Gene therapy for severe combined immunodeficiencies and beyond

J Exp Med. 2020 Jan 6;217(2):e20190607. doi: 10.1084/jem.20190607.


Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine deaminase (ADA) deficiency. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural gene therapy. Nevertheless, the first attempts of gene therapy for SCID X1 were associated with insertional mutagenesis causing leukemia, because the viral enhancer induced transactivation of oncogenes. Removal of this element and use of a promoter instead led to safer but still efficacious gene therapy. It was observed that a fully diversified T cell repertoire could be generated by a limited set (<1,000) of progenitor cells. Further advances in gene transfer technology, including the use of lentiviral vectors, has led to success in the treatment of Wiskott-Aldrich syndrome, while further applications are pending. Genome editing of the mutated gene may be envisaged as an alternative strategy to treat SCID diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine Deaminase / deficiency*
  • Agammaglobulinemia / therapy*
  • Animals
  • Gene Editing
  • Gene Transfer Techniques
  • Genetic Therapy / adverse effects
  • Genetic Therapy / methods*
  • Genetic Vectors / genetics
  • Humans
  • Interleukin Receptor Common gamma Subunit / genetics
  • Leukemia / etiology
  • Mutagenesis, Insertional / methods
  • Mutation, Missense
  • Retroviridae / genetics
  • Severe Combined Immunodeficiency / therapy*
  • T-Lymphocytes / immunology
  • Wiskott-Aldrich Syndrome / therapy*
  • X-Linked Combined Immunodeficiency Diseases / therapy*


  • IL2RG protein, human
  • Interleukin Receptor Common gamma Subunit
  • Adenosine Deaminase

Supplementary concepts

  • Severe combined immunodeficiency due to adenosine deaminase deficiency