Safety of gene therapy: New insights to a puzzling case

Current Gene Therapy

Volumn 14, Issue 6, 2014, Pages 429-436

  Rothe, Michael ^a   Schambach, Axel ^a   Biasco, Luca ^b  

^a HANNOVER MEDICAL SCHOOL   (Germany)

^b SAN RAFFAELE SCIENTIFIC INSTITUTE   (Italy)

Author keywords

Clinical trials; Gene therapy; Insertional mutagenesis; Lentiviral; Preclinical; Retroviral; Safety

Indexed keywords

ADVERSE EFFECTS; ANIMAL; CLINICAL TRIAL (TOPIC); GENE THERAPY; GENE VECTOR; GENETIC DISEASES, X-LINKED; GENETICS; HUMAN; SAFETY; STANDARDS;

ANIMALS; CLINICAL TRIALS AS TOPIC; GENETIC DISEASES, X-LINKED; GENETIC THERAPY; GENETIC VECTORS; HUMANS; SAFETY;

EID: 84924764258     PISSN: 15665232     EISSN: 18755631     Source Type: Journal    
DOI: 10.2174/1566523214666140918110905     Document Type: Article

References (81)

1. [1] Cavazzana-Calvo M, Fischer A, Hacein-Bey-Abina S, Aiuti A. Gene therapy for primary immunodeficiencies: Part 1. Curr Opin Immunol 2012; 24: 580-4.
2. [2] Aiuti A, Bacchetta R, Seger R, Villa A, Cavazzana-Calvo M. Gene therapy for primary immunodeficiencies: Part 2. Curr Opin Immunol 2012; 24: 585-91.
3. [3] Naldini L. Ex vivo gene transfer and correction for cell-based therapies. Nat Rev Genet 2011; 12: 301-15.
4. [4] Biasco L, Baricordi C, Aiuti A. Retroviral integrations in gene therapy trials. Mol Ther 2012; 20: 709-16.
5. [5] Hacein-bey-abina S, Schmidt M. A Serious Adverse Event after Successful Gene Therapy for X-Linked Severe Combined Immunodeficiency. N Engl J Med 2003; 348: 255-66.
6. [6] 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.
7. [7] Ott MG, Schmidt M, Schwarzwaelder K, et al. Correction of Xlinked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med 2006; 12: 401-9.
8. [8] 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.
9. [9] 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.
10. [10] Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003; 302: 415-9.
11. [11] Aiuti A, Cassani B, Andolfi G, et al. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest 2007; 117: 2233-40.
12. [12] Schwarzwaelder K, Howe SJ, Schmidt M, et al. Gammaretrovirusmediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo. J Clin Invest 2007; 117: 2241-9.
13. [13] 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.
14. [14] Cattoglio C, Facchini G, Sartori D, et al. Hot spots of retroviral integration in human CD34+ hematopoietic cells. Blood 2007; 110: 1770-8.
15. [15] 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.
16. [16] Woods N-B, Bottero V, Schmidt M, von Kalle C, Verma IM. Gene therapy: therapeutic gene causing lymphoma. Nature 2006; 440: 1123.
17. [17] 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: 28-35.
18. [18] Pike-Overzet K, de Ridder D, Weerkamp F, et al. Gene therapy: is IL2RG oncogenic in T-cell development? Nature 2006; 443: E5.discussion E6-7.
19. [19] Pike-Overzet K, van der Burg M, Wagemaker G, van Dongen JJM, Staal FJT. New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy. Mol Ther 2007; 15: 1910-6.
20. [20] Thrasher AJ, Gaspar HB, Baum C, et al. Gene therapy: X-SCID transgene leukaemogenicity. Nature 2006; 443: E5-E6.discussion E6-E7.
21. [21] Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in Xlinked adrenoleukodystrophy. Science 2009; 326: 818-23.
22. [22] Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human _-thalassaemia. Nature 2010; 467: 318-22.
23. [23] Kaiser J. _-Thalassemia Treatment Succeeds, With a Caveat. Science (80) 2009; 326: 1468-9.
24. [24] Payen E, Leboulch P. Advances in stem cell transplantation and gene therapy in the _-hemoglobinopathies. Hematology Am Soc Hematol Educ Program 2012; 2012: 276-83.
25. [25] Biffi A, Montini E, Lorioli L, et al. Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy. Science 2013; 341.
26. [26] 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.
27. [27] Boztug K, Schmidt M, Schwarzer A, et al. Stem-Cell Gene Therapy for the Wiskott-Aldrich Syndrome. N Engl J Med 2010; 363: 1918-27.
28. [28] Zhang L, Thrasher a J, Gaspar HB. Current progress on gene therapy for primary immunodeficiencies. Gene Ther 2013; 20: 963-9.
