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Gene therapy of severe combined immunodeficiencies

Nature Reviews Immunology volume 2, pages 615–621 (2002)Cite this article

Abstract

The concept that the outcome of a devastating disease can be modified by inserting a transgene into abnormal cells is appealing. However, the gene-transfer technologies that are available at present have limited the success of gene therapy so far. Nevertheless, severe combined immunodeficiencies are a useful model, because gene transfer can confer a selective advantage to transduced cells. In this way, a proof of concept for gene therapy has been provided.

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Figure 1: Defects in T-cell development that result in severe combined immunodeficiencies.
Figure 2: Schemes of γ-chain-containing cytokine receptors.
Figure 3: Principle of ex vivo gene therapy of the SCID-X condition.
Figure 4: Scheme of the transduction protocol for the SCID-X gene-therapy trial.

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References

  1. Fischer, A. Primary immunodeficiencies: an experimental model for molecular medicine. Lancet 357, 1863–1869 (2001).

    CAS  PubMed  Google Scholar 

  2. Buckley, R. H. et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N. Engl. J. Med. 340, 508–516 (1999).

    CAS  PubMed  Google Scholar 

  3. Haddad, E. et al. Long-term chimerism and B-cell function after bone marrow transplantation in patients with severe combined immunodeficiency with B cells: a single center study of 22 patients. Blood 94, 2923–2930 (1999).

    CAS  PubMed  Google Scholar 

  4. Patel, D. D. et al. Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N. Engl. J. Med. 342, 1325–1332 (2000).

    CAS  PubMed  Google Scholar 

  5. Blaese, R. M. et al. T-lymphocyte-directed gene therapy for ADA-SCID: initial trial result after 4 years. Science 270, 475–480 (1995).

    CAS  PubMed  Google Scholar 

  6. Onodera, M. et al. Sucessful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency. Blood 91, 30–36 (1999).

    Google Scholar 

  7. Bordignon, C. et al. Gene therapy in peripheral-blood lymphocytes and bone marrow for ADA-immunodeficient patients: gene therapy in peripheral-blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science 270, 470–475 (1995).

    CAS  PubMed  Google Scholar 

  8. Kohn, D. B. et al. Engraftment of gene-modified umbilical-cord blood cells in neonates with adenosine deaminase deficiency. Nature Med. 10, 1017–1023 (1995).

    Google Scholar 

  9. Hoogerbrugge, P. M. et al. Bone-marrow gene transfer in three patients with adenosine deaminase deficiency. Gene Ther. 3, 179–183 (1996).

    CAS  PubMed  Google Scholar 

  10. Cavazzana-Calvo, M. et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288, 669–672 (2000).

    CAS  PubMed  Google Scholar 

  11. Giblett, E. R., Anderson, J. E., Cohen, F., Pollara, B. & Meuwissen, H. J. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet 2, 1067–1069 (1972).

    CAS  PubMed  Google Scholar 

  12. Valerio, D. et al. Cloning of human adenosine deaminase cDNA and expression in mouse cells. Gene 31, 147–153 (1984).

    CAS  PubMed  Google Scholar 

  13. Miller, A. D. Retroviral vectors. Curr. Top. Microbiol. Immunol. 158, 1–24 (1992).

    CAS  PubMed  Google Scholar 

  14. Ferrari, G. et al. An in vivo model of somatic-cell gene therapy for human severe combined immunodeficiency. Science 251, 1363–1366 (1991).

    CAS  PubMed  Google Scholar 

  15. Hersfield, M. S. Adenosine deaminase deficiency: clinical expression, molecular basis and therapy. Semin. Hematol. 4, 291–298 (1998).

    Google Scholar 

  16. Kohn, D. B. et al. T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical-cord blood CD34+ cells in ADA-deficient SCID neonates. Nature Med. 4, 775–780 (1998).

    CAS  PubMed  Google Scholar 

  17. Aiuti, F. et al. Immune reconstitution after PBL gene therapy in ADA-deficient SCID: the impact of discontinuation of enzyme replacement therapy. Nature Med. 8, 423–425 (2002).

