Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Gene Therapy of X-Linked Severe Combined Immunodeficiency

  • 149 Accesses

  • 40 Citations


Severe combined immunodeficiency (SCID) conditions appear to be the best possible candidates for a gene therapy approach. Transgene expression by lymphocyte precursors should confer to these cells a selective growth advantage that gives rise to long-lived T-lymphocytes. This rationale was used as a basis for a clinical trial of the SCID-X1 disorder caused by common γ (γc) gene mutations. This trial consists of ex vivo retroviral-mediated (MFG-B2 γc vector) γc gene transfer into marrow CD34+ cells in CH-296 fibronectin fragment—coated bags. Up to now, 9 patients with typical SCID-X1 diagnosed within the first year of life and lacking an HLA-identical donor have been enrolled. More than 2 years’ assessment of 5 patients and more than 1 year for 7 patients provide evidence for full development of functional, mature T-cells in the absence of any adverse effects. Functional transduced natural killer cells are also detectable, although in low numbers. All but 1 patient with T-cell immunity have also developed immunoglobulin production, which has alleviated the need for intravenous immunoglobulin substitution despite a low detection frequency of transduced B-cells. These 8 patients are doing well and living in a normal environment. This yet successful gene therapy demonstrates that in a setting where transgene expression provides a selective advantage, a clinical benefit can be expected.Int J Hematol. 2002;76:295-298.

This is a preview of subscription content, log in to check access.


  1. 1.

    Halene S, Kohn DB. Gene therapy using hematopoietic stem cells: Sisyphus approaches the crest.Hum Gene Ther. 2000;11:1259–1267.

  2. 2.

    Williams DA, Smith FO. Progress in the use of gene transfer methods to treat genetic blood diseases.Hum Gene Ther. 2000;11: 2059–2066.

  3. 3.

    Hanenberg H, Xiao XL, Dilloo D, Hashino K, Kato I,Williams DA. Colocalization of retrovirus and target cells on specific fibronectin fragments increases genetic transduction of mammalian cells.Nat Med. 1996;2:876–882.

  4. 4.

    Kelly PF,Vandergriff J, Nathwani A, Nienhuis AW,Vanin EF. Highly efficient gene transfer into cord blood nonobese diabetic/severe combined immunodeficiency repopulating cells by oncoretroviral vector particles pseudotyped with the feline endogenous retrovirus (RD114) envelope protein.Blood. 2000;96:1206–1214.

  5. 5.

    Noguchi M, Nakamura Y, Russell SM, et al. Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor.Science. 1993;262:1877–1880.

  6. 6.

    Sugamura K, Asao H, Kondo M, et al. The common gamma-chain for multiple cytokine receptors.Adv Immunol. 1995;59:225–277.

  7. 7.

    Parrish-Novak J, Dillon SR, Nelson A, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function.Nature. 2000;408:57–63.

  8. 8.

    von Freeden-Jeffry U, Viera P, Lucian LA, McNeil T, Burdach SE, Murray R. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.J Exp Med. 1995;181: 1519–1526.

  9. 9.

    Di Santo JP, Kuhn R, Muller W. Common cytokine receptor gamma chain (gamma c)-dependent cytokines: understanding in vivo functions by gene targeting.Immunol Rev. 1995;148:19–34.

  10. 10.

    Fischer A. Thirty years of bone marrow transplantation for severe combined immunodeficiency.N Engl J Med. 1999;340:559–561.

  11. 11.

    Buckley RH, Schriff SE, Schriff RI, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.N Engl J Med. 1999;340:508–516.

  12. 12.

    Johnston JA, Bacon CM, Riedy MC, O’Shea JJ. Signaling by IL-2 and related cytokines: JAKs, STATs, and relationship to immunodeficiency.J Leukoc Biol. 1996;60:441–452.

  13. 13.

    Bousso P, Wahn V, Douagi I, et al. Diversity, functionality, and stability of the T cell repertoire derived in vivo from a single human T cell precursor.Proc Natl Acad Sci U S A. 2000;97:274–278.

  14. 14.

