Journal of Inherited Metabolic Disease

, Volume 37, Issue 4, pp 525–533 | Cite as

Lentiviral vectors for the treatment of primary immunodeficiencies

  • Giada Farinelli
  • Valentina Capo
  • Samantha Scaramuzza
  • Alessandro Aiuti
ICIEM Symposium 2013

Abstract

In the last years important progress has been made in the treatment of several primary immunodeficiency disorders (PIDs) with gene therapy. Hematopoietic stem cell (HSC) gene therapy indeed represents a valid alternative to conventional transplantation when a compatible donor is not available and recent success confirmed the great potential of this approach. First clinical trials performed with gamma retroviral vectors were promising and guaranteed clinical benefits to the patients. On the other hand, the outcome of severe adverse events as the development of hematological abnormalities highlighted the necessity to develop a safer platform to deliver the therapeutic gene. Self-inactivating (SIN) lentiviral vectors (LVVs) were studied to overcome this hurdle through their preferable integration pattern into the host genome. In this review, we describe the recent advancements achieved both in vitro and at preclinical level with LVVs for the treatment of Wiskott-Aldrich syndrome (WAS), chronic granulomatous disease (CGD), ADA deficiency (ADA-SCID), Artemis deficiency, RAG1/2 deficiency, X-linked severe combined immunodeficiency (γchain deficiency, SCIDX1), X-linked lymphoproliferative disease (XLP) and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.

