mutations in the CD3D gene. Researchers have developed an adenine base editing strategy to correct the CD3D mutation in patients' own hematopoietic stem and progenitor cells. The edited cells can differentiate into functional T cells, providing a potential treatment for CD3 delta SCID.