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Gene Editing Rescues In vitro T Cell Development of RAG2-Deficient Induced Pluripotent Stem Cells in an Artificial Thymic Organoid System

  1. Author:
    Gardner, Cameron L
    Pavel-Dinu, Mara
    Dobbs, Kerry
    Bosticardo, Marita
    Reardon, Paul K
    Lack,Justin
    DeRavin, Suk See
    Le, Kent
    Bello, Ezekiel
    Pala, Francesca
    Delmonte, Ottavia M
    Malech, Harry
    Montel-Hagan, Amelie
    Crooks, Gay
    Acuto, Oreste
    Porteus, Matthew H
    Notarangelo, Luigi D [ORCID]

  2. Author Address

    Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, DIR, NIAID, NIH, 10 Center Drive, Bldg. 10 CRC, Room 5-3950, Bethesda, MD, 20892-1456, USA., Sir William Dunn School of Pathology, University of Oxford, Oxford, OX14RE, UK., Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA., NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, MD, USA., Advanced Biomedical Computational Science (ABCS), Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Sir William Dunn School of Pathology, University of Oxford, Oxford, OX14RE, UK. oreste.acuto@path.ox.ac.uk., Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA. mporteus@stanford.edu., Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, DIR, NIAID, NIH, 10 Center Drive, Bldg. 10 CRC, Room 5-3950, Bethesda, MD, 20892-1456, USA. luigi.notarangelo2@nih.gov.,
    1. Year: 2021
    2. Date: Jul
    3. Epub Date: 2021 03 01
  2. Journal: Journal of Clinical Immunology
  4. Type of Article: Article
  5. ISSN: 0271-9142
  1. Abstract:

    Severe combined immune deficiency (SCID) caused by RAG1 or RAG2 deficiency is a genetically determined immune deficiency characterized by the virtual absence of T and B lymphocytes. Unless treated with hematopoietic stem cell transplantation (HSCT), patients with RAG deficiency succumb to severe infections early in life. However, HSCT carries the risk of graft-versus-host disease. Moreover, a high rate of graft failure and poor immune reconstitution have been reported after unconditioned HSCT. Expression of the RAG genes is tightly regulated, and preclinical attempts of gene therapy with heterologous promoters have led to controversial results. Using patient-derived induced pluripotent stem cells (iPSCs) and an in vitro artificial thymic organoid system as a model, here we demonstrate that gene editing rescues the progressive T cell differentiation potential of RAG2-deficient cells to normal levels, with generation of a diversified T cell repertoire. These results suggest that targeted gene editing may represent a novel therapeutic option for correction of this immunodeficiency.

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External Sources

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  2. DOI: 10.1007/s10875-021-00989-6
  3. PMID: 33650026
  4. View record in Web of Science®
  5. WOS: 000623832300001
  6. PII : 10.1007/s10875-021-00989-6

Library Notes

  1. Fiscal Year: FY2020-2021
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