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

• Published in: Nature reviews. Immunology Vol. 23; no. 6; pp. 397 - 408
• Main Author: Fischer, Alain
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2023; Nature Publishing Group
• Subjects: 631/250/2152; 692/699/249/1570; Autoimmunity; Biomedical and Life Sciences; Biomedicine; Chronic granulomatous disease; Gene therapy; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunology; Lymphocytes T; Perspective; Progenitor cells; Severe combined immunodeficiency; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - metabolism; Severe Combined Immunodeficiency - therapy; Stem cell transplantation; Stem cells; Wiskott-Aldrich syndrome; Wiskott-Aldrich Syndrome - genetics; Wiskott-Aldrich Syndrome - therapy
• ISSN: 1474-1733; 1474-1741
• DOI: 10.1038/s41577-022-00800-6

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. In this Perspective, Alain Fischer reflects on the development of gene therapy for patients with inborn errors of immunity. He discusses the challenges the field has faced as well as the progress seen in the past 25 years.