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Gene Therapy for Primary Immunodeficiencies

  • Maria Pia Cicalese
  • Alessandro Aiuti
Chapter

Abstract

Hematopoietic stem cell (HSC) gene therapy has become in the recent years an attractive therapeutic strategy for primary immunodeficiencies and other inherited disorders, offering several potential advantages over allogeneic HSC transplantation. Early-generation gammaretroviral vectors have shown important limitations and risks, with the exception of adenosine deaminase-deficient SCID (ADA-SCID), for which the cumulative experience has established the long-term efficacy and safety. Gene therapy for ADA-SCID has now become the first ex vivo HSC gene therapy approved in the European Union. Currently, self-inactivating vectors, and particularly HIV-derived lentiviral vectors, are the most used platform for genetic correction of HSC. Clinical trials for SCID-X1, Wiskott-Aldrich syndrome, and recently ADA-SCID showed sustained engraftment of gene-corrected cells, restored immune function, and general improvement of clinical condition, with a positive safety profile. Continuous monitoring will be important to confirm long-term safety and efficacy. Preclinical proof of concept has been obtained for several other primary immunodeficiencies (e.g., from deficiencies in gp91 phox , Artemis, RAG1, RAG2, perforin, Munc 13-4, and FOXP3 deficiencies), with important hurdles due to requirement of highly controlled transgene expression. Recent advances in gene-editing technology may allow to further expand the applications of gene therapy to other primary immunodeficiencies.

Keywords

Gene therapy Primary immunodeficiency SCID-X1 Adenosine-deaminase deficiency Wiskott-Aldrich syndrome Chronic granulomatous disease Retrovirus Lentivirus 

References

  1. 1.
    Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014;46(2):154–68.PubMedCrossRefGoogle Scholar
  2. 2.
    Fischer A, Hacein-Bey Abina S, Touzot F, et al. Gene therapy for primary immunodeficiencies. Clin Genet. 2015;88:507–15.PubMedCrossRefGoogle Scholar
  3. 3.
    Al-Herz W, Bousfiha A, Casanova JL, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011;8:2–54.Google Scholar
  4. 4.
    Zhang L, Thrasher AJ, Gaspar HB. Current progress on gene therapy for primary immunodeficiencies. Gene Ther. 2013;20:963–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Mukherjee S, Thrasher AJ. Gene therapy for PIDs: progress, pitfalls and prospects. Gene. 2013;525:174–81.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Bousfiha AA, Jeddane L, Ailal F, et al. Primary immunodeficiency diseases worldwide: more common than generally thought. J Clin Immunol. 2013;33(1):1–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Pachlopnik Schmid J, Gungor T, Seger R. Modern management of primary T-cell immunodeficiencies. Pediatr Allergy Immunol. 2014;25(4):300–13.PubMedCrossRefGoogle Scholar
  8. 8.
    Griffith LM, Cowan MJ, Notarangelo LD, et al. Primary immune deficiency treatment consortium (PIDTC) report. J Allergy Clin Immunol. 2014;133(2):335–47.PubMedCrossRefGoogle Scholar
  9. 9.
    Hernandez-Trujillo HS, Chapel H, Lo Re V 3rd, et al. Comparison of American and European practices in the management of patients with primary immunodeficiencies. Clin Exp Immunol. 2012;169(1):57–69.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Modell V1, Knaus M, Modell F, et al. Global overview of primary immunodeficiencies: a report from Jeffrey Modell Centers worldwide focused on diagnosis, treatment, and discovery. Immunol Res. 2014;60(1):132–44.PubMedCrossRefGoogle Scholar
  11. 11.
    Casanova JL, Conley ME, Seligman SJ, et al. Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies. J ExpMed. 2014;211(11):2137–49.CrossRefGoogle Scholar
  12. 12.
    Chinen J, Notarangelo LD, Shearer WT. Advances in basic and clinical immunology in 2013. J Allergy Clin Immunol. 2014;133(4):967–76.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Somech R, Lev A, Simon AJ, et al. Newborn screening for severe T and B cell immunodeficiency in Israel: a pilot study. Isr Med Assoc J. 2013;15(8):404–9.PubMedGoogle Scholar
  14. 14.
    Audrain M, Thomas C, Mirallie S, et al. Evaluation of the T-cell receptor excision circle assay performances for severe combined immunodeficiency neonatal screening on Guthrie cards in a French single centre study. Clin Immunol. 2014;150(2):137–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Borte S, von Dobeln U, Fasth A, et al. Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood. 2012;119(11):2552–5.PubMedCrossRefGoogle Scholar
  16. 16.
    la Marca G, Malvagia S, Casetta B, et al. Progress in expanded newborn screening for metabolic conditions by LC–MS/MS in Tuscany: update on methods to reduce false tests. J Inherit Metab Dis. 2008;2:395–404.CrossRefGoogle Scholar
  17. 17.
