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Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector.
Lancet. 2004 Dec 18-31; 364(9452):2181-7.Lct

Abstract

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have shown substantial improvements in clinical and immunological features, and prophylactic medication could be withdrawn in two.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.

Authors+Show Affiliations

Molecular Immunology Unit, Institute of Child Health, University College London, London, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15610804

Citation

Gaspar, H Bobby, et al. "Gene Therapy of X-linked Severe Combined Immunodeficiency By Use of a Pseudotyped Gammaretroviral Vector." Lancet (London, England), vol. 364, no. 9452, 2004, pp. 2181-7.
Gaspar HB, Parsley KL, Howe S, et al. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet. 2004;364(9452):2181-7.
Gaspar, H. B., Parsley, K. L., Howe, S., King, D., Gilmour, K. C., Sinclair, J., Brouns, G., Schmidt, M., Von Kalle, C., Barington, T., Jakobsen, M. A., Christensen, H. O., Al Ghonaium, A., White, H. N., Smith, J. L., Levinsky, R. J., Ali, R. R., Kinnon, C., & Thrasher, A. J. (2004). Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet (London, England), 364(9452), 2181-7.
Gaspar HB, et al. Gene Therapy of X-linked Severe Combined Immunodeficiency By Use of a Pseudotyped Gammaretroviral Vector. Lancet. 2004 Dec 18-31;364(9452):2181-7. PubMed PMID: 15610804.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. AU - Gaspar,H Bobby, AU - Parsley,Kathryn L, AU - Howe,Steven, AU - King,Doug, AU - Gilmour,Kimberly C, AU - Sinclair,Joanna, AU - Brouns,Gaby, AU - Schmidt,Manfred, AU - Von Kalle,Christof, AU - Barington,Torben, AU - Jakobsen,Marianne A, AU - Christensen,Hans O, AU - Al Ghonaium,Abdulaziz, AU - White,Harry N, AU - Smith,John L, AU - Levinsky,Roland J, AU - Ali,Robin R, AU - Kinnon,Christine, AU - Thrasher,Adrian J, PY - 2004/12/22/pubmed PY - 2005/1/20/medline PY - 2004/12/22/entrez SP - 2181 EP - 7 JF - Lancet (London, England) JO - Lancet VL - 364 IS - 9452 N2 - 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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/15610804/Gene_therapy_of_X_linked_severe_combined_immunodeficiency_by_use_of_a_pseudotyped_gammaretroviral_vector_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140673604175909 DB - PRIME DP - Unbound Medicine ER -