    CAS  PubMed  Google Scholar 

  18. Blackburn, M. R., Knudsen, T. B. & Kellems, R. E. Genetically engineered mice demonstrate that adenosine deaminase is essential for early postimplantation development. Development 16, 3089–3097 (1997).

    Google Scholar 

  19. Blackburn, M. R., Datta S. K. & Kellems, R. E. Adenosine deaminase deficient mice generated using a two-stage genetic engineering strategy exhibit a combined immunodeficiency. J. Biol. Chem. 273, 5093–5098 (1998).

    CAS  PubMed  Google Scholar 

  20. Anderson, D. C. & Springer, T. A. Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1 and p150,95 glycoproteins. Annu. Rev. Med. 38, 175–194 (1987).

    CAS  PubMed  Google Scholar 

  21. Segal, B. H., Leto, T. L, Gallin, J. I., Malech, H. L. & Holland, S. M. Genetic, biochemical and clinical features of chronic granulomatous disease. Medicine 79, 170–200 (2000).

    CAS  PubMed  Google Scholar 

  22. Bauer, T. R. Jr & Hickstein, D. D. Gene therapy for leukocyte adhesion deficiency. Curr Opin. Mol. Ther. 4, 383–388 (2000).

    Google Scholar 

  23. Dinauer, M. C., Li, L. L., Bjorgvinsdottirh, H., Ding, C. & Pech, N. Long-term correction of phagocyte NADPH oxidase activity by retroviral-mediated gene transfer in murine X-inked chronic granulomatous disease. Blood 94, 914–922 (1999).

    CAS  PubMed  Google Scholar 

  24. Mardiney, M. III, Jackson, S. H., Spratt, S. K., Li, F., Holland, S. M. & Malech, H. L. Enhanced host defense after gene transfer in the murine p47 phox-deficient model of chronic granulomatous disease. Blood 89, 2268–2275 (1997).

    CAS  PubMed  Google Scholar 

  25. Bauer, T. R., Schwartz, B., Liles, W. C., Ochs, H. D. & Hickstein, D. D. Retroviral-mediated gene transfer of the leukocyte integrin CD18 into peripheral blood CD34+ cells derived from a patient with leukocyte adhesion deficiency type 1. Blood 91, 1520–1526 (1998).

    CAS  PubMed  Google Scholar 

  26. Malech, H. L. et al. Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proc. Natl Acad. Sci. USA 94, 12133–12138 (1997).

    CAS  PubMed  Google Scholar 

  27. Malech, H. L. Use of serum-free medium with fibronectin fragment enhanced transduction in a system of gas-permeable plastic containers to achieve high levels of retrovirus transduction at clinical scale. Stem Cells 18, 155–156 (2000).

    CAS  PubMed  Google Scholar 

  28. Dinauer, M. C., Lekstrom-Himes, J. A. & Dale, D. C. Inherited neutrophil disorders: molecular basis and new therapies. Hematology 303–318 (2000).

  29. Kiem, H. P. et al. Gene transfer into marrow repopulating cells: comparison between amphotropic and gibbon ape leukemia virus pseudotyped retroviral vectors in a competitive repopulation assay in baboons. Blood 90, 4638–4645 (1997).

    CAS  PubMed  Google Scholar 

  30. Hanenberg, H. et al. Colocalization of retrovirus and target cells on specific fibronectin fragments increases genetic transduction of mammalian cells. Nature Med. 2, 876–882 (1996).

    CAS  PubMed  Google Scholar 

  31. Noguchi, M. et al. Interleukin-2 receptor γ-chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73, 147–157 (1993).

    CAS  Google Scholar 

  32. Macchi, P. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377, 65–68 (1995).

    CAS  Google Scholar 

  33. Russell, S.M. et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270, 797–800 (1995).

    CAS  PubMed  Google Scholar 

  34. Puel, A, Ziegler, S. F., Buckley, R. H. & Leonard, W. J. Defective IL7Rα expression in T-B+NK+ severe combined immunodeficiency. Nature Genet. 20, 394–397 (1998).

