Clinical applications of gene therapy for primary immunodeficiencies

Human Gene Therapy

Volumn 26, Issue 4, 2015, Pages 210-219

  Cicalese, Maria Pia ^a,b   Aiuti, Alessandro ^a,b,c  

^a SAN RAFFAELE SCIENTIFIC INSTITUTE   (Italy)

^b SAN RAFFAELE HOSPITAL   (Italy)

^c VITA SALUTE SAN RAFFAELE UNIVERSITY   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE DEAMINASE; ANTIBIOTIC AGENT; COMPLEMENTARY DNA; GAMMA INTERFERON; GENE THERAPY AGENT; GRANULOCYTE COLONY STIMULATING FACTOR; MICRORNA 126;

ADENOSINE DEAMINASE DEFICIENCY; ANTIBIOTIC PROPHYLAXIS; BONE MARROW TRANSPLANTATION; CHRONIC GRANULOMATOUS DISEASE; CLINICAL TRIAL (TOPIC); ENZYME REPLACEMENT; GENE THERAPY; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMAN; IMMUNE DEFICIENCY; IMMUNOTHERAPY; LONG TERMINAL REPEAT; MOLONEY MURINE LEUKEMIA VIRUS; MULTICENTER STUDY (TOPIC); NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); REVIEW; WISKOTT ALDRICH SYNDROME; X LINKED SEVERE COMBINED IMMUNODEFICIENCY; ANIMAL; GENETICS; SEVERE COMBINED IMMUNODEFICIENCY;

ANIMALS; CLINICAL TRIALS AS TOPIC; GENETIC THERAPY; HUMANS; SEVERE COMBINED IMMUNODEFICIENCY;

EID: 84928475324     PISSN: 10430342     EISSN: 15577422     Source Type: Journal    
DOI: 10.1089/hum.2015.047     Document Type: Review

References (122)

