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Correction of Genetic Blood Defects by Gene Transfer

  • Marina Cavazzana-Calvo
  • Salima Hacein-Bey-Abina
  • Adrian J. Thrasher
  • Philippe Leboulch
  • Alain Fischer

Abstract

Gene therapy has been proposed as an appealing tool for introducing a normal gene into affected hematopoietic stem cells to correct their inherited defect. Theoretically, in the absence of a related human leukocyte antigen identical donor, gene therapy could be an alternative given the accessibility and the information available on the hematopoietic stem cell biology. This chapter describes the progress and limits of the gene therapy approach applied to some genetic blood defects that appear to be good targets for this strategy.

Key Words

ADA Fanconi anemia gene therapy hematopoietic SCD SCID 

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Selected References

  1. Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 2002;296:2410–2413.PubMedCrossRefGoogle Scholar
  2. Aiuti A, Vai S, Mortellaro A, et al. Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat Med 2002;8:423–425.PubMedCrossRefGoogle Scholar
  3. Antoine C, Muller S, Cant A, et al. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99. Lancet 2003;361:553–560.PubMedCrossRefGoogle Scholar
  4. Badour K, Zhang J, Siminovitch KA. The Wiskott-Aldrich syndrome protein: forging the link between actin and cell activation. Immunol Rev 2003; 192: 98–112.PubMedCrossRefGoogle Scholar
  5. Blaese RM, Culver KW, Miller AD, et al. T lymphocyte-directed gene therapy for ADA-SCID: Initial trial results after 4 years. Science 1995; 270: 475–480.PubMedCrossRefGoogle Scholar
  6. Bordignon C, Notarangelo LD, Nobili N, et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science 1995; 270: 470–475.PubMedCrossRefGoogle Scholar
  7. Buckley RH, Schiff SE, Schiff RI, et al. Haploidentical bone marrow stem cell transplantation in human severe combined immunodeficiency. SeminHematol 1993; 30: 92–104.Google Scholar
  8. Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999; 340: 508–516.PubMedCrossRefGoogle Scholar
  9. Bunting KD, Sangster MY, Ihle JN, Sorrentino BP. Restoration of lymphocyte function in Janus kinase 3-deficient mice by retroviral-mediated gene transfer. Nat Med 1998; 4: 58–64.PubMedCrossRefGoogle Scholar
  10. Candotti F, Facchetti F, Blanzuoli L, Stewart DM, Nelson DL, Blaese RM. Retrovirus-mediated WASP gene transfer corrects defective actin polymerization in B cell lines from Wiskott-Aldrich syndrome patients carrying’ null’ mutations. Gene Ther 1999; 6: 1170–1174.PubMedCrossRefGoogle Scholar
  11. Candotti F, Johnston JA, Puck JM, Sugamura K, O’ Shea JJ, Blaese RM. Retroviral-mediated gene correction for X-linked severe combined immunodeficiency. Blood 1996; 87: 3097–3102.PubMedGoogle Scholar
  12. Candotti F, Notarangelo L, Visconti R, O’ Shea J. Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways. J Clin Invest 2002; 109: 1261–1269.PubMedCrossRefGoogle Scholar
  13. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al. Role of inter-leukin-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.PubMedGoogle Scholar
  14. Devriendt K, Kim AS, Mathijs G, et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet 2001; 27: 313–317.PubMedCrossRefGoogle Scholar
  15. Fischer A, Cavazzana-Calvo M, De Saint Basile G, et al. Naturally occurring primary deficiencies of the immune system. Annu Rev Immunol 1997; 15: 93–124.PubMedCrossRefGoogle Scholar
  16. Galimi F, Noll M, Kanazawa Y, et al. Gene therapy of Fanconi anemia: Preclinical efficacy using lentiviral vectors. Blood 2002; 100: 2732–2736.PubMedCrossRefGoogle Scholar
  17. Gregory JJ Jr, Wagner JE, Verlander PC, et al. Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lympho-hematopoietic stem cells. Proc Natl Acad Sci USA 2001;98: 2532–2537.PubMedCrossRefGoogle Scholar
  18. Grompe M, D’Andrea A. Fanconi anemia and DNA repair. Hum Mol Genet 2001; 10: 2253–2259.PubMedCrossRefGoogle Scholar
