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  • Perspective
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Gene therapy for inborn errors of immunity: past, present and future

Nature Reviews Immunology volume 23, pages 397–408 (2023)Cite this article

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Abstract

Inborn errors of immunity (IEI) are diseases caused by genetic mutations that affect the immune system’s ability to fight pathogens, cope with the microbiota or regulate autoimmunity and inflammation. More than 500 IEI have been described and many are life-threatening and require curative therapy. Allogeneic haematopoietic stem cell transplantation is an increasingly effective curative strategy, and autologous transplantation of gene-modified haematopoietic stem and progenitor cells is also a treatment option. Gene therapy was first successfully used to restore T cell development in patients with severe combined immunodeficiency, with ex vivo engineered gammaretroviral vectors enabling the sustained correction of T cell immunodeficiency more than 20 years later. The generation of safer and more potent vectors has increased the efficacy and application of this therapy to other IEI, such as Wiskott–Aldrich syndrome and chronic granulomatous disease. Nevertheless, gene therapy based on gene addition has some limitations, the greatest of which is the lack of a physiological gene expression control. This Perspective summarizes the journey of the past 25 years that has led to the successful use of gene therapy for IEI and discusses the next steps for the field.

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Fig. 1: Defects in immune cell differentiation in severe combined immunodeficiencies.
Fig. 2: Timeline of key advances in gene therapy for SCID-X1.
Fig. 3: Lymphopoiesis after gene therapy for SCID-X1.
Fig. 4: Timeline of gene therapy for ADA deficiency.
Fig. 5: Timeline of progress in genome editing.

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Acknowledgements

The author thanks M. Tiouri for excellent secretarial assistance.

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Authors and Affiliations

  1. Paediatric Immuno-Hematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France

    Alain Fischer

  2. Université de Paris, Imagine Institute, Paris, France

    Alain Fischer

  3. Paris-Cité University, Inserm UMR 1163, Paris, France

    Alain Fischer

  4. Chaire de médecine experimentale, Collège de France, Paris, France

    Alain Fischer

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Fischer, A. Gene therapy for inborn errors of immunity: past, present and future. Nat Rev Immunol 23, 397–408 (2023). https://doi.org/10.1038/s41577-022-00800-6

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