Gene therapy of inherited immunodeficiencies

Expert Opinion on Biological Therapy

Volumn 8, Issue 4, 2008, Pages 397-407

  Santilli, Giorgia ^b   Thornhill, Susannah I ^a   Kinnon, Christine ^a   Thrasher, Adrian J ^a,c  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

^c Department of Clinical Immunology ^*  (United Kingdom)

Author keywords

Chronic granulomatous disease; Gene therapy; Retroviral vectors; Severe combined immunodeficiency; WASP

Indexed keywords

ADENOSINE DEAMINASE; ANTIBIOTIC AGENT; ANTIFUNGAL AGENT; BUSULFAN; LENTIVIRUS VECTOR; MACROGOL; MELPHALAN; PROTEIN P47; RECOMBINANT GAMMA INTERFERON; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 2; RETROVIRUS VECTOR;

ADENOSINE DEAMINASE DEFICIENCY; CLINICAL TRIAL; DRUG DELIVERY SYSTEM; GENE EXPRESSION; GENE MUTATION; GENE THERAPY; GENE TRANSFER; GRANULOMATOSIS; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HLA SYSTEM; HUMAN; INHERITANCE; NONHUMAN; REVIEW; WISKOTT ALDRICH SYNDROME; X LINKED SEVERE COMBINED IMMUNODEFICIENCY; ANIMAL; CHRONIC GRANULOMATOUS DISEASE; GENE VECTOR; GENETICS; IMMUNE DEFICIENCY; IMMUNOLOGY; METHODOLOGY; RETROVIRUS; SEVERE COMBINED IMMUNODEFICIENCY; TREATMENT OUTCOME;

ANIMALS; GENE THERAPY; GENETIC VECTORS; GRANULOMATOUS DISEASE, CHRONIC; HUMANS; IMMUNOLOGIC DEFICIENCY SYNDROMES; RETROVIRIDAE; SEVERE COMBINED IMMUNODEFICIENCY; TREATMENT OUTCOME; WISKOTT-ALDRICH SYNDROME; X-LINKED COMBINED IMMUNODEFICIENCY DISEASES;

EID: 42149136941     PISSN: 14712598     EISSN: None     Source Type: Journal    
DOI: 10.1517/14712598.8.4.397     Document Type: Review

References (96)

