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Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing.
McAuley, Grace E; Yiu, Gloria; Chang, Patrick C; Newby, Gregory A; Campo-Fernandez, Beatriz; Fitz-Gibbon, Sorel T; Wu, Xiaomeng; Kang, Sung-Hae L; Garibay, Amber; Butler, Jeffrey; Christian, Valentina; Wong, Ryan L; Everette, Kelcee A; Azzun, Anthony; Gelfer, Hila; Seet, Christopher S; Narendran, Aru; Murguia-Favela, Luis; Romero, Zulema; Wright, Nicola; Liu, David R; Crooks, Gay M; Kohn, Donald B.
Afiliación
  • McAuley GE; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Yiu G; Department of Medicine, Division of Rheumatology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Chang PC; Department of Pathology & Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Newby GA; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
  • Campo-Fernandez B; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Fitz-Gibbon ST; Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Wu X; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Kang SL; Department of Pathology & Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Garibay A; Department of Pathology & Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Butler J; Department of Pathology & Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Christian V; Department of Pathology & Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Wong RL; Department of Molecular & Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Everette KA; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
  • Azzun A; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Gelfer H; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Seet CS; Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles,
  • Narendran A; Department of Pediatrics, University of Calgary, Calgary, AB T2N 1N4, Canada.
  • Murguia-Favela L; Department of Pediatrics, University of Calgary, Calgary, AB T2N 1N4, Canada.
  • Romero Z; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Wright N; Department of Pediatrics, University of Calgary, Calgary, AB T2N 1N4, Canada.
  • Liu DR; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
  • Crooks GM; Department of Pathology & Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los An
  • Kohn DB; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular & Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Pediatric Hematology-Oncology, Univer
Cell ; 186(7): 1398-1416.e23, 2023 03 30.
Article en En | MEDLINE | ID: mdl-36944331
ABSTRACT
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Linfocitos T / Inmunodeficiencia Combinada Grave Idioma: En Revista: Cell Año: 2023 Tipo del documento: Article
Texto completo
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Linfocitos T / Inmunodeficiencia Combinada Grave Idioma: En Revista: Cell Año: 2023 Tipo del documento: Article