  19. Hacein-Bey H, Cavazzana-Calvo M, Le Deist F, et al. gamma-c gene transfer into SCID X1 patients’ B-cell lines restores normal high-affinity interleukin-2 receptor expression and function. Blood 1996; 87: 3108–3116.PubMedGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003; 348: 255–256.PubMedCrossRefGoogle Scholar
  22. 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-center study of 22 patients. Blood 1999; 94: 2923–2930.PubMedGoogle Scholar
  23. Hershfield MS. Adenosine deaminase deficiency: clinical expression, molecular basis, and therapy. Semin Hematol 1998; 35: 291–298.PubMedGoogle Scholar
  24. Hoogerbrugge PM, van Beusechem VW, Fischer A, et al. Bone marrow gene transfer in three patients with adenosine deaminase deficiency. Gene Ther 1996; 3: 179–183.PubMedGoogle Scholar
  25. Howlett NG, Taniguchi T, Olson S, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 2002; 297: 606–609.PubMedCrossRefGoogle Scholar
  26. Imren S, Payen E, Westerman KA, et al. Permanent and panerythroid correction of murine beta thalassemia by multiple lentiviral integration in hematopoietic stem cells. Proc Natl Acad Sci USA 2002; 99: 14, 380–14,385.CrossRefGoogle Scholar
  27. Joenje H, Patel The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet 2001; 2: 446–457.PubMedCrossRefGoogle Scholar
  28. Jones GE, Zicha Dunn GA, Blundell M, Thrasher A. Restoration of podosomes and chemotaxis in Wiskott-Aldrich syndrome macro-phages following induced expression of WASp. Int J Biochem Cell Biol 2002; 34:806–815.PubMedCrossRefGoogle Scholar
  29. Kalberer CP, Pawliuk R, Imren S, et al. Preselection of retrovirally transduced bone marrow avoids subsequent stem cell gene silencing and age-dependent extinction of expression of human beta-globin in engrafted mice. Proc Natl Acad Sci USA 2000; 97: 5411–5415.PubMedCrossRefGoogle Scholar
  30. Klein C, Nguyen D, Liu CH, et al. Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in ice. Blood 2003; 101: 2159–2166.PubMedCrossRefGoogle Scholar
  31. Kohn DB, Hershfield MS, Carbonaro D, et al. T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autolo-ai]gous umbilical cord blood CD34+cells in ADA-deficient SCID neonates. Nat Med 1998; 4: 775–780.PubMedCrossRefGoogle Scholar
  32. Koka R, Burkett PR, Chien M, et al. Interleukin (IL)-15R[alpha]-deficient natural killer cells survive in normal but not IL-15R[alpha]-deficient mice. J Exp Med 2003; 197: 977–984.PubMedCrossRefGoogle Scholar
  33. Kutler DI, Singh B, Satagopan J, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 2003; 101: 1249–1256.PubMedCrossRefGoogle Scholar
  34. Lacout C, Haddad E, Sabri S, et al. A defect in hematopoietic stem cell migration explains the non-random X-chromosome inactivation in carriers of Wiskott-Aldrich syndrome. Blood 2003; 1:1.Google Scholar
  35. Leboulch P, Huang GM, Humphries RK, et al. Mutagenesis of retroviral vectors transducing human beta-globin gene and beta-globin locus control region derivatives results in stable transmission of an active transcriptional structure. EMBO J 1994; 13: 3065–3076.PubMedGoogle Scholar
  36. Marchand JB, Kaiser DA, Pollard TD, Higgs HN. Interaction of WASP/Scar proteins with actin and vertebrate Arp2/3 complex. Nat Cell Biol 2001; 3: 76–82.PubMedCrossRefGoogle Scholar
  37. May C, Rivella S, Callegari J, et al. Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. Nature 2000; 406: 82–86.PubMedCrossRefGoogle Scholar
  38. May C, Rivella S, Chadburn A, Sadelain M. Successful treatment of murine beta-thalassemia intermedia by transfer of the human beta-globin gene. Blood 2002; 99: 1902–1908.PubMedCrossRefGoogle Scholar
  39. Moshous D, Callebaut I, de Chasseval R, et al. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 2001; 105: 177–186.PubMedCrossRefGoogle Scholar
  40. Otsu M, Anderson SM, Bodine DM, Puck JM, O’Shea JJ, Candotti F. Lymphoid development and function in X-linked severe combined immunodeficiency mice after stem cell gene therapy. Mol Ther 2000; 1: 145–153.PubMedCrossRefGoogle Scholar
  41. Pawliuk R, Westerman KA, Fabry ME, et al. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science 2001; 294: 2368–2371.PubMedCrossRefGoogle Scholar