    Azzari C, la Marca G, Resti M. Neonatal screening for severe combined immunodeficiency caused by an adenosine deaminase defect: a reliable and inexpensive method using tandem mass spectrometry. J Allergy Clin Immunol. 2011;127(6):1394–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Bach FH, Albertini RJ, Joo P, et al. Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet. 1968;2(7583):1364–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Gatti RA, Meuwissen HJ, Allen HD, et al. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968;2(7583):1366–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Naik S, Nicholas SK, Martinez CA, et al. Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes. J Allergy Clin Immunol. 2016;137(5):1498–505.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Buckley RH. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res. 2011;49:25–43.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Pai SY, Logan BR, Griffith LM, et al. Transplantation outcomes for severe combined immunodeficiency, 2000–2009. N Engl J Med. 2014;371:434–46.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Gennery AR, Slatter MA, Grandin L, et al. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? J Allergy Clin Immunol. 2010;126:602–10. e601-611CrossRefPubMedGoogle Scholar
  24. 24.
    Moratto D, Giliani S, Bonfim C, et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980–2009: an international collaborative study. Blood. 2011;118:1675–84.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Bertaina A, Merli P, Rutella S, et al. HLA-haploidentical stem cell transplantation after removal of alphabeta+ T and B cells in children with nonmalignant disorders. Blood. 2014;124:822–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Gungor T, Teira P, Slatter M, et al. Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. Lancet. 2014;383:436–48.PubMedCrossRefGoogle Scholar
  27. 27.
    Kildebeck E, Checketts J, Porteus M. Gene therapy for primary immunodeficiencies. Curr Opin Pediatr. 2012;24(6):731–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Rivat C, Santilli G, Gaspar HB, et al. Gene therapy for primary immunodeficiencies. Hum Gene Ther. 2012;23(7):668–75.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Fischer A, Cavazzana-Calvo M. Gene therapy of inherited diseases. Lancet. 2008;371(9629):2044–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Hacein Bey Abina S, Pai SY, Gaspar HB, et al. A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med. 2014;371(15):1407–17.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Gaspar HB, Qasim W, Davies EG, Rao K, Amrolia PJ, Veys P. How I treat severe combined immunodeficiency. Blood. 2013;122(23):3749–58.CrossRefPubMedGoogle Scholar
  32. 32.
    Stephan V, Wahn V, Le Deist F, Dirksen U, Broker B, Muller-Fleckenstein I, Horneff G, Schroten H, Fischer A, de Saint Basile G. Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N Engl J Med. 1996;335:1563–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Speckmann C, Pannicke U, Wiech E, Schwarz K, Fisch P, Friedrich W, Niehues T, Gilmour K, Buiting K, Schlesier M, Eibel H, Rohr J, Superti-Furga A, Gross-Wieltsch U, Ehl S. Clinical and immunologic consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency. Blood. 2008;112:4090–7.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Touzot F, Moshous D, Creidy R, et al. Faster T-cell development following gene therapy compared with haploidentical HSCT in the treatment of SCID-X1. Blood. 2015;125(23):3563–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, De Villartay JP, Thrasher AJ, Wulffraat N, Sorensen R, Dupuis-Girod S, Fischer A, Davies EG, Kuis W, Leiva L, Cavazzana-Calvo M. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med. 2002;346:1185–93.PubMedCrossRefGoogle Scholar
  36. 36.
    Hacein-Bey-Abina S, Hauer J, Lim A, et al. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2010;363(4):355–64.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Gaspar HB, Cooray S, Gilmour KC, et al. Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2011;3(97):97ra79.PubMedGoogle Scholar
  38. 38.
    Ghosh S, Thrasher A, Gaspar B. Gene therapy for monogenic disorders of the bone marrow. Br J Haematol. 2015;171:155–70.PubMedCrossRefGoogle Scholar
  39. 39.
    Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2008;118(9):3132–42.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Howe SJ, Mansour MR, Schwarzwaelder K, et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest. 2008;118:3143–50.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Candotti F. Gene transfer into hematopoietic stem cells as treatment for primary immunodeficiency diseases. Int J Hematol. 2014;99:383–92.PubMedCrossRefGoogle Scholar
  42. 42.