1. Heissig B, Ohki Y, Sato Y, et al. A role for niches in hematopoietic cell development. Hematology 2005;10:247-53
2. Dornburg R. The history and principles of retroviral vectors. Front Biosci 2003;8:d818-35
3. Miller DG, Adam MA, Miller AD. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol Cell Biol 1990;10:4239-42
4. Fischer A, Le DF, Hacein-Bey-Abina S, et al. Severe combined immunodeficiency. A model disease for molecular immunology and therapy. Immunol Rev 2005;203:98-109
5. Noguchi M, Yi H, Rosenblatt HM, et al. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 1993;73:147-57
6. Parrish-Novak J, Dillon SR, Nelson A, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 2000;408:57-63
7. White H, Thrasher A, Veys P, Kinnon C, Gaspar HB. Intrinsic defects of B cell function in X-linked severe combined immunodeficiency. Eur J Immunol 2000;30:732-7
8. Macchi P, Villa A, Giliani S, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 1995;377:65-8
9. Antoine C, Muller S, Cant A, et al. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-1999. Lancet 2003;361:553-60
10. Haddad E, Landais P, Friedrich W, et al. Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients. Blood 1998;91:3646-53
11. Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999;340:508-16
12. Bousso P, Wahn V, Douagi I, et al. Diversity, functionality, and stability of the T cell repertoire derived in vivo from a single human T cell precursor. Proc Natl Acad Sci USA 2000;97:274-8
13. Cavazzana-Calvo M, Hacein-Bey S, De Saint BG, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000;288:669-72 •• The first successful gene therapy trial for SCID-X1 using a gammaretroviral vector.
14. Hacein-Bey-Abina S, Le DF, Carlier F, et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 2002;346:1185-93
15. Gaspar HB, Parsley KL, Howe S, et al. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 2004;364:2181-7
16. Thrasher AJ, Hacein-Bey-Abina S, Gaspar HB, et al. Failure of SCID-X1 gene therapy in older patients. Blood 2005;105:4255-7 • In this paper it is reported that success of gene therapy for SCID-X1 is dependent on patient age.
17. Chinen J, Davis J, De Ravin SS, et al. Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency. Blood 2007;110:67-73
18. Hale LP, Buckley RH, Puck JM, Patel DD. Abnormal development of thymic dendritic and epithelial cells in human X-linked severe combined immunodeficiency. Clin Immunol 2004;110:63-70
19. Booth C, Hershfield M, Notarangelo L, et al. Management options for adenosine deaminase deficiency. Proceedings of the EBMT Satellite Workshop (Hamburg, March 2006). Clin Immunol 2007;123:139-47
20. Chaffee S, Mary A, Stiehm ER, et al. IgG antibody response to polyethylene glycol-modified adenosine deaminase in patients with adenosine deaminase deficiency. J Clin Invest 1992;89:1643-51
21. Blaese RM, Culver KW, Miller AD, et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 1995;270:475-80
22. 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
23. Bordignon C, Notarangelo LD, Nobili N, et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science 1995;270:470-5
24. Hoogerbrugge PM, van BV, Fischer A, et al. Bone marrow gene transfer in three parients with adenosine deaminase deficiency. Gene Ther 1996;3:179-83
25. Kohn DB, Weinberg KI, Nolta JA, et al. Engraftment of gene-modified umbilical cord blood cells in neonates with adenosine deaminase deficiency. Nat Med 1995;1:1017-23
26. 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;8:423-5
27. Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 2002;296:2410-3 •• The first successful gene therapy trial for ADA-SCID with non-myeloablative conditioning prior to reinfusion of the virally-transduced stem cells and cessation of PEG-ADA treatment.
28. Gaspar HB, Bjorkegren E, Parsley K, et al. Successful reconstitution of immunity in ADA-SCID by stem cell gene therapy following cessation of PEG-ADA and use of mild preconditioning. Mol Ther 2006;14:505-13
29. Candotti F, Kohn DB. Gene Therapy for adenosine deaminase deficiency in the USA. IVth Conference on Stem Cell Gene Therapy; 2007
30. Engel BC, Podsakoff GM, Ireland JL, et al. Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report. Blood 2007;109:503-6
31. Ariga T. Hematopoietic stem cell (HSC) gene therapy for two patients with adenosine deaminase (ADA) deficiency without cytoreductive conditioning; a suggestion for the optimal protocol for HSC gene therapy for ADA deficiency. IVth Conference on Stem Cell Gene Therapy; 2007
32. 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;108:2979-88
33. Carbonaro DA, Jin X, Petersen D, et al. In vivo transduction by intravenous injection of a lentiviral vector expressing human ADA into neonatal ADA gene knockout mice: a novel form of enzyme replacement therapy for ADA deficiency. Mol Ther 2006;13:1110-20
34. Deny JM, Ochs HD, Francke U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell 1994;78(4):635-44. Erratum in: Cell 1994;79(5):following page 922
35. Ochs HD, Thrasher AJ. The Wiskott-Aldrich syndrome. J Allergy Clin Immunol 2006;117:725-38