  42. Persons DA, Allay ER, Sawai N, et al. Successful treatment of murine ta-thalassemia using in vivo selection of genetically modified, drug-resistant hematopoietic stem cells. Blood 2003; 102: 506–513.Google Scholar
  43. Prlic M, Blazar BR, Farrar MA, Jameson SC. In vivo survival and homeo-static proliferation of natural killer cells. J Exp Med 2003; 197: 967–976.PubMedCrossRefGoogle Scholar
  44. Rabbitts TH. Chromosomal translocation master genes, mouse models and experimental therapeutics. Oncogene 2001; 20: 5763–5777.PubMedCrossRefGoogle Scholar
  45. Rivella S, Sadelain M. Genetic treatment of severe hemoglobinopathies: The combat against transgene variegation and transgene silencing. SeminHematol 1998; 35: 112–125.Google Scholar
  46. Rivella S, May C, Chadburn A, Riviere I, Sadelain M. A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human beta-globin gene transfer. Blood 2003;101: 2932–2939.PubMedCrossRefGoogle Scholar
  47. Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood 2003; 101: 822–826.PubMedCrossRefGoogle Scholar
  48. Sadelain M, Wang CH, Antoniou M, Grosveld F, Mulligan RC. Generation of a high-titer retroviral vector capable of expressing high levels of the human beta-globin gene. Proc Natl Acad Sci USA 1995; 92: 6728–6732.PubMedCrossRefGoogle Scholar
  49. Samakoglu S, Fattori E, Lamartina S, et al. betaMinor-globin messenger RNA accumulation in reticulocytes governs improved erythropoiesis in beta thalassemic mice after erythropoietin complementary DNA electrotransfer in muscles. Blood 2001; 97: 2213–2220.PubMedCrossRefGoogle Scholar
  50. Sarzotti M, Patel DD, Li X, et al. T cell repertoire development in humans with SCID after nonablative allogeneic marrow transplantation. J Immunol 2003; 170: 2711–2718.PubMedGoogle Scholar
  51. Snapper SB, Rosen FS. The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Annu Rev Immunol 1999; 17::905–929PubMedCrossRefGoogle Scholar
  52. Snapper SB, Rosen FS, Mizogiuti A, Slavin SGoogle Scholar
  53. uchi E, et al. Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell acti-vation. Immunity 1998; 9: 81-Bunting KD,91.Google Scholar
  54. 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.PubMedGoogle Scholar
  55. Strom TS, Gabbard W, Kelly PF, Cunningham JM, Nienhuis AW. Functional correction of T cells derived from patients with the Wiskott-Aldrich syndrome (WAS) by transduction with an oncoretro-viral vector encoding the WAS protein. Gene Ther 2003; 10: 803–809.PubMedCrossRefGoogle Scholar
  56. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitu-tional survey of the Wiskott-Aldrich syndrome. J Pediatr 1994; 125: 876–885.PubMedCrossRefGoogle Scholar
  57. Thrasher AJ. WASp in immune-system organization and function. Nat Rev Immunol 2002; 2: 635–646.PubMedCrossRefGoogle Scholar
  58. Wada T, Jagadeesh GJ, Nelson DL, Candotti F. Retrovirus-mediated WASP gene transfer corrects Wiskott-Aldrich syndrome T-cell dysfunction. Hum Gene Ther 2002; 13: 1039–1046.PubMedCrossRefGoogle Scholar
  59. Wada T, Konno A, Schurman SH, et al. Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings J Clin Invest 2003; 111: 1389–1397.PubMedCrossRefGoogle Scholar
  60. Wada T, Schurman SH, Otsu M, et al. Somatic mosaicism in WiskottAldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proc Natl Acad Sci USA 2001; 98: 8697–8702.PubMedCrossRefGoogle Scholar
  61. Yates F, Malassis-Seris M, Stockholm D, et al. Gene therapy of RAG-2-/-mice: Sustained correction of the immunodeficiency. Blood 2002; 100: 3942–3949.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2006

Authors and Affiliations

  • Marina Cavazzana-Calvo
    • 1
  • Salima Hacein-Bey-Abina
    • 1
  • Adrian J. Thrasher
    • 2
  • Philippe Leboulch
    • 3
  • Alain Fischer
    • 4
  1. 1.Department of Biotherapy AP-HPHôpital NeckerParisFrance
  2. 2.Molecular Immunology UnitInstitute of Child HealthLondonUK
  3. 3.Harvard Medical School and Genetics DivisionBrigham and Women’s HospitalBoston
  4. 4.Unité d’Immunologie et d’Hématologie PédiatriquesHôpital NeckerParisFrance

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