    Deichmann A, Hacein-Bey-Abina S, Schmidt M, et al. Vector integration is non random and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy. J Clin Invest. 2007;117:2225–32.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Schwarzwaelder K, Howe SJ, Schmidt M, et al. Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo. J Clin Invest. 2007;117:2241–9.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Chinen J, Davis J, De Ravin SS, Hay BN, Hsu AP, Linton GF, Naumann N, Nomicos EY, Silvin C, Ulrick J, Whiting-Theobald NL, Malech HL, Puck JM. Gene therapy improves immune function in pre-adolescents with X-linked severe combined immunodeficiency. Blood. 2007;110:67–73.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Zhou S, Mody D, DeRavin SS, et al. A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells. Blood. 2010;116:900–8.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    De Ravin SS, Choi U, Theobald N, et al. Lentiviral gene transfer for treatment of children 2 years old with x-linked severe combined immunodeficiency. Mol Ther. 2013;21:S118.Google Scholar
  47. 47.
    Kohn DB. Gene therapy outpaces haplo for SCID-X1. Blood. 2015;125(23):3521–2.PubMedCrossRefGoogle Scholar
  48. 48.
    Naldini L. Ex vivo gene transfer and correction for cell-based therapies. Nat Rev Genet. 2011;12:301–15.PubMedCrossRefGoogle Scholar
  49. 49.
    Genovese P., Schiroli G, , Escobar G, et al. Targeted genome editing in human repopulating haematopoietic stem cells. Nature 2014;510(7504):235–240.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Aiuti A, Brigida I, Ferrua F, et al. Hematopoietic stem cell gene therapy for adenosine deaminase deficient-SCID. Immunol Res. 2009;44:150–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Gaspar HB, Aiuti A, Porta F, et al. How I treat ADA deficiency. Blood. 2009;114:3524–32.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Grunebaum E, Cohen A, Roifman CM. Recent advances in understanding and managing adenosine deaminase and purine nucleoside phosphorylase deficiencies. Curr Opin Allergy Clin Immunol. 2013;13(6):630–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Hirschhorn, R., Candotti, F. Immunodeficiency due to defects of purine metabolism. in: H.D. Ochs, C.I.E. Smith, J.M. Puck (Eds.) Primary immunodeficiency diseases. A molecular and genetic approach. Oxford University Press, Oxford; 2007:169–196.CrossRefGoogle Scholar
  54. 54.
    Honig M, Albert MH, Schulz A, et al. Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications. Blood. 2007;109:3595–602.PubMedCrossRefGoogle Scholar
  55. 55.
    Sauer AV, Mrak E, Hernandez RJ, et al. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood. 2009;114:3216–26.PubMedCrossRefGoogle Scholar
  56. 56.
    Brigida I, Sauer AV, Ferrua F, et al. B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients. J Allergy Clin Immunol. 2014;133:799–806.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Hassan A, Booth C, Brightwell A, et al. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood. 2012;120(17):3615–24. quiz 3626PubMedCrossRefGoogle Scholar
  58. 58.
    Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, Shearer G, Chang L, Chiang Y, Tolstoshev P, Greenblatt JJ, B Rosenberg SA, Klein H, Berger M, Mullen CA, Ramsey WJ, Muul L, Morgan RA, Anderson WF. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science. 1995;270:475–80.PubMedCrossRefGoogle Scholar
  59. 59.
    Bordignon C, Notarangelo LD, Nobili N, Ferrari G, Casorati G, Panina P, Mazzolari E, Maggioni D, Rossi C, Servida P, Ugazio AG, Mavilio F. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science. 1995;270:470–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Onodera M, Ariga T, Kawamura N, Kobayashi I, Ohtsu M, Yamada M, Tame A, Furuta H, Okano M, Matsumoto S, Kotani H, McGarrity GJ, Blaese RM, Sakiyama Y. Successful peripheral T-lymphocyte directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency. Blood. 1998;91:30–6.PubMedGoogle Scholar
  61. 61.
    Aiuti A, Vai S, Mortellaro A, Casorati G, Ficara F, Andolfi G, Ferrari G, Tabucchi A, Carlucci F, Ochs HD, Notarangelo LD, Roncarolo MG, Bordignon C. Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat Med. 2002;8:423–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Muul LM, Tuschong LM, Soenen SL, et al. Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial. Blood. 2003;101:2563–9. Epub Nov 2002PubMedCrossRefGoogle Scholar
  63. 63.
    Biasco L, Scala S, Basso Ricci L, et al. In vivo tracking of T cells in humans unveils decadelong survival and activity of genetically modified T memory stem cells. Sci Transl Med. 2015;7(273):273ra13.PubMedCrossRefGoogle Scholar
  64. 64.
    Montiel-Equihua CA, Thrasher AJ, Gaspar HB. Gene therapy for severe combined immunodeficiency due to adenosine deaminase deficiency. Curr Gene Ther. 2012;12:57–65.PubMedCrossRefGoogle Scholar
  65. 65.
    Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002;296(5577):2410–3.PubMedCrossRefGoogle Scholar
  66. 66.
    Aiuti A, Cattaneo F, Galimberti S, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009;360(5):447–58.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Cicalese MP, Ferrua F, Castagnaro L, et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood. 2016;128:45–54.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
  69. 69.
