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Cell ; 186(7): 1398-1416.e23, 2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-36944331

RESUMO

CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3δ 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 CD3δ SCID, providing a foundation for the development of a one-time treatment for CD3δ SCID patients.


Assuntos
Imunodeficiência Combinada Severa , Linfócitos T , Humanos , Animais , Camundongos , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Edição de Genes , Camundongos SCID , Complexo CD3 , Receptores de Antígenos de Linfócitos T/genética
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