Uncovering and dissecting the genotoxicity of self-inactivating lentiviral vectors in vivo

Molecular Therapy

Volumn 22, Issue 4, 2014, Pages 774-785

  Cesana, Daniela ^a   Ranzani, Marco ^a   Volpin, Monica ^a,b   Bartholomae, Cynthia ^c   Duros, Caroline ^d   Artus, Alexandre ^d   Merella, Stefania ^a,e   Benedicenti, Fabrizio ^a   Sergi Sergi, Lucia ^a   Sanvito, Francesca ^e   Brombin, Chiara ^b   Nonis, Alessandro ^b   Serio, Clelia Di ^b   Doglioni, Claudio ^e   Von Kalle, Christof ^c   Schmidt, Manfred ^c   Cohen Haguenauer, Odile ^d,f   Naldini, Luigi ^a,b   Montini, Eugenio ^a,b  

^a SAN RAFFAELE SCIENTIFIC INSTITUTE   (Italy)

^b VITA SALUTE SAN RAFFAELE UNIVERSITY   (Italy)

^c GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^d UNIVERSITÉ PARIS SACLAY   (France)

^e SAN RAFFAELE HOSPITAL   (Italy)

^f SAINT LOUIS HOSPITAL   (France)

Author keywords

[No Author keywords available]

Indexed keywords

LENTIVIRUS VECTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BIOSAFETY; CARCINOGENESIS; CONTROLLED STUDY; GENE ACTIVATION; GENE CASSETTE; GENE INACTIVATION; GENE INSERTION; GENE SEQUENCE; GENOTOXICITY; HISTIOCYTIC SARCOMA; IN VIVO STUDY; MOLECULAR DYNAMICS; MOUSE; NEWBORN; NONHUMAN; ONCOGENE; PROMOTER REGION; QUANTITATIVE ANALYSIS; TUMOR SUPPRESSOR GENE; GENE EXPRESSION REGULATION; GENE THERAPY; GENE VECTOR; GENETICS; HUMAN; LENTIVIRINAE; PATHOGENICITY;

CARCINOGENESIS; GENETIC THERAPY; GENETIC VECTORS; HUMANS; LENTIVIRUS; MUTAGENESIS, INSERTIONAL; PROMOTER REGIONS, GENETIC;

EID: 84897570147     PISSN: 15250016     EISSN: 15250024     Source Type: Journal    
DOI: 10.1038/mt.2014.3     Document Type: Article

References (50)