36. Millard TH, Sharp SJ, Machesky LM. Signalling to actin assembly via the WASP (Wiskott-Aldrich syndrome protein)-family proteins and the Arp2/3 complex. Biochem J 2004;380:1-17
37. Proust A, Guillet B, Picard C, et al. Detection of 28 novel mutations in the Wiskott-Aldrich syndrome and X-linked thrombocytopenia based on multiplex PCR. Blood Cells Mol Dis 2007;39:102-6
38. Devriendt K, Kim AS, Mathijs G, et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet 2001;27:313-7
39. Moulding DA, Blundell MP, Spiller DG, et al. Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia. J Exp Med 2007;204:2213-24
40. 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;6:1170-4
41. Wada T, Jagadeesh GJ, Nelson DL, Candotti F. Retrovirus-mediated WASP gene transfer corrects Wiskott-Aldrich syndrome T-cell dysfunction. Hum Gene Ther 2002;13:1039-46
42. Strom TS, Turner SJ, Andreansky S, et al. Defects in T-cell-mediated immunity to influenza virus in murine Wiskott-Aldrich syndrome are corrected by oncoretroviral vector-mediated gene transfer into repopulating hematopoietic cells. Blood 2003;102:3108-16
43. 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 oncoretroviral vector encoding the WAS protein. Gene Ther 2003;10:803-9
44. 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;101:2159-66
45. Boztug K, Dewey RA, Klein C. Development of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome. Curr Opin Mol Ther 2006;8:390-5
46. Dupre 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;10:903-15
47. Dupre 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;17:303-13
48. Charrier S, Stockholm D, Seye K, et al. A lentiviral vector encoding the human Wiskott-Aldrich syndrome protein corrects immune and cytoskeletal defects in WASP knockout mice. Gene Ther 2005;12:597-606
49. Charrier S, Dupre L, Scaramuzza S, et al. Lentiviral vectors targeting WASp expression to hematopoietic cells, efficiently transduce and correct cells from WAS patients. Gene Ther 2007;14:415-28 • First report of gene correction with a lentiviral vector containing the haematopoietic-specific WAS promoter.
50. Ariga T, Kondoh T, Yamaguchi K, et al. Spontaneous in vivo reversion of an inherited mutation in the Wiskott-Aldrich syndrome. J Immunol 2001;166:5245-9
51. Wada T, Schurman SH, Otsu M, et al. Somatic mosaicism in Wiskott - Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proc Natl Acad Sci USA 2001;98:8697-702
52. Wengler G, Gorlin JB, Williamson JM, Rosen FS, Bing DH. Nonrandom inactivation of the X chromosome in early lineage hematopoietic cells in carriers of Wiskott-Aldrich syndrome. Blood 1995;85:2471-7
53. Martin F, Toscano MG, Blundell M, et al. Lentiviral vectors transcriptionally targeted to hematopoietic cells by WASP gene proximal promoter sequences. Gene Ther 2005;12:715-23
54. Galy A, Roncarolo MG, Thrasher AJ. Development of lentiviral gene therapy for Wiskott Aldrich syndrome. Expert Opin Biol Ther 2008;8:181-90
55. Babior BM. NADPH oxidase. Curr Opin Immunol 2004;16:42-7
56. Segal AW. How neutrophils kill microbes. Ann Rev Immunol 2005;23:197-223
57. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 2000;79:155-69
58. Seger RA, Gungor T, Belohradsky BH, et al. Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985 - 2000. Blood 2002;100:4344-50
59. Horwitz ME, Barrett AJ, Brown MR, et al. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. N Engl J Med 2001;344:881-8
60. Woodman RC, Newburger PE, Anklesaria P, et al. A new X-linked variant of chronic granulomatous disease characterized by the existence of a normal clone of respiratory burst-competent phagocytic cells. Blood 1995;85:231-41
61. Malech HL, Choi U, Brenner S. Progress toward effective gene therapy for chronic granulomatous disease. Jpn J Infect Dis 2004;57:S27-8
62. 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;12:401-9 •• Report describing gene therapy for X-CGD achieved with a gammaretroviral vector and a non-myeloablative dose of busulphan.
63. European Society of Gene Therapy (ESGT). One of three successfully treated CGD patients in a Swiss-German gene therapy trial died due to his underlying disease: a position statement from the European Society of Gene Therapy (ESGT). J Gene Med 2006;8:1435
64. Grez M, Hoelzer D, Ott MG. Gene therapy of chronic granulomatous disease: results and perspectives. 4th Annual Conference of British Society for Gene Therapy; 2007
65. Grez M, Ott M, Stein S, et al. PhaseI/II gene therapy study for X-CGD: results, lessons and perspectives. IVth Conference on Stem Cell Gene Therapy; 2007
66. Hacein-Bey-Abina S, von KC, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003;348:255-6 •• First report of insertional mutagenesis after gene therapy. Retroviral vector integration in proximity to the LMO2 proto-oncogene promoter results in the dysregulated expression of LMO2 and the clonal cell expansion of T cells.
67. Deichmann A, Hacein-Bey-Abina S, Schmidt M, et al. Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy. J Clin Invest 2007;117:2225-32 •• A study of retroviral vector integration sites in SCID-X1 patients treated with gene therapy, revealing that one quarter of all integrations were clustered at common integration sites, several of which may influence cell engraftment, survival and proliferation.