References

  1. Aiuti A, Vai S, Mortellaro A et al (2002) Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat Med 8(5):423–425PubMedCrossRefGoogle Scholar
  2. Aiuti A, Cattaneo F, Galimberti S et al (2009) Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360(5):447–458PubMedCrossRefGoogle Scholar
  3. Aiuti A, Bacchetta R, Seger R, Villa A, Cavazzana-Calvo M (2012) Gene therapy for primary immunodeficiencies: Part 2. Curr Opin Immunol 24(5):585–591PubMedCrossRefGoogle Scholar
  4. Aiuti A, Biasco L, Scaramuzza S et al (2013a) Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341(6148):1233151PubMedCrossRefGoogle Scholar
  5. Aiuti A, Cossu G, de Felipe P et al (2013b) The committee for advanced therapies' of the European Medicines Agency reflection paper on management of clinical risks deriving from insertional mutagenesis. Hum Gene Ther Clin Dev 24(2):47–54PubMedCrossRefGoogle Scholar
  6. Allan SE, Passerini L, Bacchetta R et al (2005) The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clin Invest 115(11):3276–3284PubMedCentralPubMedCrossRefGoogle Scholar
  7. Allan SE, Alstad AN, Merindol N et al (2008) Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3. Mol Ther 16(1):194–202PubMedCrossRefGoogle Scholar
  8. Antoniou M, Harland L, Mustoe T et al (2003) Transgenes encompassing dual-promoter CpG islands from the human TBP and HNRPA2B1 loci are resistant to heterochromatin-mediated silencing. Genomics 82(3):269–279PubMedCrossRefGoogle Scholar
  9. Astrakhan A, Sather BD, Ryu BY et al (2012) Ubiquitous high-level gene expression in hematopoietic lineages provides effective lentiviral gene therapy of murine Wiskott-Aldrich syndrome. Blood 119(19):4395–4407PubMedCentralPubMedCrossRefGoogle Scholar
  10. Barde I, Laurenti E, Verp S et al (2011) Lineage- and stage-restricted lentiviral vectors for the gene therapy of chronic granulomatous disease. Gene Ther 18(11):1087–1097PubMedCrossRefGoogle Scholar
  11. Barzaghi F, Passerini L, Gambineri E et al (2012) Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome. J Autoimmun 38(1):49–58PubMedCrossRefGoogle Scholar
  12. Benjelloun F, Garrigue A, Demerens-de Chappedelaine C et al (2008) Stable and functional lymphoid reconstitution in artemis-deficient mice following lentiviral artemis gene transfer into hematopoietic stem cells. Mol Ther 16(8):1490–1499PubMedCrossRefGoogle Scholar
  13. Bianchi M, Hakkim A, Brinkmann V et al (2009) Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood 114(13):2619–2622PubMedCentralPubMedCrossRefGoogle Scholar
  14. Biasco L, Ambrosi A, Pellin D et al (2011) 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 3(2):89–101PubMedCentralPubMedCrossRefGoogle Scholar
  15. Biasco L, Baricordi C, Aiuti A (2012) Retroviral integrations in gene therapy trials. Mol Ther 20:709–716PubMedCentralPubMedCrossRefGoogle Scholar
  16. Biffi A, Montini E, Lorioli L et al (2013) Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341(6148):1233158PubMedCrossRefGoogle Scholar
  17. Booth C, Gilmour KC, Veys P et al (2011) X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood 117(1):53–62PubMedCentralPubMedCrossRefGoogle Scholar
  18. Bousfiha AA, Jeddane L, Ailal F et al (2013) A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol 33(6):1078–1087PubMedCrossRefGoogle Scholar
  19. Bousso P, Wahn V, Douagi I et al (2000) 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 97(1):274–278PubMedCentralPubMedCrossRefGoogle Scholar
  20. Boztug K, Schmidt M, Schwarzer A et al (2010) Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med 363(20):1918–1927PubMedCentralPubMedCrossRefGoogle Scholar
  21. Brady T, Agosto LM, Malani N, Berry CC, O'Doherty U, Bushman F (2009) HIV integration site distributions in resting and activated CD4+ T cells infected in culture. AIDS 23(12):1461–1471PubMedCentralPubMedCrossRefGoogle Scholar
  22. Brendel C, Muller-Kuller U, Schultze-Strasser S et al (2011) Physiological regulation of transgene expression by a lentiviral vector containing the A2UCOE linked to a myeloid promoter. Gene Ther 24(3):1018–1029Google Scholar
  23. Brown BD, Naldini L (2009) Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nat Rev Genet 10(8):578–585PubMedCrossRefGoogle Scholar
  24. Brown BD, Gentner B, Cantore A et al (2007) Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nat Biotechnol 25(12):1457–1467PubMedCrossRefGoogle Scholar
  25. Candotti F, Shaw KL, Muul L et al (2012) Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood 120(18):3635–3646PubMedCentralPubMedCrossRefGoogle Scholar
  26. Carbonaro DA, Jin X, Cotoi D et al (2008) Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion. Blood 111(12):5745–5754PubMedCentralPubMedCrossRefGoogle Scholar
  27. Carbonaro DA, Zhang L, Jin X, et al (2013) Pre-clinical demonstration of lentiviral vector mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency. Mol Ther doi:10.1038/mt.2013.265
  28. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G et al (2000) Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288(5466):669–672PubMedCrossRefGoogle Scholar
  29. Charrier S, Dupre L, Scaramuzza S et al (2007) Lentiviral vectors targeting WASp expression to hematopoietic cells, efficiently transduce and correct cells from WAS patients. Gene Ther 14(5):415–428PubMedCrossRefGoogle Scholar