    CAS  PubMed  Google Scholar 

  35. Leonard, W. J. Cytokines and immunodeficiency diseases. Nature Rev. Immunol. 1, 200–208 (2001).

    CAS  Google Scholar 

  36. Stephan, V. et al. Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N. Engl. J. Med. 335, 1563–1567 (1996).

    CAS  PubMed  Google Scholar 

  37. Bousso, P. 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. USA 97, 274–278 (2000).

    CAS  PubMed  Google Scholar 

  38. Bunting, K. D., Sangster, M. Y., Ihle, J. N. & Sorrentino, B. P. Restoration of lymphocyte function in Janus kinase-3-deficient mice by retroviral-mediated gene transfer. Nature Med. 4, 58–64 (1998).

    CAS  PubMed  Google Scholar 

  39. Bunting, K., Lu, T., Kelly, P. F. & Sorrentino, B. P. Self-selection by genetically modified committed lymphocyte precursors reverses the phenotype of JAK3-deficient mice without myeloblation. Hum. Gene Ther. 11, 2353–2364 (2000).

    CAS  PubMed  Google Scholar 

  40. Lo, M. et al. Restoration of lymphoid populations in a murine model of X-linked severe combined immunodeficiency by a gene-therapy approach. Blood 94, 3027–3038 (1999).

    CAS  PubMed  Google Scholar 

  41. Soudais, C. et al. Stable and functional lymphoid reconstitution of common cytokine receptor γ-chain-deficient mice by retroviral-mediated gene transfer. Blood 95, 3071–3077 (2000).

    CAS  PubMed  Google Scholar 

  42. Otsu, M. et al. Lymphoid development and function in X-linked severe combined immunodeficiency mice after stem-cell gene therapy. Mol. Ther. 1, 145–153 (2000).

    CAS  PubMed  Google Scholar 

  43. Candotti, F., Johnston, J. A., Puck, J. M., Sugamura, K., O'Shea, J. J. & Blaese, R. M. Retroviral-mediated gene correction for X-linked severe combined immunodeficiency. Blood 87, 3097–3102 (1996).

    CAS  PubMed  Google Scholar 

  44. Taylor, N. et al. Correction of interleukin-2 receptor function in X-SCID lymphoblastoid cells by retrovirally mediated transfer of the γc gene. Blood 87, 3103–3107 (1996).

    CAS  PubMed  Google Scholar 

  45. Hacein-Bey, S. et al. γc gene transfer into SCID-X1 patients' B-cell lines restores normal high-affinity interleukin-2 receptor expression and function. Blood 87, 3108–3116 (1996).

    CAS  PubMed  Google Scholar 

  46. Cavazzana-Calvo, M. 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 γc-transduced severe combined immunodeficiency X1 bone-marrow cells. Blood 88, 3901–3909 (1996).

    CAS  PubMed  Google Scholar 

  47. Hacein-Bey, S., Basile, G. D., Lemerle, J., Fischer, A. & Cavazzana-Calvo, M. γc 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 γc X-linked severe combined immunodeficiency hematopoietic progenitor cells in murine fetal thymic organ cultures. Blood 92, 4090–4097 (1998).

    CAS  PubMed  Google Scholar 

  48. Hacein-Bey-Abina, S. et al. Sustained correction of human X-linked severe combined immunodeficiency (SCID-X1) by ex vivo gene therapy. N. Engl. J. Med. 346, 1185–1193 (2002).

    CAS  PubMed  Google Scholar 

  49. Kondo, M., Weissman I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).

    CAS  Google Scholar 

  50. Hao, Q. L. et al. Identification of a novel, human multilymphoid progenitor in cord blood. Blood 12, 3683–3690 (2001).

    Google Scholar 

  51. Hirschhorn, R. et al. Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency. Nature Genet. 13, 290–295 (1996).

    CAS  PubMed  Google Scholar 

  52. Schwarz, K. et al. RAG mutations in human B-cell-negative SCID. Science 274, 97–99 (1996).

    CAS  Google Scholar 

  53. Moshous, D. et al. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105, 177–186 (2001).

    CAS  PubMed  Google Scholar 

  54. Wada, T. et al. Somatic mosaicism in Wiskott–Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proc. Natl Acad. Sci. USA 98, 8697–8702 (2001).

