Gene Therapy for Primary Immunodeficiencies: Current Status and Future Prospects

• Published in: Drugs (New York, N.Y.) Vol. 74; no. 9; pp. 963 - 969
• Main Authors: Qasim, Waseem, Gennery, Andrew R.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2014; Springer Nature B.V
• Subjects: Chemotherapy; Disease; Gene therapy; Genetic Therapy - methods; Genetic Therapy - trends; Hematopoietic Stem Cell Transplantation; Humans; Immune system; Immunoglobulins; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - therapy; Infections; Internal Medicine; Leading Article; Leukemia; Lymphocyte receptors; Lymphocytes; Medicine; Medicine & Public Health; Pharmacology/Toxicology; Pharmacotherapy; Stem cells; Steroids; Transplantation, Autologous; Vaccines; Vectors (Biology); Viral infections; Enzyme Replacement Therapy; Chronic Granulomatous Disease; Gene Therapy Trial; Haematopoietic Stem Cell Transplantation; Long Terminal Repeat
• ISSN: 0012-6667; 1179-1950
• DOI: 10.1007/s40265-014-0223-7

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.