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Gene Therapy for Primary Immunodeficiencies: Current Status and Future Prospects

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Abstract

Gene therapy using autologous haematopoietic stem cells offers a valuable treatment option for patients with primary immunodeficiencies who do not have access to an HLA-matched donor, although such treatments have not been without their problems. This review details gene therapy trials for X-linked and adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID), Wiskott–Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). X-linked SCID was chosen for gene therapy because of previous ‘natural’ genetic correction through a reversion event in a single lymphoid precursor, demonstrating limited thymopoiesis and restricted T-lymphocyte receptor repertoire, showing selective advantage of progenitors possessing the wild-type gene. In early studies, patients were treated with long terminal repeats-intact gamma-retroviral vectors, without additional chemotherapy. Early results demonstrated gene-transduced cells, sustained thymopoiesis, and a diverse T-lymphocyte repertoire with normal function. Serious adverse effects were subsequently reported in 5 of 20 patients, with T-lymphocyte leukaemia developing, secondary to the viral vector integrating adjacent to a known oncogene. New trials using self-inactivating gamma-retroviral vectors are progressing. Trials for ADA-SCID using gamma-retroviral vectors have been successful, with no similar serious adverse effects reported; trials using lentiviral vectors are in progress. Patients with WAS and CGD treated with early gamma-retroviral vectors have developed similar lymphoproliferative adverse effects to those seen in X-SCID—current trials are using new-generation vectors. Targeted gene insertion using homologous recombination of corrected gene sequences by cellular DNA repair pathways following targeted DNA breakage will improve efficacy and safety of gene therapy. A number of new techniques are discussed.

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Acknowledgments

Waseem Qasim is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.

Waseem Qasim and Andrew R. Gennery declare no relevant conflicts of interest. No sources of funding were used to support the writing of this manuscript.

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  1. Institute of Child Health, University College London, London, UK

    Waseem Qasim

  2. Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE4 6BE, UK

    Andrew R. Gennery

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Correspondence to Andrew R. Gennery.

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Qasim, W., Gennery, A.R. Gene Therapy for Primary Immunodeficiencies: Current Status and Future Prospects. Drugs 74, 963–969 (2014). https://doi.org/10.1007/s40265-014-0223-7

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