1. 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.
2. Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol 2014;46:154-168.
3. Fischer A, Hacein-Bey-Abina S, Touzot F, et al. Gene therapy for primary immunodeficiencies. Clin Genet 2015. [Epub ahead of print]
4. Zhang L, Thrasher AJ, Gaspar HB. Current progress on gene therapy for primary immunodeficiencies. Gene Ther 2013;20:963-969.
5. Mukherjee S, Thrasher AJ. Gene therapy for PIDs: progress, pitfalls and prospects. Gene 2013;525:174-181.
6. Borte S, von Dobeln U, Fasth A, et al. Neonatal screening for severe primary immunodeficiency diseases using highthroughput triplex real-time PCR. Blood 2012;119:2552-2555.
7. Kildebeck E, Checketts J, Porteus M. Gene therapy for primary immunodeficiencies. Curr Opin Pediatr 2012;24: 731-738.
8. Rivat C, Santilli G, Gaspar HB, et al. Gene therapy for primary immunodeficiencies. Hum Gene Ther 2012;23: 668-675.
9. Chinen J, Notarangelo LD, Shearer WT. Advances in basic and clinical immunology in 2013. J Allergy Clin Immunol 2014;133:967-976.
10. 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.
11. 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;127:1394-1399.
12. Buckley RH. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res 2011;49:25-43.
13. Pai SY, Logan BR, Griffith LM, et al. Transplantation outcomes for severe combined immunodeficiency, 2000- 2009. N Engl J Med 2014;371:434-446.
14. 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; 126:602-610.
15. 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;118:1675-1684.
16. 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;124:822-826.
17. 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: 436-448.
18. Fischer A, Cavazzana-Calvo M. Gene therapy of inherited diseases. Lancet 2008;371:2044-2047.
19. Hacein-Bey-Abina S, Pai SY, Gaspar HB, et al. A modified c-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med 2014;371:1407-1417.
20. Neven B, Leroy S, Decaluwe H, et al. Long-term outcome after haematopoietic stem cell transplantation of a single-centre cohort of 90 patients with severe combined immunodeficiency: long-term outcome of HSCT in SCID. Blood 2009;113:4114-4124.
21. Antoine C, Muller S, Cant A, et al. Long-term survival and transplantation of haemopoietic stem cells forimmunodeficiencies: report of the European experience 1968-99. Lancet 2003;361:553-560.
22. 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;97:274-278.
23. Candotti F. Gene transfer into hematopoietic stem cells as treatment for primary immunodeficiency diseases. Int J Hematol 2014;99:383-392.
24. Cavazzana-Calvo M, Fischer A, Hacein-Bey-Abina S, et al. Gene therapy for primary immunodeficiencies: part 1. Curr Opin Immunol 2012;24:580-584.
25. 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;363:355-364.
26. 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;3:97ra79.
27. Thornhill SI, Schambach A, Howe SJ, et al. Selfinactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency. Mol Ther 2008;16:590-598.
28. Zychlinski D, Schambach A, Modlich U, et al. Physiological promoters reduce the genotoxic risk of integrating gene vectors. Mol Ther 2008;16:718-725.
29. 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; 116:900-908.
30. 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.
31. Aiuti A, Brigida I, Ferrua F, et al. Hematopoietic stem cell gene therapy for adenosine deaminase deficient-SCID. Immunol Res 2009;44:150-159.
32. Gaspar HB, Aiuti A, Porta F, et al. How I treat ADA deficiency. Blood 2009;114:3524-3532.
33. 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;13:630-638.
34. Hirschhorn R, Candotti F. Immunodeficiency due to defects of purine metabolism. In: Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, 2nd ed. H Ochs, CIE Smith, JM Puck, eds. (Oxford University Press, New York, NY). 2006; pp. 169-196.
35. 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;109:3595-3602.
36. 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;114:3216-3226.
37. Hassan A, Booth C, Brightwell A, et al. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency Blood 2012;120:3615-3624; quiz 3626.
38. Pai SY, Logan BR, Griffith LM, et al. Transplantation outcomes for severe combined immunodeficiency, 2000- 2009. N Engl J Med 2014;371:434-446.
39. Weinberg K, Hershfield MS, Bastian J, et al. T lymphocyte ontogeny in adenosine deaminase-deficient severe combined immune deficiency after treatment with polyethylene glycol-modified adenosine deaminase. J Clin Invest 1993;92:596-602.
40. Kohn DB. Gene therapy for childhood immunological diseases. Bone Marrow Transplant 2008;41:199-205.
41. Malacarne F, Benicchi T, Notarangelo LD, et al. Reduced thymic output, increased spontaneous apoptosis and oligoclonal B cells in polyethylene glycol-adenosine deaminase- treated patients. Eur J Immunol 2005;35:3376-3386.