    Candotti F, Shaw KL, Muul L, et al. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood. 2012;120:3635–46.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Otsu M, Nakajima S, Kida M, et al. Steady ongoing hematological and immunological reconstitution achieved in ADA-deficiency patients treated by stem cell gene therapy with no myelopreparative conditioning. J Gene Med. 2006;8:1436–75.CrossRefGoogle Scholar
  71. 71.
    Carbonaro D, Jin X, Wang X, et al. Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction. Blood. 2012;120(18):3677–87.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Rivers L, Gaspar HB. Severe combined immunodeficiency: recent developments and guidance on clinical management. Arch Dis Child. 2015;100(7):667–72.PubMedCrossRefGoogle Scholar
  73. 73.
    Biasco L, Ambrosi A, Pellin D, et al. Integration profile of retroviral vector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell. EMBO Mol Med. 2011;3:89–101.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Cicalese MP, Aiuti A. Clinical applications of gene therapy for primary immunodeficiencies. Hum Gene Ther. 2015;26(4):210–9.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Siler U, Paruzynski A, Holtgreve-Grez H, et al. Successful combination of sequential gene therapy and rescue allo-HSCT in two children with X-CGD—importance of timing. Curr Gene Ther. 2015;15(4):416–27.PubMedCrossRefGoogle Scholar
  76. 76.
    Grez M, Reichenbach J, Schwäble J, Seger R, Dinauer MC, Thrasher AJ. Gene therapy of chronic granulomatous disease: the engraftment dilemma. Mol Ther. 2011;19(1):28–35.PubMedCrossRefGoogle Scholar
  77. 77.
    Braun CJ, Boztug K, Paruzynski A, et al. Gene therapy for Wiskott-Aldrich syndrome: long-term efficacy and genotoxicity. Sci Transl Med. 2014;6(227):227ra33.CrossRefPubMedGoogle Scholar
  78. 78.
    Mortellaro A, Hernandez RJ, Guerrini MM, et al. Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)-deficient mice and corrects their immune and metabolic defects. Blood. 2006;108(9):2979–88.PubMedCrossRefGoogle Scholar
  79. 79.
    Carbonaro DA, Zhang L, Jin X, et al. Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency. Mol Ther. 2014;22(3):607–22.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Gaspar B, Buckland K, Rivat C, et al. Immunological and metabolic correction after lentiviral vector mediated haematopoietic stem cell gene therapy for ADA deficiency. J Clin Immunol. 2014;34(Suppl 2):S167.Google Scholar
  81. 81.
    Derry JM, Kerns JA, Weinberg KI, et al. WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. Hum Mol Genet. 1995;4(7):1127–35.PubMedCrossRefGoogle Scholar
  82. 82.
    Catucci M, Castiello MC, Pala F, et al. Autoimmunity in wiskott-Aldrich syndrome: an unsolved enigma. Front Immunol. 2012;3:209.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Silvin C, Belisle B, Abo A. A role for Wiskott-Aldrich syndrome protein in T-cell receptor mediated transcriptional activation independent of actin polymerization. J Biol Chem. 2001;276(24):21450–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Blundell MP, Worth A, Bouma G, Thrasher AJ. The Wiskott-Aldrich syndrome: the actin cytoskeleton and immune cell function. Dis Markers. 2010;29:157–75.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Thrasher AJ. New insights into the biology of Wiskott-Aldrich syndrome (WAS). Hematology Am Soc Hematol Educ Program. 2009;2009:132–8.Google Scholar
  86. 86.
    Massaad MJ, Ramesh N, Geha RS. Wiskott-Aldrich syndrome: a comprehensive review. Ann N Y Acad Sci. 2013;1285:26–43.PubMedCrossRefGoogle Scholar
  87. 87.
    Thrasher AJ, Burns SO. WASP: a key immunological multitasker. Nat Rev Immunol. 2010;10:182–92.PubMedCrossRefGoogle Scholar
  88. 88.
    Ozsahin H, Cavazzana-Calvo M, Notarangelo LD, et al. Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation. Blood. 2008;111(1):439–45.CrossRefPubMedGoogle Scholar
  89. 89.
    Filipovich AH, Stone JV, Tomany SC, et al. Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood. 2001;97(6):1598–603.PubMedCrossRefGoogle Scholar
  90. 90.
    Kobayashi R, Ariga T, Nonoyama S, et al. Outcome in patients with Wiskott-Aldrich syndrome following stem cell transplantation: an analysis of 57 patients in Japan. Br J Haematol. 2006;135(3):362–6.PubMedCrossRefGoogle Scholar
  91. 91.
    Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. 20 years of gene therapy for SCID. Nat Immunol. 2010;11(6):457–60.PubMedCrossRefGoogle Scholar
  92. 92.