29. [29] Farinelli G, Capo V, Scaramuzza S, Aiuti A. Lentiviral vectors for the treatment of primary immunodeficiencies. J Inherit Metab Dis 2014; 37(4): 525-33.
30. [30] Braun CJ, Boztug K, Paruzynski A., et al. Gene Therapy for Wiskott-Aldrich Syndrome--Long-Term Efficacy and Genotoxicity. Sci Transl Med 2014; 6: 22733-22733.
31. [31] 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 U S A 2006; 103: 11730-5.
32. [32] Ginn SL, Liao SHY, Dane AP, et al. Lymphomagenesis in SCIDX1 mice following lentivirus-mediated phenotype correction independent of insertional mutagenesis and gammac overexpression. Mol Ther 2010; 18: 965-76.
33. [33] Bosticardo M, Marangoni F, Aiuti A, Villa A, Grazia Roncarolo M. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood 2009; 113: 6288-95.
34. [34] Catucci M, Zanoni I, Draghici E, et al. Wiskott-Aldrich syndrome protein deficiency in natural killer and dendritic cells affects antitumor immunity. Eur J Immunol 2014; 44(4): 1039-45.
35. [35] 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.
36. [36] Mitchell RS, Beitzel BF, Schroder ARW, et al. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol 2004; 2: E234.
37. [37] Montini E, Cesana D, Schmidt M, et al. The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy. J Clin Invest 2009; 119(4): 964-75.
38. [38] Zychlinski D, Schambach A, Modlich U, et al. Physiological promoters reduce the genotoxic risk of integrating gene vectors. Mol Ther 2008; 16: 718-25.
39. [39] Modlich U, Navarro S, Zychlinski D, et al. Insertional transformation of hematopoietic cells by self-inactivating lentiviral and gammaretroviral vectors. Mol Ther 2009; 17: 1919-28.
40. [40] Cornils K, Bartholomae CC, Thielecke L, et al. Comparative clonal analysis of reconstitution kinetics after transplantation of hematopoietic stem cells gene marked with a lentiviral SIN or a _-retroviral LTR vector. Exp Hematol 2012; 41: 28.e3-38.e3.
41. [41] Aiuti A, Cossu G, de Felipe P, et al. 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 2013; 24: 47-54.
42. [42] U.S. Food and Drug Administration. Guidance for Industry Preclinical Assessment of Investigational Cellular and Gene Therapy Products. 2013.
43. [43] Rothe M, Modlich U, Schambach A. Biosafety challenges for use of lentiviral vectors in gene therapy. Curr Gene Ther 2013; 13: 453-68.
44. [44] Deichmann A, Schmidt M. Biosafety Considerations Using Gamma-Retroviral Vectors in Gene Therapy. Curr Gene Ther 2013; 13: 469-77.
45. [45] 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.
46. [46] Huston MW, van Til NP, Visser TP, et al. Correction of murine SCID-X1 by lentiviral gene therapy using a codon-optimized IL2RG gene and minimal pretransplant conditioning. Mol Ther 2011; 19: 1867-77.
47. [47] Marangoni F, Bosticardo M, Charrier S, et al. Evidence for longterm efficacy and safety of gene therapy for Wiskott-Aldrich syndrome in preclinical models. Mol Ther 2009; 17: 1073-82.
48. [48] Stein S, Scholz S, Schwäble J, et al. From bench to bedside: preclinical evaluation of a self-inactivating gammaretroviral vector for the gene therapy of X-linked chronic granulomatous disease. Hum Gene Ther Clin Dev 2013; 24: 86-98.
49. [49] Zhou S, Ma Z, Lu T, Janke L, Gray JT, Sorrentino BP. Mouse transplant models for evaluating the oncogenic risk of a selfinactivating XSCID lentiviral vector. PLoS One 2013; 8(4): e62333.
50. [50] Paruzynski A, Arens A, Gabriel R, et al. Genome-wide highthroughput integrome analyses by nrLAM-PCR and nextgeneration sequencing. Nat Protoc 2010; 5: 1379-95.
51. [51] Schmidt M, Schwarzwaelder K, Bartholomae C, et al. Highresolution insertion-site analysis by linear amplification-mediated PCR (LAM-PCR). Nat Methods 2007; 4: 1051-7.
52. [52] Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature 2013; 502: 333-9.
53. [53] Akagi K, Suzuki T, Stephens RM, Jenkins NA, Copeland NG. RTCGD: retroviral tagged cancer gene database. Nucleic Acids Res 2004; 32: D523-7.
54. [54] Modlich U, Schambach A, Brugman MH, et al. Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16. Leukemia 2008; 22: 1519-28.
55. [55] Davé UP, Akagi K, Tripathi R, et al. Murine leukemias with retroviral insertions at Lmo2 are predictive of the leukemias induced in SCID-X1 patients following retroviral gene therapy. PLoS Genet 2009; 5: e1000491.