42. Notarangelo LD, Stoppoloni G, Toraldo R, et al. Insulindependent diabetes mellitus and severe atopic dermatitis in a child with adenosine deaminase deficiency. Eur J Pediatr 1992;151:811-814.
43. Ozsahin H, Arredondo-Vega FX, Santisteban I, et al. Adenosine deaminase deficiency in adults. Blood 1997; 89:2849-2855.
44. Sauer AV, Brigida I, Carriglio N, et al. Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency. Front Immunol 2012;3:265.
45. Sauer AV, Brigida I, Carriglio N, et al. Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID. Blood 2012;119:1428-1439.
46. Brigida I, Sauer AV, Ferrua F, et al. B-cell development and functions and herapeutic options in adenosine deaminase- deficient patients. J Allergy Clin Immunol 2014; 133:799-806.
47. Bordignon C, Mavilio F, Ferrari G, et al. Transfer of the ADA gene into bone marrow cells and peripheral blood lymphocytes for the treatment of patients affected by ADA-deficient SCID. Hum Gene Ther 1993;4:513-520.
48. Blaese RM. Optimism regarding the use of RNA/DNA hybrids to repair genes at high efficiency. J Gene Med 1999;1:144-147.
49. 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;101:2563-2569.
50. Biasco L, Scala S, Basso Ricci L, et al. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Sci Transl Med 2015;7:273ra13.
51. Gaspar HB, Qasim W, Davies EG, et al. How I treat severe combined immunodeficiency. Blood 2013;122:3749-3758.
52. 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.
53. 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.
54. Aiuti A, Cattaneo F, Galimberti S, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 2009;360:447-458.
55. Gaspar HB, Cooray S, Gilmour KC, et al. Hematopoietic stem cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction. Sci Transl Med 2011;3:97ra80.
56. 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;120:3635-3646.
57. Biasco L, Ambrosi A, Pellin D, et al. Integration profile of retroviral vector in gene therapy treated patients is cellspecific according to gene expression and chromatin onformation of target cell. EMBO Mol Med 2011;3:89-101.
58. Aiuti A, Cassani B, Andolfi G, et al. Multilineage hematopoietic reconstitution without clonal selection in ADASCID patients treated with stem cell gene therapy. J Clin Invest 2007;117:2233-2240.
59. 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;108:2979-2988.
60. 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: 607-622.
61. EBMT/ESID Guidelines for Haematopoietic Stem Cell Transplantation for Primary Immunodeciencies, 2011. www.ebmt.org/Contents/About-EBMT/Who-We-Are/ScientificCouncil/Documents/EBMT-ESID%20GUIDELINES%20FOR%20INBORN%20ERRORS%20FINAL%202011.pdf (accessed April 16, 2015).
62. Derry JM, Kerns JA, Weinberg KI, et al. WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. Hum Mol Genet 1995;4:1127-1135.
63. Catucci M, Castiello MC, Pala F, et al. Autoimmunity in wiskott-Aldrich syndrome: an unsolved enigma. Front Immunol 2012;3:209.
64. Thrasher AJ. WASp in immune-system organization and function. Nat Rev Immunol 2002;2:635-646.
65. Huang H, Manton KG. Newborn screening for severe combined immunodeficiency (SCID): a review. Front Biosci 2005;10:1024-1039.
66. 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;276:21450-21457.
67. 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 Bloodand Marrow Transplantation. Blood 2008;111:439-445.
68. 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;97:1598-1603.
69. 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;135:362-366.
70. Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. 20 years of gene therapy for SCID. Nat Immunol 2010;11: 457-460.
71. 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;6:1170-1174.
72. Wada T, Jagadeesh GJ, Nelson DL, et al. Retrovirusmediated WASP gene transfer corrects Wiskott-Aldrich syndrome T-cell dysfunction. Hum Gene Ther 2002;13: 1039-1046.
73. 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;101:2159-2166.
74. 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;10:803-809.
75. Galy A, Roncarolo MG, Thrasher AJ. Development of lentiviral gene therapy for Wiskott Aldrich syndrome. Expert Opin Biol Ther 2008;8:181-190.
76. Dupré L, Trifari S, Follenzi A, et al. Lentiviral vectormediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction. Mol Ther 2004;10:903-915.
77. Braun CJ, Boztug K, Paruzynski A, et al. Gene therapy for Wiskott-Aldrich Syndrome-long-term efficacy and genotoxicity. Sci Transl Med 2014;6:227ra33.
78. Thrasher AJ, Burns SO. WASP: a key immunological multitasker. Nat Rev Immunol 2010;10:182-192.
79. Boztug K, Schmidt M, Schwarzer A, et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med 2010;363:1918-1927.
80. 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;112:4139-4147.