    Hacein-Bey S, Cavazzana-Calvo M, Le Deist F, et al. gamma-c gene transfer into SCID X1 patients’ B-cell lines restores normal highaffinity interleukin-2 receptor expression and function.Blood. 1996;87:3108–3116.

  15. 15.

    Hacein-Bey S, Basile GD, Lemerle J, Fischer A, Cavazzana-Calvo M. Gammac gene transfer in the presence of stem cell factor, FLT-3L, interleukin-7 (IL-7), IL-1, and IL-15 cytokines restores T-cell differentiation from gammac(-) X-linked severe combined immunodeficiency hematopoietic progenitor cells in murine fetal thymic organ cultures.Blood. 1998;92:4090–4097.

  16. 16.

    Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al. Role of interleukin-2 (IL-2), IL-7, and IL-15 in natural killer cell differentiation from cord blood hematopoietic progenitor cells and from gamma c transduced severe combined immunodeficiency X1 bone marrow cells.Blood. 1996;88:3901–3909.

  17. 17.

    Soudais C, Shiho T, Sharara LI, et al. Stable and functional lymphoid reconstitution of common cytokine receptor gamma chain deficient mice by retroviral-mediated gene transfer.Blood. 2000; 95:3071–3077.

  18. 18.

    Lo M, Bloom ML, Imada K, et al. Restoration of lymphoid populations in a murine model of X-linked severe combined immunodeficiency by a gene-therapy approach.Blood. 1999;94:3027–3036.

  19. 19.

    Bunting KD, Sangster MY, Ihle JN, Sorrentino BP. Restoration of lymphocyte function in Janus kinase 3-deficient mice by retroviralmediated gene transfer.Nat Med. 1998;4:58–64.

  20. 20.

    Bunting KD, Lu T, Kelly PF, Sorrentino BP. Self-selection by genetically modified committed lymphocyte precursors reverses the phenotype of JAK3-deficient mice without myeloablation.Hum Gene Ther. 2000;11:2353–2364.

  21. 21.

    Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1disease. Science. 2000;288:669–672.

  22. 22.

    Hacein-Bey-Abina S, Le Deist F, Carlier F, et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.N Engl J Med. 2002;346:1185–1193.

  23. 23.

    Otsu M, Sugamura K, Candotti F. Lack of dominant-negative effects of a truncated gamma(c) on retroviral-mediated gene correction of immunodeficient mice.Blood. 2001;97:1618–1624.

  24. 24.

    Kong F, Chen CH, Cooper MD. Thymic function can be accurately monitored by the level of recent T cell emigrants in the circulation.Immunity. 1998;8:97–104.

  25. 25.

    Douek DC, McFarland RD, Keiser PH, et al. Changes in thymic function with age and during the treatment of HIV infection.Nature. 1998;396:690–695.

  26. 26.

    Haddad E, Le Deist F, Aucouturier P, et al. Long-term chimerism and B-cell function after bone marrow transplantation in patients with severe combined immunodeficiency with B cells: a single-cen- ter study of 22 patients.Blood. 1999;94:2923–2930.

  27. 27.

    Izuhara K, Heike T, Otsuka T, et al. Signal transduction pathway of interleukin-4 and interleukin-13 in human B cells derived from X- linked severe combined immunodeficiency patients.J Biol Chem. 1996;271:619–622.

  28. 28.

    White H, Thrasher A, Veys P, Kinnon C, Gaspar HB. Intrinsic defects of B cell function in X-linked severe combined immunodeficiency.Eur J Immunol. 2000;30:732–737.

  29. 29.

    Haddad E, Landais P, Friedrich W, et al. Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients.Blood. 1998; 91:3646–3653.

Download references

Author information

Correspondence to Salima Hacein-Bey-Abina or Alain Fischer or Marina Cavazzana-Calvoa.

About this article

Cite this article

Hacein-Bey-Abina, S., Fischer, A. & Cavazzana-Calvoa, M. Gene Therapy of X-Linked Severe Combined Immunodeficiency. Int J Hematol 76, 295–298 (2002). https://doi.org/10.1007/BF02982686

Download citation

Key words

  • Gene transfer
  • γc Chain
  • SCID-X1
  • Selective advantage
  • Retroviral vector