56. [56] Li Z, Düllmann J, Schiedlmeier B, et al. Murine leukemia induced by retroviral gene marking. Science 2002; 296: 497.
57. [57] Brugman MH, Suerth JD, Rothe M, et al. Evaluating a ligationmediated PCR and pyrosequencing method for the detection of clonal contribution in polyclonal retrovirally transduced samples. Hum Gene Ther Methods 2013; 24: 68-79.
58. [58] 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.
59. [59] Bosticardo M, Ghosh A, Du Y, Jenkins NA, Copeland NG, Candotti F. Self-inactivating retroviral vector-mediated gene transfer induces oncogene activation and immortalization of primary murine bone marrow cells. Mol Ther 2009; 17: 1910-8.
60. [60] Du Y, Jenkins NA, Copeland NG. Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells. Blood 2005; 106: 3932-9.
61. [61] Bokhoven M, Stephen SL, Knight S, et al. Insertional gene activation by lentiviral and gammaretroviral vectors. J Virol 2009; 83: 283-94.
62. [62] Ryu BY, Evans-Galea MV, Gray JT, Bodine DM, Persons DA, Nienhuis AW. An experimental system for the evaluation of retroviral vector design to diminish the risk for proto-oncogene activation. Blood 2008; 111: 1866-75.
63. [63] 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.
64. [64] Modlich U, Navarro S, Zychlinski D, et al. Insertional transformation of hematopoietic cells by self-inactivating lentiviral and gammaretroviral vectors. Mol Ther 2009; 17: 1919-28.
65. [65] Bartholomae CC, Arens A, Balaggan KS, et al. Lentiviral vector integration profiles differ in rodent postmitotic tissues. Mol Ther 2011; 19: 703-10.
66. [66] Rittelmeyer I, Rothe M, Brugman MH, et al. Hepatic lentiviral gene transfer is associated with clonal selection, but not with tumor formation in serially transplanted rodents. Hepatology 2013; 58: 397-408.
67. [67] Verma IM. Gene Therapy That Works. Science 2013; 341: 853-5.
68. [68] Emery DW. The use of chromatin insulators to improve the expression and safety of integrating gene transfer vectors. Hum Gene Ther 2011; 22: 761-74.
69. [69] Antoniou MN, Skipper KA, Anakok O. Optimizing retroviral gene expression for effective therapies. Hum Gene Ther 2013; 24: 363-74.
70. [70] Gentner B, Naldini L. Exploiting microRNA regulation for genetic engineering. Tissue Antigens 2012; 80: 393-403.
71. [71] Trono D. Gene therapy: too much splice can spoil the dish. J Clin Invest 2012; 122: 2012-4.
72. [72] Mayr C, Hemann MT, Bartel DP. Disrupting the Pairing Between let-7 and Hmga2 Enhances Oncogenic Transformation. Science 2007; 315: 1576-9.
73. [73] Suerth JD, Maetzig T, Brugman MH, et al. Alpharetroviral selfinactivating vectors: long-term transgene expression in murine hematopoietic cells and low genotoxicity. Mol Ther 2012; 20: 1022-32.
74. [74] Moldt B, Miskey C, Staunstrup NH, et al. Comparative genomic integration profiling of Sleeping Beauty transposons mobilized with high efficacy from integrase-defective lentiviral vectors in primary human cells. Mol Ther 2011; 19: 1499-510.
75. [75] Kaufmann KB, Brendel C, Suerth JD, et al. Alpharetroviral vectormediated gene therapy for X-CGD: functional correction and lack of aberrant splicing. Mol Ther 2013; 21: 648-61.
76. [76] Singh H, Huls H, Kebriaei P, Cooper LJN. A new approach to gene therapy using Sleeping Beauty to genetically modify clinical-grade T cells to target CD19. Immunol Rev 2014; 257: 181-90.
77. [77] Lombardo A, Genovese P, Beausejour CM, et al. Gene editing in human stem cells using zinc finger nucleases and integrasedefective lentiviral vector delivery. Nat Biotechnol 2007; 25: 1298-306.
78. [78] Gaj T, Gersbach CA, Barbas CF. ZFN, TALEN, and CRISPR/Casbased methods for genome engineering. Trends Biotechnol 2013; 31: 397-405.
79. [79] Gabriel R, Lombardo A, Arens A, et al. An unbiased genome-wide analysis of zinc-finger nuclease specificity. Nat Biotechnol 2011; 29: 816-23.
80. [80] Pauwels K, Podevin N, Breyer D, Carroll D, Herman P. Engineering nucleases for gene targeting: Safety and regulatory considerations. N Biotechnol 2014; 31: 18-27.
81. [81] Tebas P, Stein D, Tang WW, et al. Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. N Engl J Med 2014; 370: 901-10.