  30. Chinen J, Davis J, De Ravin SS et al (2007) Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency. Blood 110(1):67–73PubMedCentralPubMedCrossRefGoogle Scholar
  31. Corrigan-Curay J, Cohen-Haguenauer O, O'Reilly M et al (2012) Challenges in vector and trial design using retroviral vectors for long-term gene correction in hematopoietic stem cell gene therapy. Mol Ther 20(6):1084–1094PubMedCentralPubMedCrossRefGoogle Scholar
  32. Di Matteo G, Giordani L, Finocchi A et al (2009) Molecular characterization of a large cohort of patients with Chronic Granulomatous Disease and identification of novel CYBB mutations: an Italian multicenter study. Mol Immunol 46(10):1935–1941PubMedCrossRefGoogle Scholar
  33. Dupre L, Marangoni F, Scaramuzza S et al (2006) Efficacy of gene therapy for Wiskott-Aldrich syndrome using a WAS promoter/cDNA-containing lentiviral vector and nonlethal irradiation. Hum Gene Ther 17(3):303–313PubMedCrossRefGoogle Scholar
  34. Fischer A, Cavazzana-Calvo M (2008) Gene therapy of inherited diseases. Lancet 371(9629):2044–2047PubMedCrossRefGoogle Scholar
  35. Gaspar HB, Cooray S, Gilmour KC et al (2011a) Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 3(97):97ra79PubMedGoogle Scholar
  36. Gaspar HB, Cooray S, Gilmour KC et al (2011b) Hematopoietic stem cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction. Sci Transl Med 3(97):97ra80PubMedGoogle Scholar
  37. Gennery AR, Slatter MA, Grandin L et al (2010) 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 126(3):602–610, e601-611PubMedCrossRefGoogle Scholar
  38. Greene MR, Lockey T, Mehta PK et al (2012) Transduction of human CD34+ repopulating cells with a self-inactivating lentiviral vector for SCID-X1 produced at clinical scale by a stable cell line. Hum Gene Ther Methods 23(5):297–308PubMedCentralPubMedCrossRefGoogle Scholar
  39. Grez M, Reichenbach J, Schwable J, Seger R, Dinauer MC, Thrasher AJ (2011) Gene therapy of chronic granulomatous disease: the engraftment dilemma. Mol Ther 19(1):28–35PubMedCentralPubMedCrossRefGoogle Scholar
  40. Griffith LM, Cowan MJ, Notarangelo LD et al (2013) Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol doi:10.1016/j.jaci.2013.07.052.
  41. Gungor T, Teira P, Slatter M et al (2014) Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. Lancet 383(9915):436–448PubMedCrossRefGoogle Scholar
  42. Hacein-Bey-Abina S, von Kalle C, Schmidt M et al (2003) A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 348(3):255–256PubMedCrossRefGoogle Scholar
  43. Hacein-Bey-Abina S, Hauer J, Lim A et al (2010) Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 363(4):355–364PubMedCentralPubMedCrossRefGoogle Scholar
  44. Hassan A, Booth C, Brightwell A et al (2012) Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood 120(17):3615–3624, quiz 3626PubMedCrossRefGoogle Scholar
  45. Henter JI, Samuelsson-Horne A, Arico M et al (2002) Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 100(7):2367–2373PubMedCrossRefGoogle Scholar
  46. Hershfield MS (1998) Adenosine deaminase deficiency: clinical expression, molecular basis, and therapy. Semin Hematol 35(4):291–298PubMedGoogle Scholar
  47. Holland SM (2013) Chronic granulomatous disease. Hematol Oncol Clin North Am 27(1):89–99, viii. doi:10.1016/j.hoc.2012.11.002
  48. Huston MW, van Til NP, Visser TP et al (2011) Correction of murine SCID-X1 by lentiviral gene therapy using a codon-optimized IL2RG gene and minimal pretransplant conditioning. Mol Ther 19(10):1867–1877PubMedCentralPubMedCrossRefGoogle Scholar
  49. Kang EM, Marciano BE, DeRavin S, Zarember KA, Holland SM, Malech HL (2011) Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol 127(6):1319–1326, quiz 1327-1318PubMedCentralPubMedCrossRefGoogle Scholar
  50. Kaufmann KB, Buning H, Galy A, Schambach A, Grez M (2013) Gene therapy on the move. EMBO Mol Med 5(11):1642–1661PubMedCentralPubMedCrossRefGoogle Scholar
  51. Lagresle-Peyrou C, Benjelloun F, Hue C et al (2008) Restoration of human B-cell differentiation into NOD-SCID mice engrafted with gene-corrected CD34+ cells isolated from Artemis or RAG1-deficient patients. Mol Ther 16(2):396–403PubMedCrossRefGoogle Scholar
  52. Ma CS, Nichols KE, Tangye SG (2007) Regulation of cellular and humoral immune responses by the SLAM and SAP families of molecules. Annu Rev Immunol 25:337–379PubMedCrossRefGoogle Scholar
  53. Marangoni F, Poli A, Agostoni C et al (2009) A consensus document on the role of breakfast in the attainment and maintenance of health and wellness. Acta Biomed 80(2):166–171PubMedGoogle Scholar
  54. Massaad MJ, Ramesh N, Geha RS (2013) Wiskott-Aldrich syndrome: a comprehensive review. Ann N Y Acad Sci 1285:26–43PubMedCrossRefGoogle Scholar
  55. Moratto D, Giliani S, Bonfim C et al (2011) 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 118(6):1675–1684PubMedCentralPubMedCrossRefGoogle Scholar
  56. Mortellaro A, Hernandez RJ, Guerrini MM et al (2006) Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)-deficient mice and corrects their immune and metabolic defects. Blood 108(9):2979–2988PubMedCrossRefGoogle Scholar
  57. Moshous D, Callebaut I, de Chasseval R et al (2001) Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105(2):177–186PubMedCrossRefGoogle Scholar
  58. Mukherjee S, Thrasher AJ (2013) Gene therapy for PIDs: progress, pitfalls and prospects. Gene 525(2):174–181PubMedCentralPubMedCrossRefGoogle Scholar