    Candotti F, Facchetti F, Blanzuoli L, et al. 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(6):1170–4.PubMedCrossRefGoogle Scholar
  93. 93.
    Wada T, Jagadeesh GJ, Nelson DL, et al. Retrovirus-mediated WASP gene transfer corrects Wiskott-Aldrich syndrome T-cell dysfunction. Hum Gene Ther. 2002;13(9):1039–46.PubMedCrossRefGoogle Scholar
  94. 94.
    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 mice. Blood. 2003;101(6):2159–66.PubMedCrossRefGoogle Scholar
  95. 95.
    Strom TS, Gabbard W, Kelly PF, et al. Functional correction of T cells derived from patients with the Wiskott-Aldrich syndrome (WAS) by transduction with an oncoretroviral vector encoding the WAS protein. Gene Ther. 2003;10(9):803–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Galy A, Roncarolo MG, Thrasher AJ. Development of lentiviral gene therapy for Wiskott Aldrich syndrome. Expert Opin Biol Ther. 2008;8(2):181–90.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Dupré L, Trifari S, Follenzi A, et al. Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction. Mol Ther. 2004;10(5):903–15.PubMedCrossRefGoogle Scholar
  98. 98.
    Boztug K, Schmidt M, Schwarzer A, et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med. 2010;363(20):1918–27.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Westerberg LS, de la Fuente MA, Wermeling F, et al. WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function. Blood. 2008;112(10):4139–47.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Paruzynski A, Glimm H, Schmidt M, et al. Analysis of the clonal repertoire of gene-corrected cells in gene therapy. Methods Enzymol. 2012;507:59–87.PubMedCrossRefGoogle Scholar
  101. 101.
    Stein S, Ott MG, Schultze-Strasser S, et al. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med. 2010;16(2):198–204.PubMedCrossRefGoogle Scholar
  102. 102.
    Dupré L, Marangoni F, Scaramuzza S, et al. Efficacy of gene therapy for Wiskott-Aldrich syndrome using a WAS promoter/cDNA-containing lentiviral vector and nonlethal irradiation. Hum Gene Ther. 2006;17(3):303–13.PubMedCrossRefGoogle Scholar
  103. 103.
    Marangoni F, Bosticardo M, Charrier S, et al. Evidence for long-term efficacy and safety of gene therapy for Wiskott-Aldrich syndrome in preclinical models. Mol Ther. 2009;17(6):1073–82.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Avedillo Diez I, Zychlinski D, Coci EG, Galla M, Modlich U, Dewey RA, Schwarzer A, Maetzig T, Mpofu N, Jaeckel E, Boztug K, Baum C, Klein C, Schambach A. Development of novel efficient SIN vectors with improved safety features for Wiskott-Aldrich syndrome stem cell based gene therapy. Mol Pharm. 2011;8:1525–37.PubMedCrossRefGoogle Scholar
  105. 105.
    Bosticardo M, Draghici E, Schena F, Sauer AV, Fontana E, Castiello MC, Catucci M, Locci M, Naldini L, Aiuti A, Roncarolo MG, Poliani PL, Traggiai E, Villa A. Lentiviral-mediated gene therapy leads to improvement of B-cell functionality in a murine model of Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2011;127:e1375.CrossRefGoogle Scholar
  106. 106.
    Scaramuzza S, Biasco L, Ripamonti A, et al. Preclinical safety and efficacy of human CD34(+) cells transduced with lentiviral vector for the treatment of Wiskott-Aldrich syndrome. Mol Ther. 2013;21(1):175–84.PubMedCrossRefGoogle Scholar
  107. 107.
    Aiuti A, Biasco L, Scaramuzza S, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341(6148):1233151.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Castiello MC, Scaramuzza S, Pala F, Ferrua F, Uva P, Brigida I, Sereni L, van der Burg M, Ottaviano G, Albert MH, Roncarolo MG, Naldini L, Aiuti A, Villa A, Bosticardo M. B-cell reconstitution after lentiviral vector- mediated gene therapy in patients with Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2015.  https://doi.org/10.1016/j.jaci.2015.01.035.
  109. 109.
    Ferrua F, Cicalese MP, Galimberti S, et al. Safety and clinical benefit of lentiviral hematopoietic stem cell gene therapy for Wiskott-Aldrich Syndrome. ASH 57th annual meeting, Orlando FL, 5–8 Dec 2015.Google Scholar
  110. 110.