    CAS  PubMed  Google Scholar 

  55. Snapper, S. B. & Rosen, F. S. The Wiskott–Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Annu. Rev. Immunol. 17, 905–929 (1999).

    CAS  PubMed  Google Scholar 

  56. Sorrentino, B. P. et al. Selection of drug-resistant bone-marrow cells in vivo after retroviral transfer of human MDR-1. Science 257, 99–103 (1992).

    CAS  PubMed  Google Scholar 

  57. Bonini, C. et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276, 1719–1724 (1997).

    CAS  PubMed  Google Scholar 

  58. Qin, G. et al. Preselective gene therapy for Fabry disease. Proc. Natl Acad. Sci. USA 98, 3428–3433 (2001).

    CAS  PubMed  Google Scholar 

  59. Kelly, P. F., Vandergriff, J., Nathwani, A., Nienhuis, A. W. & Vanin, E. F. 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) enveloppe protein. Blood 96, 1206–1214 (2000).

    CAS  PubMed  Google Scholar 

  60. Halene, S. et al. Improved expression in hematopoietic and lymphoid cells in mice after transplantation of bone marrow transduced with a modified retroviral vector. Blood 10, 3349–3357 (1999).

    Google Scholar 

  61. Sadelain, M., Frassoni, F. & Riviere, I. Issues in the manufacture and transplantation of genetically modified hematopoietic stem cells. Curr. Opin. Hematol. 7, 364–377 (2000).

    CAS  PubMed  Google Scholar 

  62. May, C. et al. Therapeutic haemoglobin synthesis in β-thalassaemic mice expressing lentivrirus-encoded human β-globin. Nature 406, 82–86 (2000).

    CAS  PubMed  Google Scholar 

  63. Aiuti, A. et al. Correction of ADA-SCID by stem-cell gene therapy combined with nonmyeloablative conditioning. Science 296, 2410–2413 (2002).

    CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. INSERM U429, Hôpital Necker, 149 rue de Sèvres, Paris, 75015, France

    Alain Fischer, Salima Hacein-Bey & Marina Cavazzana-Calvo

Authors
  1. Alain Fischer
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  2. Salima Hacein-Bey
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  3. Marina Cavazzana-Calvo
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Corresponding author

Correspondence to Alain Fischer.

Related links

Related links

DATABASES

Entrez

GALV

HIV-1

Moloney murine sarcoma virus

LocusLink

ADA

Artemis

β2-integrin

CD3ɛ

CD3γ

CD24

CD34

CD45

DHFR

fibronectin

FLT3L

γc

GP91PHOX

IL-2

IL-3

IL-4

IL-7

IL-7Rα

IL-9

IL-11

IL-15

IL-21

IL-2 receptor α-chain

JAKs

JAK3

Jak3

MDR1

MGDF

NADPH oxidase

P22PHOX

P47PHOX

P67PHOX

RAG1

RAG2

SCF

STATs

WASP

ZAP70

OMIM

ADA deficiency

CGD

LAD

SCID-X

WAS

FURTHER INFORMATION

American Society of Gene Therapy

European Society for Immunodeficiencies

European Society of Gene Therapy

Glossary

BLOOD APHERESIS

The ex vivo selection of blood cells. Unwanted cells are infused back into the donor.

CDR3-SEQUENCE DETERMINATION

Sequencing of the complementarity-determining region 3 (CDR3) of rearranged T-cell receptor genes of individual T-cell clones.

COMMON LYMPHOID PROGENITOR

(CLP). A progenitor that is committed to the lymphoid lineage that can give rise to all lymphocyte subsets, including T cells, B cells and natural killer cells.

EX VIVO TRANSDUCTION

The ex vivo insertion of a transgene into cells. Cells are then placed back into the host.

V(D)J RECOMBINATION

Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of antigen-receptor-encoding genes, which leads to the repertoire diversity of both T- and B-cell receptors.

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Fischer, A., Hacein-Bey, S. & Cavazzana-Calvo, M. Gene therapy of severe combined immunodeficiencies. Nat Rev Immunol 2, 615–621 (2002). https://doi.org/10.1038/nri859

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