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Gene therapy for PIDs: progress, pitfalls and prospects.
Gene. 2013 Aug 10; 525(2):174-81.GENE

Abstract

Substantial progress has been made in the past decade in treating several primary immunodeficiency disorders (PIDs) with gene therapy. Current approaches are based on ex-vivo transfer of therapeutic transgene via viral vectors to patient-derived autologous hematopoietic stem cells (HSCs) followed by transplantation back to the patient with or without conditioning. The overall outcome from all the clinical trials targeting different PIDs has been extremely encouraging but not without caveats. Malignant outcomes from insertional mutagenesis have featured prominently in the adverse events associated with these trials and have warranted intense pre-clinical investigation into defining the tendencies of different viral vectors for genomic integration. Coupled with issues pertaining to transgene expression, the therapeutic landscape has undergone a paradigm shift in determining safety, stability and efficacy of gene therapy approaches. In this review, we aim to summarize the progress made in the gene therapy trials targeting ADA-SCID, SCID-X1, CGD and WAS, review the pitfalls, and outline the recent advancements which are expected to further enhance favourable risk benefit ratios for gene therapeutic approaches in the future.

Authors+Show Affiliations

Centre for Immunodeficiency, Molecular Immunology Unit, University College London Institute of Child Health, 30 Guilford Street, London WC1N1EH, UK.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

23566838

Citation

Mukherjee, Sayandip, and Adrian J. Thrasher. "Gene Therapy for PIDs: Progress, Pitfalls and Prospects." Gene, vol. 525, no. 2, 2013, pp. 174-81.
Mukherjee S, Thrasher AJ. Gene therapy for PIDs: progress, pitfalls and prospects. Gene. 2013;525(2):174-81.
Mukherjee, S., & Thrasher, A. J. (2013). Gene therapy for PIDs: progress, pitfalls and prospects. Gene, 525(2), 174-81. https://doi.org/10.1016/j.gene.2013.03.098
Mukherjee S, Thrasher AJ. Gene Therapy for PIDs: Progress, Pitfalls and Prospects. Gene. 2013 Aug 10;525(2):174-81. PubMed PMID: 23566838.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gene therapy for PIDs: progress, pitfalls and prospects. AU - Mukherjee,Sayandip, AU - Thrasher,Adrian J, Y1 - 2013/04/06/ PY - 2013/01/05/received PY - 2013/03/04/revised PY - 2013/03/07/accepted PY - 2013/4/10/entrez PY - 2013/4/10/pubmed PY - 2013/9/21/medline KW - ADA-SCID KW - CGD KW - DSB KW - EF-1α KW - ERT KW - GALV KW - GSH KW - Gene therapy KW - GvHD KW - HLA KW - HR KW - HSCT KW - HSCs KW - IFN KW - IL KW - LCR KW - LTR KW - LVs KW - MDS KW - MLV KW - MN KW - NADPH KW - NK cells KW - PEG KW - PGK KW - PID KW - PIDs KW - ROS KW - RVs KW - SAE KW - SCID KW - SCID-X1 KW - SFFV KW - SIN KW - T cell-acute lymphoblastic leukaemia KW - T-ALL KW - TALEN KW - UCOE KW - VSV-G KW - WAS KW - WASp KW - Wiskott–Aldrich syndrome KW - Wiskott–Aldrich syndrome protein KW - X-linked neutropenia KW - X-linked severe combined immunodeficiency KW - X-linked thrombocytopenia KW - XLN KW - XLT KW - ZFN KW - adenosine deaminase deficiency-severe combined immunodeficiency KW - chronic granulomatous disorder KW - double strand break KW - elongation factor 1α KW - enzyme replacement therapy KW - genomic safe harbour KW - gibbon ape leukaemia virus KW - graft versus host disease KW - haematopoietic stem cell transplant KW - haematopoietic stem cells KW - homologous recombination KW - human leukocyte antigen KW - interferon KW - interleukin KW - lentiviral vectors KW - locus control region KW - long terminal repeat KW - meganucleases KW - miR KW - microRNA KW - murine leukaemia virus KW - myelodysplastic syndrome KW - natural killer cells KW - nicotinamide adenine dinucleotide phosphate hydrogen KW - phosphoglycerokinase KW - polyethylene glycol KW - primary immunodeficiency disorders KW - reactive oxygen species KW - retroviral vectors KW - self-inactivating KW - serious adverse event KW - spleen focus-forming virus KW - transcription activator-like effector nucleases KW - ubiquitous chromatin opening element KW - vesicular stomatitis virus-G protein KW - zinc finger nuclease SP - 174 EP - 81 JF - Gene JO - Gene VL - 525 IS - 2 N2 - Substantial progress has been made in the past decade in treating several primary immunodeficiency disorders (PIDs) with gene therapy. Current approaches are based on ex-vivo transfer of therapeutic transgene via viral vectors to patient-derived autologous hematopoietic stem cells (HSCs) followed by transplantation back to the patient with or without conditioning. The overall outcome from all the clinical trials targeting different PIDs has been extremely encouraging but not without caveats. Malignant outcomes from insertional mutagenesis have featured prominently in the adverse events associated with these trials and have warranted intense pre-clinical investigation into defining the tendencies of different viral vectors for genomic integration. Coupled with issues pertaining to transgene expression, the therapeutic landscape has undergone a paradigm shift in determining safety, stability and efficacy of gene therapy approaches. In this review, we aim to summarize the progress made in the gene therapy trials targeting ADA-SCID, SCID-X1, CGD and WAS, review the pitfalls, and outline the recent advancements which are expected to further enhance favourable risk benefit ratios for gene therapeutic approaches in the future. SN - 1879-0038 UR - https://www.unboundmedicine.com/medline/citation/23566838/Gene_therapy_for_PIDs:_progress_pitfalls_and_prospects_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-1119(13)00367-3 DB - PRIME DP - Unbound Medicine ER -