    Hacein-Bey Abina S, Gaspar HB, Blondeau J, Caccavelli L, Charrier S, Buckland K, Picard C, Six E, Himoudi N, Gilmour K, McNicol AM, Hara H, Xu-Bayford J, Rivat C, Touzot F, Mavilio F, Lim A, Treluyer JM, Héritier S, Lefrère F, Magalon J, Pengue-Koyi I, Honnet G, Blanche S, Sherman EA, Male F, Berry C, Malani N, Bushman FD, Fischer A, Thrasher AJ, Galy A, Cavazzana M. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 2015;313:1550–63.CrossRefPubMedGoogle Scholar
  111. 111.
    Chu JI, Henderso LA, Armant M et al. Gene therapy using a self-inactivating lentiviral vector improves clinical and laboratory manifestations of Wiskott-Aldrich syndrome. ASH 57th annual meeting, Orlando FL, 5–8 Dec 2015.Google Scholar
  112. 112.
    Astrakhan A, Sather BD, Ryu BY, et al. Ubiquitous high-level gene expression in hematopoietic lineages provides effective lentiviral gene therapy of murine Wiskott-Aldrich syndrome. Blood. 2012;119(19):4395–407.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Aiuti A, Bacchetta R, Seger R, et al. Gene therapy for primary immunodeficiencies: part 2. Curr Opin Immunol. 2012;24(5):585–91.PubMedCrossRefGoogle Scholar
  114. 114.
    Goldblatt D. Recent advances in chronic granulomatous disease. J Inf. 2014;69:S32–5.CrossRefGoogle Scholar
  115. 115.
    Holland SM. Chronic granulomatous disease. Hematol Oncol Clin N Am. 2013;27:89–99. viiiCrossRefGoogle Scholar
  116. 116.
    Sekhsaria S, Fleisher TA, Vowells S, et al. Granulocyte colony-stimulating factor recruitment of CD34+ progenitors to peripheral blood: impaired mobilization in chronic granulomatous disease and adenosine deaminase – deficient severe combined immunodeficiency disease patients. Blood. 1996;88(3):1104–12.PubMedGoogle Scholar
  117. 117.
    Goebel WS, Dinauer MC. Gene therapy for chronic granulomatous disease. Acta Haematol. 2003;110(2–3):86–92.PubMedCrossRefGoogle Scholar
  118. 118.
    Qasim W, Gennery AR. Gene therapy for primary immunodeficiencies: current status and future prospects. Drugs. 2014;74(9):963–9.PubMedCrossRefGoogle Scholar
  119. 119.
    Malech HL, Maples PB, Whiting-Theobald N, Linton GF, Sekhsaria S, Vowells SJ, Li F, Miller JA, DeCarlo E, Holland SM, Leitman SF, Carter CS, Butz RE, Read EJ, Fleisher TA, Schneiderman RD, Van Epps DE, Spratt SK, Maack CA, Rokovich JA, Cohen LK, Gallin JI. Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proc Natl Acad Sci U S A. 1997;94:12133–8.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Kang EM, Choi U, Theobald N, et al. Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. Blood. 2010;115(4):783–91.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Ott MG, Schmidt M, Schwarzwaelder K, et al. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006;12(4):401–9.PubMedCrossRefGoogle Scholar
  122. 122.
    Kang EM, Marciano BE, DeRavin S, et al. Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2011;127(6):1319–26. quiz 1327-8PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Farinelli G, Capo V, Scaramuzza S, et al. Lentiviral vectors for the treatment of primary immunodeficiencies. J Inherit Metab Dis. 2014;37(4):525–33.PubMedCrossRefGoogle Scholar
  124. 124.
    Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87(1):245–313.PubMedCrossRefGoogle Scholar
  125. 125.
    Yahata T, Takanashi T, Muguruma Y, et al. Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood. 2011;118(11):2941–50.PubMedCrossRefGoogle Scholar
  126. 126.
    Chiriaco M, Farinelli G, Capo V, et al. Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis. Mol Ther. 2014;22(8):1472–83.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Bianchi M, Hakkim A, Brinkmann V, et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009;114(13):2619–22.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Santilli G, Almarza E, Brendel C, Choi U, Beilin C, Blundell MP, Haria S, Parsley KL, Kinnon C, Malech HL, Bueren JA, Grez M, Thrasher AJ. Biochemical correction of X-CGD by a novel chimeric promoter regulating high levels of transgene expression in myeloid cells. Mol Ther. 2011;19:122–32.PubMedCrossRefGoogle Scholar
  129. 129.
    Barde I, Laurenti E, Verp S, et al. Lineage- and stage-restricted lentiviral vectors for the gene therapy of chronic granulomatous disease. Gene Ther. 2011;18(11):1087–97.PubMedCrossRefGoogle Scholar
  130. 130.
    Brendel C, Müller-Kuller U, Schultze-Strasser S, et al. Physiological regulation of transgene expression by a lentiviral vector containing the A2UCOE linked to a myeloid promoter. Gene Ther. 2012;19(10):1018–29.PubMedCrossRefGoogle Scholar
  131. 131.
