Gene therapy for PIDs: progress, pitfalls and prospects

Gene. 2013 Aug 10;525(2):174-81. doi: 10.1016/j.gene.2013.03.098. Epub 2013 Apr 6.


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.

Keywords: ADA-SCID; CGD; DSB; EF-1α; ERT; GALV; GSH; Gene therapy; GvHD; HLA; HR; HSCT; HSCs; IFN; IL; LCR; LTR; LVs; MDS; MLV; MN; NADPH; NK cells; PEG; PGK; PID; PIDs; ROS; RVs; SAE; SCID; SCID-X1; SFFV; SIN; T cell-acute lymphoblastic leukaemia; T-ALL; TALEN; UCOE; VSV-G; WAS; WASp; Wiskott–Aldrich syndrome; Wiskott–Aldrich syndrome protein; X-linked neutropenia; X-linked severe combined immunodeficiency; X-linked thrombocytopenia; XLN; XLT; ZFN; adenosine deaminase deficiency-severe combined immunodeficiency; chronic granulomatous disorder; double strand break; elongation factor 1α; enzyme replacement therapy; genomic safe harbour; gibbon ape leukaemia virus; graft versus host disease; haematopoietic stem cell transplant; haematopoietic stem cells; homologous recombination; human leukocyte antigen; interferon; interleukin; lentiviral vectors; locus control region; long terminal repeat; meganucleases; miR; microRNA; murine leukaemia virus; myelodysplastic syndrome; natural killer cells; nicotinamide adenine dinucleotide phosphate hydrogen; phosphoglycerokinase; polyethylene glycol; primary immunodeficiency disorders; reactive oxygen species; retroviral vectors; self-inactivating; serious adverse event; spleen focus-forming virus; transcription activator-like effector nucleases; ubiquitous chromatin opening element; vesicular stomatitis virus-G protein; zinc finger nuclease.

Publication types

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

MeSH terms

  • Adenosine Deaminase / deficiency
  • Agammaglobulinemia / therapy*
  • Clinical Trials as Topic
  • Genetic Therapy / methods*
  • Granulomatous Disease, Chronic / therapy*
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / immunology
  • Humans
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / therapy*
  • Mutagenesis, Insertional
  • Severe Combined Immunodeficiency / therapy*
  • Transgenes
  • Transplantation, Autologous / methods
  • X-Linked Combined Immunodeficiency Diseases / therapy*


  • Adenosine Deaminase

Supplementary concepts

  • Severe combined immunodeficiency due to adenosine deaminase deficiency