68. 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 •• A study describing the mapping of retroviral integration sites in T cells from SCID-X1 patients treated in the London gene therapy trial. It shows that vector integration sites are skewed towards refseq genes with no integrations detected at the LMO2 locus.
69. Schroder AR, Shinn P, Chen H, et al. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002;110:521-9 •• A landmark study of HIV-1 integration. It shows that HIV-1 lentiviral vectors integrate preferentially within genes.
70. Wu X, Li Y, Crise B, Burgess SM. Transcription start regions in the human genome are favored targets for MLV integration. Science 2003;300:1749-51 •• A landmark study of MLV integration site preferences revealing a bias for transcriptional start sites.
71. Bushman FD. Targeting survival: integration site selection by retroviruses and LTR-retrotransposons. Cell 2003;115:135-8
72. Thrasher AJ, Gaspar HB, Baum C, et al. X-SCID transgene leukaemogenicity. Nature 2006;443:E5-6. Published online 20 September 2006, doi:10.1038/ nature05219
73. Pike-Overzet K, de RD, Weerkamp F, et al. Gene therapy: is IL2RG oncogenic in T-cell development? Nature 2006;443:E5. Published online 20 September 2006, doi:10.1038/nature05218
74. Boehm T, Foroni L, Kaneko Y, Perutz MF, Rabbitts TH. The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. Proc Natl Acad Sci USA 1991;88:4367-71
75. Pike-Overzet K, de RD, Weerkamp F, et al. Ectopic retroviral expression of LMO2, but not IL2Rγ, blocks human T-cell development from CD34+ cells: implications for leukemogenesis in gene therapy. Leukemia 2007;21:754-63
76. Dave UP, Jenkins NA, Copeland NG. Gene therapy insertional mutagenesis insights. Science 2004;303:333
77. Woods NB, Bottero V, Schmidt M, von KC, Verma IM. Gene therapy: therapeutic gene causing lymphoma. Nature 2006;440:1123 • A report of a possible role of gc in the development of lymphomas with a long latency in a lentivirus-mediated gene therapy model.
78. Calmels B, Ferguson C, Laukkanen MO, et al. Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells. Blood 2005;106:2530-3
79. Montini E, Cesana D, Schmidt M, et al. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol 2006;24:687-96
80. Shou Y, Ma Z, Lu T, Sorrentino BP. Unique risk factors for insertional mutagenesis in a mouse model of XSCID gene therapy. Proc Natl Acad Sci USA 2006;103:11730-5
81. Modlich U, Bohne J, Schmidt M, et al. Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity. Blood 2006;108:2545-53
82. Mostoslavsky G, Fabian AJ, Rooney S, Alt FW, Mulligan RC. Complete correction of murine Artemis immunodeficiency by lentiviral vector-mediated gene transfer. Proc Natl Acad Sci USA 2006;103:16406-11
83. Adjali O, Marodon G, Steinberg M, et al. In vivo correction of ZAP-70 immunodeficiency by intrathymic gene transfer. J Clin Invest 2005;115:2287-95
84. Yates F, Malassis-Seris M, Stockholm D, et al. Gene therapy of RAG-2-/- mice: sustained correction of the immunodeficiency. Blood 2002;100:3942-9
85. Lagresle-Peyrou C, Yates F, Malassis-Seris M, et al. Long-term immune reconstitution in RAG-1-deficient mice treated by retroviral gene therapy: a balance between efficiency and toxicity. Blood 2006;107:63-72
86. Yu SF, von RT, Kantoff PW, et al. Self-inactivating retroviral vectors designed for transfer of whole genes into mammalian cells. Proc Natl Acad Sci USA 1986;83:3194-8
87. Thornhill SI, Schambach A, Howe SJ, et al. Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency. Mol Ther 2008
88. Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996;272:263-7
89. Yanez-Munoz RJ, Balaggan KS, MacNeil A, et al. Effective gene therapy with nonintegrating lentiviral vectors. Nat Med 2006;12:348-53 • The first report of stable expression of therapeutic genes in rodent models of retinal degeneration using non-integrating lentiviral vectors. The use of non-integrating vectors is an important step towards safer gene therapy.
90. Papapetrou EP, Ziros PG, Micheva ID, Alt FW, Mulligan RC. Gene transfer into human hematopoietic progenitor cells with an episomal vector carrying an S/MAR element. Gene Ther 2006;13:40-51
91. Thyagarajan B, Olivares EC, Hollis RP, Ginsburg DS, Calos MP. Site-specific genomic integration in mammalian cells mediated by phage phiC31 integrase. Mol Cell Biol 2001;21:3926-34
92. Urnov FD, Miller JC, Lee YL, et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 2005;435:646-51
93. Sorrentino BP, Brandt SJ, Bodine D, et al. Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDRI. Science 1992;257:99-103
94. Davis BM, Koc ON, Gerson SL. Limiting numbers of G156A O(6)-methylguanine-DNA methyltransferase-transduced marrow progenitors repopulate nonmyeloablated mice after drug selection. Blood 2000;95:3078-84
95. Allay JA, Persons DA, Galipeau J, et al. In vivo selection of retrovirally transduced hematopoietic stem cells. Nat Med 1998;4:1136-43
96. Rappa G, Anzanello F, Alexeyev M, Fodstad O, Lorico A. Gamma-glutamylcysteine synthetase-based selection strategy for gene therapy of chronic granulomatous disease and graft-vs.-host disease. Eur J Haematol 2007;78:440-8