    Sauer AV, Di Lorenzo B, Carriglio N, et al. Progress in gene therapy for primary immunodeficiencies using lentiviral vectors. Curr Opin Allergy Clin Immunol. 2014;14(6):527–34.PubMedCrossRefGoogle Scholar
  132. 132.
    Williams S, Mustoe T, Mulcahy T, et al. CpG-island fragments from the HNRPA2B1/CBX3 genomic locus reduce silencing and enhance transgene expression from the hCMV promoter/enhancer in mammalian cells. BMC Biotechnol. 2005;5:17.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Zhang F, Frost AR, Blundell MP, et al. A ubiquitous chromatin opening element (UCOE) confers resistance to DNA methylation-mediated silencing of lentiviral vectors. Mol Ther. 2010;18(9):1640–9.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Farinelli G, Jofra Hernandez R, Rossi A, et al. Lentiviral vector gene therapy protects XCGD mice from acute Staphylococcus aureus pneumonia and inflammatory response. Mol Ther. 2016.  https://doi.org/10.1038/mt.2016.150.
  135. 135.
    Multhaup MM, Podetz-Pedersen KM, Karlen AD, et al. Role of transgene regulation in ex vivo lentiviral correction of Artemis deficiency. Hum Gene Ther. 2015;26(4):232–43.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Pike-Overzet K, Rodijk M, Ng YY, et al. Correction of murine Rag1 deficiency by self-inactivating lentiviral vector-mediated gene transfer. Leukemia. 2011;25(9):1471–83.PubMedCrossRefGoogle Scholar
  137. 137.
    van Til NP, Sarwari R, Visser TP, et al. Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome. J Allergy Clin Immunol. 2014;133(4):1116–23.PubMedCrossRefGoogle Scholar
  138. 138.
    van Til NP, de Boer H, Mashamba N, et al. Correction of murine Rag2 severe combined immunodeficiency by lentiviral gene therapy using a codon-optimized RAG2 therapeutic transgene. Mol Ther. 2012;20(10):1968–80.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Rivat C, Booth C, Alonso-Ferrero M, et al. SAP gene transfer restores cellular and humoral immune function in a murine model of X-linked lymphoproliferative disease. Blood. 2013;121(7):1073–6.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Carmo M, Risma KA, Arumugam P, et al. Perforin gene transfer into hematopoietic stem cells improves immune dysregulation in murine models of perforin deficiency. Mol Ther. 2015;23(4):737–45.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Goettel JA, Biswas S, Lexmond WS, et al. Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3. Blood. 2015;125(25):3886–95.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature. 2010;467:318e22.CrossRefGoogle Scholar
  143. 143.
    Payen E, Leboulch P. Advances in stem cell transplantation and gene therapy in the beta-hemoglobinopathies. Hematol Am Soc Hematol Educ Progr. 2012;2012:276e83.Google Scholar
  144. 144.
    Cavazzana M, Ribeil JA, Payen E, et al. Outcomes of gene therapy for beta thalassemia major via transplantation of autologous hematopoietic stem cells transduced ex vivo with a lentiviral beta globin vector. Haematologica. 2014;99. abstract:S742.Google Scholar
  145. 145.
    Negre O, Bartholomae C, Beuzard Y, et al. Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of beta-thalassemia and sickle cell disease. Curr Gene Ther. 2015;15:64e81.Google Scholar
  146. 146.
    Cavazzana M, Ribeil J-A, Payen E, et al. Outcomes of gene therapy for beta-thalassemia major and severe sickle disease via transplantation of autologous hematopoietic stem cells transduced ex vivo with a lentiviral beta globin vector. EHA20, Wien, Jun 11–14 2015.Google Scholar
  147. 147.
    Walters MC, MD1, Rasko J, MBBS, PhD2, Hongeng S, MD3 et al. Update of results from the Northstar study (HGB-204): a phase 1/2 study of gene therapy for beta-thalassemia major via transplantation of autologous hematopoietic stem cells transduced ex-vivo with a lentiviral beta AT87Q-Globin vector (LentiGlobin BB305 Drug Product). ASH 57th annual meeting, Orlando FL, 5–8 Dec 2015.Google Scholar
  148. 148.
    Boulad F, Wang X, Qu J, et al. Safe mobilization of CD34þ cells in adults with betathalassemia and validation of effective globin gene transfer for clinical investigation. Blood. 2014;123:1483e6.CrossRefGoogle Scholar
  149. 149.
    Sadelain M, Boulad F, Riviere I, Maggio A, Taher A. Gene therapy. In: Cappellini MD, Cohen A, Porter J, Taher A, Viprakasit V, editors. Guidelines for the management of transfusion dependent thalassaemia (TDT) [internet]. 3rd ed. Nicosia: Thalassaemia International Federation; 2013.Google Scholar
  150. 150.