  59. Multhaup M, Karlen AD, Swanson DL et al (2010) Cytotoxicity associated with artemis overexpression after lentiviral vector-mediated gene transfer. Hum Gene Ther 21(7):865–875PubMedCentralPubMedCrossRefGoogle Scholar
  60. Neven B, Leroy S, Decaluwe H et al (2009) Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency. Blood 113(17):4114–4124PubMedCrossRefGoogle Scholar
  61. Noguchi M, Yi H, Rosenblatt HM et al (1993) Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73(1):147–157PubMedCrossRefGoogle Scholar
  62. Ott MG, Schmidt M, Schwarzwaelder K et al (2006) Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med 12(4):401–409PubMedCrossRefGoogle Scholar
  63. Pachlopnik Schmid J, Canioni D, Moshous D et al (2011) Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 117(5):1522–1529PubMedCrossRefGoogle Scholar
  64. Pai SY, Notarangelo LD (2010) Hematopoietic cell transplantation for Wiskott-Aldrich syndrome: advances in biology and future directions for treatment. Immunol Allergy Clin North Am 30(2):179–194PubMedCentralPubMedCrossRefGoogle Scholar
  65. Passerini L, Mel ER, Sartirana C et al (2013) CD4+ T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene transfer. Sci Transl Med 5(215):215ra174PubMedCrossRefGoogle Scholar
  66. Pike-Overzet K, Rodijk M, Ng YY et al (2011) Correction of murine Rag1 deficiency by self-inactivating lentiviral vector-mediated gene transfer. Leukemia 25(9):1471–1483PubMedCrossRefGoogle Scholar
  67. Revy P, Buck D, le Deist F, de Villartay JP (2005) The repair of DNA damages/modifications during the maturation of the immune system: lessons from human primary immunodeficiency disorders and animal models. Adv Immunol 87:237–295PubMedCrossRefGoogle Scholar
  68. Rivat C, Booth C, Alonso-Ferrero M et al (2013) SAP gene transfer restores cellular and humoral immune function in a murine model of X-linked lymphoproliferative disease. Blood 121(7):1073–1076PubMedCentralPubMedCrossRefGoogle Scholar
  69. Santilli G, Almarza E, Brendel C et al (2011) Biochemical correction of X-CGD by a novel chimeric promoter regulating high levels of transgene expression in myeloid cells. Mol Ther 19(1):122–132PubMedCentralPubMedCrossRefGoogle Scholar
  70. Scaramuzza S, Biasco L, Ripamonti A et al (2013) Preclinical safety and efficacy of human CD34(+) cells transduced with lentiviral vector for the treatment of Wiskott-Aldrich syndrome. Mol Ther 21(1):175–184PubMedCentralPubMedCrossRefGoogle Scholar
  71. Schwarz K, Gauss GH, Ludwig L et al (1996) RAG mutations in human B cell-negative SCID. Science 274(5284):97–99PubMedCrossRefGoogle Scholar
  72. Scobie L, Hector RD, Grant L et al (2009) A novel model of SCID-X1 reconstitution reveals predisposition to retrovirus-induced lymphoma but no evidence of gammaC gene oncogenicity. Mol Ther 17(6):1031–1038PubMedCentralPubMedCrossRefGoogle Scholar
  73. Seger RA (2010) Advances in the diagnosis and treatment of chronic granulomatous disease. Curr Opin Hematol Nov 11. [Epub ahead of print]Google Scholar
  74. Stein S, Ott MG, Schultze-Strasser S et al (2010) Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med 16(2):198–204PubMedCrossRefGoogle Scholar
  75. Thrasher AJ, Burns SO (2010) WASP: a key immunological multitasker. Nat Rev Immunol 10(3):182–192PubMedCrossRefGoogle Scholar
  76. van der Loo JC, Swaney WP, Grassman E et al (2012) Critical variables affecting clinical-grade production of the self-inactivating gamma-retroviral vector for the treatment of X-linked severe combined immunodeficiency. Gene Ther 19(8):872–876PubMedCrossRefGoogle Scholar
  77. Winkelstein JA, Marino MC, Johnston RB Jr et al (2000) Chronic granulomatous disease. Report on a national registry of 368 patients. Med (Baltimore) 79(3):155–169CrossRefGoogle Scholar
  78. Yagi H, Nomura T, Nakamura K et al (2004) Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol 16(11):1643–1656PubMedCrossRefGoogle Scholar
  79. Zhang F, Thornhill SI, Howe SJ et al (2007) Lentiviral vectors containing an enhancer-less ubiquitously acting chromatin opening element (UCOE) provide highly reproducible and stable transgene expression in hematopoietic cells. Blood 110(5):1448–1457PubMedCentralPubMedCrossRefGoogle Scholar
  80. Zhang F, Frost AR, Blundell MP, Bales O, Antoniou MN, Thrasher AJ (2010) A ubiquitous chromatin opening element (UCOE) confers resistance to DNA methylation-mediated silencing of lentiviral vectors. Mol Ther 18(9):1640–1649PubMedCentralPubMedCrossRefGoogle Scholar
  81. Zhou S, Mody D, DeRavin SS et al (2010) A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells. Blood 116(6):900–908PubMedCentralPubMedCrossRefGoogle Scholar
  82. Ziegler SF (2006) FOXP3: of mice and men. Annu Rev Immunol 24:209–226PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Giada Farinelli
    • 1
  • Valentina Capo
    • 1
  • Samantha Scaramuzza
    • 2
  • Alessandro Aiuti
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of PediatricsChildren’s Hospital Bambino Gesù and University of Rome Tor Vergata School of MedicineRomeItaly
  2. 2.San Raffaele Telethon Institute for Gene Therapy (TIGET)Scientific Institute HS RaffaeleMilanItaly
  3. 3.Dip. di Medicina dei SistemiUniversity of Rome Tor VergataRomaItaly
  4. 4.HSR-TIGET, Scientific Institute San RaffaeleMilanoItaly

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