Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector

Lancet. 2004 Dec;364(9452):2181-7. doi: 10.1016/S0140-6736(04)17590-9.


Background: X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the common cytokine-receptor gamma chain (gamma(c)), resulting in disruption of development of T lymphocytes and natural-killer cells. B-lymphocyte function is also intrinsically compromised. Allogeneic bone-marrow transplantation is successful if HLA-matched family donors are available, but HLA-mismatched procedures are associated with substantial morbidity and mortality. We investigated the application of somatic gene therapy by use of a gibbon-ape-leukaemia-virus pseudotyped gammaretroviral vector.

Methods: Four children with SCID-X1 were enrolled. Autologous CD34-positive haemopoietic bone-marrow stem cells were transduced ex vivo and returned to the patients without preceding cytoreductive chemotherapy. The patients were monitored for integration and expression of the gamma(c) vector and for functional immunological recovery.

Findings: All patients have shown substantial improvements in clinical and immunological features, and prophylactic medication could be withdrawn in two. No serious adverse events have been recorded. T cells responded normally to mitogenic and antigenic stimuli, and the T-cell-receptor (TCR) repertoire was highly diverse. Where assessable, humoral immunity, in terms of antibody production, was also restored and associated with increasing rates of somatic mutation in immunoglobulin genes.

Interpretation: Gene therapy for SCID-X1 is a highly effective strategy for restoration of functional cellular and humoral immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD34 / analysis
  • Bone Marrow Cells / immunology
  • Bone Marrow Transplantation
  • Child, Preschool
  • Gammaretrovirus
  • Gene Transfer Techniques
  • Genetic Diseases, X-Linked / genetics
  • Genetic Diseases, X-Linked / therapy*
  • Genetic Therapy* / adverse effects
  • Genetic Therapy* / methods
  • Genetic Vectors
  • Humans
  • Immunity
  • Immunoglobulins / blood
  • Infant
  • Interleukin Receptor Common gamma Subunit
  • Lymphocyte Activation
  • Lymphocyte Culture Test, Mixed
  • Mutation
  • Receptors, Interleukin-7 / genetics
  • Severe Combined Immunodeficiency / genetics
  • Severe Combined Immunodeficiency / immunology
  • Severe Combined Immunodeficiency / therapy*
  • T-Lymphocytes / immunology
  • Transduction, Genetic


  • Antigens, CD34
  • IL2RG protein, human
  • Immunoglobulins
  • Interleukin Receptor Common gamma Subunit
  • Receptors, Interleukin-7