    Mansilla-Soto J, Riviere I, Boulad F, et al. Cell and gene therapy for the beta-thalassemias: advances and prospects. Hum Gene Ther. 2016;27(4):295–304.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Miccio A, Cesari R, Lotti F, et al. In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of beta-thalassemia. Proc Natl Acad Sci U S A. 2008;105:10547–52.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Lidonnici MR, Aprile A, Paleari Y, et al. Update on gene therapy clinical trial for the treatment of beta thalassemia major in Italy [abstract]. Presented at the Tenth Cooley’s Anemia Symposium, Chicago, IL, 18–22 Oct 2015.Google Scholar
  153. 153.
    Marktel S Giglio F, Cicalese MP, et al. A phase I/II study of autologous hemapoietic stem cells genetically modified with globe Lentiviral vector for the treatment of transfusion dependent beta-thalassemia. EHA21, Copenhagen, 9–12 Jun 2016.Google Scholar
  154. 154.
    Cartier N, Hacein-Bey-Abina S, Von Kalle C, et al. Gene therapy of x-linked adrenoleukodystrophy using hematopoietic stem cells and a lentiviral vector. Bull Acad Natl Med. 2010;194(2):255–64. discussion 264-8PubMedGoogle Scholar
  155. 155.
    Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341(6148):1233158.PubMedCrossRefGoogle Scholar
  156. 156.
    Sessa M, Lorioli L, Fumagalli F, et al. Lentiviral haematopoietic stem-cell gene therapy in early-onset metacromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1 trail. Lancet. 2016:S0140–6736(16). 30374-9Google Scholar
  157. 157.
    van Til NP, Stok M, Aerts Kaya FS, de Waard MC, Farahbakhshian E, Visser TP, Kroos MA, Jacobs EH, Willart MA, van der Wegen P, Scholte BJ, Lambrecht BN, Duncker DJ, van der Ploeg AT, Reuser AJ, Verstegen MM, Wagemaker G. Lentiviral gene therapy of murine hematopoietic stem cells ameliorates the Pompe disease phenotype. Blood. 2010;115:5329–37.PubMedCrossRefGoogle Scholar
  158. 158.
    Visigalli I, Delai S, Politi LS, Di Domenico C, Cerri F, Mrak E, D’Isa R, Ungaro D, Stok M, Sanvito F, Mariani E, Staszewsky L, Godi C, Russo I, Cecere F, Del Carro U, Rubinacci A, Brambilla R, Quattrini A, Di Natale P, Ponder K, Naldini L, Biffi A. Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. Blood. 2010;116:5130–9.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Langford-Smith A, Wilkinson FL, Langford-Smith KJ, Holley RJ, Sergijenko A, Howe SJ, Bennett WR, Jones SA, Wraith J, Merry CL, Wynn RF, Bigger BW. Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice. Mol Ther. 2012;20:1610–21.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Gaj T, Gersbach CA, Barbas CF 3rd. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 2013;31:397–405.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Sun N, Zhao H. Seamless correction of the sickle cell disease mutation of the HBB gene in human induced pluripotent stem cells using TALENs. Biotechnol Bioeng. 2014;111:1048–53.PubMedCrossRefGoogle Scholar
  162. 162.
    Xie F, Ye L, Chang JC, Beyer AI, Wang J, Muench MO, Kan YW. Seamless gene correction of beta-thalassemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyBac. Genome Res. 2014;24:1526–33.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    De Ravin SS, Li L, Wu X, et al. CRISPR-Cas9 gene repair of hematopoietic stem cells from patients with X-linked chronic granulomatous disease. Sci Transl Med. 2017;9:372.CrossRefGoogle Scholar
  164. 164.
    Tubsuwan A, Abed S, Deichmann A, Kardel MD, et al. Parallel assessment of globin lentiviral transfer in induced pluripotent stem cells and adult hematopoietic stem cells derived from the same transplanted beta-thalassemia patient. Stem Cells. 2013;31:1785e94.CrossRefGoogle Scholar
  165. 165.
    Papapetrou EP, Lee G, Malani N, et al. Genomic safe harbors permit high beta-globin transgene expression in thalassemia induced pluripotent stem cells. Nat Biotechnol. 2011;29:73e8.CrossRefGoogle Scholar
  166. 166.
    de Dreuzy E, Bhukhai K, Leboulch P, et al. Current and future alternative therapies for beta-thalassemia major. Biomed J. 2016;39:24–38.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific InstituteMilanItaly
  2. 2.Pediatric Immunohematology and Bone Marrow Transplantation UnitIRCCS San Raffaele Scientific InstituteMilanItaly
  3. 3.Vita-Salute San Raffaele UniversityMilanItaly

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