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Gene Therapy for Primary Immunodeficiencies

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Abstract

Hematopoietic stem cell (HSC) gene therapy has become in the recent years an attractive therapeutic strategy for primary immunodeficiencies and other inherited disorders, offering several potential advantages over allogeneic HSC transplantation. Early-generation gammaretroviral vectors have shown important limitations and risks, with the exception of adenosine deaminase-deficient SCID (ADA-SCID), for which the cumulative experience has established the long-term efficacy and safety. Gene therapy for ADA-SCID has now become the first ex vivo HSC gene therapy approved in the European Union. Currently, self-inactivating vectors, and particularly HIV-derived lentiviral vectors, are the most used platform for genetic correction of HSC. Clinical trials for SCID-X1, Wiskott-Aldrich syndrome, and recently ADA-SCID showed sustained engraftment of gene-corrected cells, restored immune function, and general improvement of clinical condition, with a positive safety profile. Continuous monitoring will be important to confirm long-term safety and efficacy. Preclinical proof of concept has been obtained for several other primary immunodeficiencies (e.g., from deficiencies in gp91phox, Artemis, RAG1, RAG2, perforin, Munc 13-4, and FOXP3 deficiencies), with important hurdles due to requirement of highly controlled transgene expression. Recent advances in gene-editing technology may allow to further expand the applications of gene therapy to other primary immunodeficiencies.

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Authors and Affiliations

  1. San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, Milan, Italy

    Maria Pia Cicalese & Alessandro Aiuti

  2. Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Maria Pia Cicalese & Alessandro Aiuti

  3. Vita-Salute San Raffaele University, Milan, Italy

    Alessandro Aiuti

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  1. Maria Pia Cicalese
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  2. Alessandro Aiuti
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  1. Departments of Medicine and Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA

    Brahm H. Segal

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Cicalese, M.P., Aiuti, A. (2018). Gene Therapy for Primary Immunodeficiencies. In: Segal, B. (eds) Management of Infections in the Immunocompromised Host. Springer, Cham. https://doi.org/10.1007/978-3-319-77674-3_21

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