81. 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.
82. 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;118:3143-3150.
83. 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;16:198-204.
84. 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;17:303-313.
85. 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;17:1073-1082.
86. 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;21:175-184.
87. Aiuti A, Biasco L, Scaramuzza S, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott- Aldrich syndrome. Science 2013;341:1233151.
88. Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013;341:1233158.
89. Bosticardo M, Ferrua F, Cavazzana M, et al. Gene therapy for Wiskott-Aldrich Syndrome. Curr Gene Ther 2014;14: 413-421.
90. Astrakhan A, Sather BD, Ryu BY, et al. Ubiquitous highlevel gene expression in hematopoietic lineages provideseffective lentiviral gene therapy of murine Wiskott-Aldrich syndrome. Blood 2012;119:4395-4407.
91. Qasim W, Gennery AR. Gene therapy for primary immunodeficiencies: current status and future prospects. Drugs 2014;74:963-969.
92. Kang EM, Marciano BE, DeRavin S, et al. Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol 2011;127: 1319-1326; quiz 1327-1328.
93. Aiuti A, Bacchetta R, Seger R, et al. Gene therapy for primary immunodeficiencies: Part 2. Curr Opin Immunol 2012;24:585-591.
94. 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;88:1104-1112.
95. Goebel WS, Dinauer MC. Gene therapy for chronic granulomatous disease. Acta Haematol 2003;110:86-92.
96. 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;115:783-791.
97. 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;12:401-409.
98. Grez M, Reichenbach J, Schwäble J, et al. Gene therapy of chronic granulomatous disease: the engraftment dilemma. Mol Ther 2011;19:28-35.
99. Farinelli G, Capo V, Scaramuzza S, et al. Lentiviral vectors for the treatment of primary immunodeficiencies. J Inherit Metab Dis 2014;37:525-533.
100. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 2007;87:245-313.
101. 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; 118:2941-2950.
102. Chiriaco M, Farinelli G, Capo V, et al. Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis. Mol Ther 2014;22:1472-1483.
103. Bianchi M, Hakkim A, Brinkmann V, et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood 2009;114:2619-2622.
104. Barde I, Laurenti E, Verp S, et al. Lineage- and stagerestricted lentiviral vectors for the gene therapy of chronic granulomatous disease. Gene Ther 2011;18:1087-1097.
105. 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;19:1018-1029.
106. 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: 527-534.
107. 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.
108. 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;18:1640-1649.
109. Kaufmann KB, Büning H, Galy A, et al. Gene therapy on the move. EMBO Mol Med 2013;5:1642-1661.
110. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human b-thalassaemia. Nature 2010;467:318-322.
111. 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;194:255-264; discussion 264-268.
112. Genovese P, Schiroli G, Escobar G, et al. Targeted genome editing in human repopulating haematopoietic stem cells. Nature 2014;510:235-240.
113. Urnov FD, Miller JC, Lee YL, et al. Highly efficient endogenous human gene correction using designed zincfinger nucleases. Nature 2005;435:646-651.
114. Paques F, Duchateau P. Meganucleases and DNA doublestrand break-induced recombination: perspectives for gene therapy. Curr Gene Ther 2007;7:49-66.
115. Wood AJ, Lo TW, Zeitler B, et al. Targeted genome editing across species using ZFNs and TALENs. Science 2011;333:307.
116. Ran FA, Hsu PD, Wright J, et al. Genome engineering using the CRISPR-Cas9 system. Nat Protoc 2013;8:2281-2308.
117. Cicalese MP, Ferrua F, Pajno R, et al. Long-term safety and efficacy of retroviral-mediated gene therapy for ADA SCID. J Clin Immunol 2014;34 Suppl 2:S311.
118. Carbonaro Sarracino D, Shaw K, Sokolic R, et al. Clinical Gene Therapy Trials for Adenosine Deaminase-Deficient Severe Combined Immune Deficiency (ADA-SCID). J Clin Immunol 2014;34 Suppl 2:S313.
119. 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.
120. Scaramuzza S, Giannelli S, Ferrua F, et al. Persistent multilineage engraftment and WASP restored expression after lentiviral mediated CD34 + cells gene therapy for the treatment of Wiskott-Aldrich Syndrome. Mol Ther 2014;22 Suppl 1:S88.
121. Williams DA, Update on gene therapy trials for severe combined immunodeficiency and Wiskott-Aldrich Syndrome. Hum Gene Ther 2014;25:A16.
122. Shaw KL, Sokolic R, Davila A, et al. Phase II clinical trial of gene therapy for adenosine deaminase-deficient Severe Combined Immune Deficiency (ADA SCID). Mol Ther 2014;22 Suppl 1:S 107.