1. Montini, E, Cesana, D, Schmidt, M, Sanvito, F, Bartholomae, CC, Ranzani, M et al. (2009). 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 119: 964-975
2. Montini, E, Cesana, D, Schmidt, M, Sanvito, F, Ponzoni, M, Bartholomae, C et al. (2006). Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol 24: 687-696
3. Modlich, U, Navarro, S, Zychlinski, D, Maetzig, T, Knoess, S, Brugman, MH et al. (2009). Insertional transformation of hematopoietic cells by self-inactivating lentiviral and gammaretroviral vectors. Mol Ther 17: 1919-1928
4. Arumugam, PI, Higashimoto, T, Urbinati, F, Modlich, U, Nestheide, S, Xia, P et al. (2009). Genotoxic potential of lineage-specific lentivirus vectors carrying the betaglobin locus control region. Mol Ther 17: 1929-1937
5. Zychlinski, D, Schambach, A, Modlich, U, Maetzig, T, Meyer, J, Grassman, E et al. (2008). Physiological promoters reduce the genotoxic risk of integrating gene vectors. Mol Ther 16: 718-725
6. Cartier, N, Hacein-Bey-Abina, S, Bartholomae, CC, Veres, G, Schmidt, M, Kutschera, I et al. (2009). Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326: 818-823
7. Aiuti, A, Biasco, L, Scaramuzza, S, Ferrua, F, Cicalese, MP, Baricordi, C et al. (2013). Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341: 1233151
8. Biffi, A, Montini, E, Lorioli, L, Cesani, M, Fumagalli, F, Plati, T et al. (2013). Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341: 1233158
9. Ramezani, A, Hawley, TS and Hawley, RG (2008). Combinatorial incorporation of enhancer-blocking components of the chicken beta-globin 5'HS4 and human T-cell receptor alpha/delta BEAD-1 insulators in self-inactivating retroviral vectors reduces their genotoxic potential. Stem Cells 26: 3257-3266
10. Ranzani, M, Cesana, D, Bartholomae, CC, Sanvito, F, Pala, M, Benedicenti, F et al. (2013). Lentiviral vector-based insertional mutagenesis identifies genes associated with liver cancer. Nat Methods 10: 155-161
11. Almarza, D, Bussadori, G, Navarro, M, Mavilio, F, Larcher, F and Murillas, R (2011). Risk assessment in skin gene therapy: Viral-cellular fusion transcripts generated by proviral transcriptional read-Through in keratinocytes transduced with self-inactivating lentiviral vectors. Gene Ther 18: 674-681
12. Cesana, D, Sgualdino, J, Rudilosso, L, Merella, S, Naldini, L and Montini, E (2012). Whole transcriptome characterization of aberrant splicing events induced by lentiviral vector integrations. J Clin Invest 122: 1667-1676
13. Moiani, A, Paleari, Y, Sartori, D, Mezzadra, R, Miccio, A, Cattoglio, C et al. (2012). Lentiviral vector integration in the human genome induces alternative splicing and generates aberrant transcripts. J Clin Invest 122: 1653-1666
14. Cavazzana-Calvo, M, Payen, E, Negre, O, Wang, G, Hehir, K, Fusil, F et al. (2010). Transfusion independence and HMGA2 activation after gene therapy of human ßthalassaemia. Nature 467: 318-322
15. Emery, DW (2011). The use of chromatin insulators to improve the expression and safety of integrating gene transfer vectors. Hum Gene Ther 22: 761-774
16. Evans-Galea, MV, Wielgosz, MM, Hanawa, H, Srivastava, DK and Nienhuis, AW (2007). Suppression of clonal dominance in cultured human lymphoid cells by addition of the cHS4 insulator to a lentiviral vector. Mol Ther 15: 801-809
17. Li, CL, Xiong, D, Stamatoyannopoulos, G and Emery, DW (2009). Genomic and functional assays demonstrate reduced gammaretroviral vector genotoxicity associated with use of the cHS4 chromatin insulator. Mol Ther 17: 716-724
18. Brown, BD, Sitia, G, Annoni, A, Hauben, E, Sergi, LS, Zingale, A et al. (2007). In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance. Blood 109: 2797-2805
19. Carrasco, DR, Fenton, T, Sukhdeo, K, Protopopova, M, Enos, M, You, MJ et al. (2006). The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans. Cancer Cell 9: 379-390
20. Suzuki, T, Shen, H, Akagi, K, Morse, HC, Malley, JD, Naiman, DQ et al. (2002). New genes involved in cancer identified by retroviral tagging. Nat Genet 32: 166-174
21. Abel, U, Deichmann, A, Nowrouzi, A, Gabriel, R, Bartholomae, CC, Glimm, H et al. (2011). Analyzing the number of common integration sites of viral vectors-new methods and computer programs. PLoS ONE 6: E24247
22. Biffi, A, Bartolomae, CC, Cesana, D, Cartier, N, Aubourg, P, Ranzani, M et al. (2011). Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection. Blood 117: 5332-5339
23. Akagi, K, Suzuki, T, Stephens, RM, Jenkins, NA and Copeland, NG (2004). RTCGD: Retroviral tagged cancer gene database. Nucleic Acids Res 32(Database issue): D523-D527
24. Keng, VW, Villanueva, A, Chiang, DY, Dupuy, AJ, Ryan, BJ, Matise, I et al. (2009). A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma. Nat Biotechnol 27: 264-274
25. Collier, LS, Carlson, CM, Ravimohan, S, Dupuy, AJ and Largaespada, DA (2005). Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse. Nature 436: 272-276
26. Lund, AH, Turner, G, Trubetskoy, A, Verhoeven, E, Wientjens, E, Hulsman, D et al. (2002). Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. Nat Genet 32: 160-165
27. Patriotis, C, Makris, A, Bear, SE and Tsichlis, PN (1993). Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the progression of rodent T-cell lymphomas and in T-cell activation. Proc Natl Acad Sci USA 90: 2251-2255
28. Patriotis, C, Makris, A, Chernoff, J and Tsichlis, PN (1994). Tpl-2 acts in concert with Ras and Raf-1 to activate mitogen-Activated protein kinase. Proc Natl Acad Sci USA 91: 9755-9759
29. Hirose, Y and Manley, JL (1998). RNA polymerase II is an essential mRNA polyadenylation factor. Nature 395: 93-96
30. Hirose, Y and Manley, JL (2000). RNA polymerase II and the integration of nuclear events. Genes Dev 14: 1415-1429
31. Proudfoot, NJ (2001). Genetic dangers in poly(A) signals. EMBO Rep 2: 891-892
32. Lombardo, A, Cesana, D, Genovese, P, Di Stefano, B, Provasi, E, Colombo, DF et al. (2011). Site-specific integration and tailoring of cassette design for sustainable gene transfer. Nat Methods 8: 861-869
33. Johannessen, CM, Boehm, JS, Kim, SY, Thomas, SR, Wardwell, L, Johnson, LA et al. (2010). COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468: 968-972
34. Kang, TW, Yevsa, T, Woller, N, Hoenicke, L, Wuestefeld, T, Dauch, D et al. (2011). Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479: 547-551
35. Michaloglou, C, Vredeveld, LC, Soengas, MS, Denoyelle, C, Kuilman, T, van der Horst, CM et al. (2005). BRAFE600-Associated senescence-like cell cycle arrest of human naevi. Nature 436: 720-724
36. Collado, M, Blasco, MA and Serrano, M (2007). Cellular senescence in cancer and aging. Cell 130: 223-233
37. Hacein-Bey-Abina, S, Garrigue, A, Wang, GP, Soulier, J, Lim, A, Morillon, E et al. (2008). Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 118: 3132-3142
38. Howe, SJ, Mansour, MR, Schwarzwaelder, K, Bartholomae, C, Hubank, M, Kempski, H et al. (2008). Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest 118: 3143-3150
39. Jacobs, JJ, Scheijen, B, Voncken, JW, Kieboom, K, Berns, A and van Lohuizen, M (1999). Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 13: 2678-2690
40. Matheu, A, Pantoja, C, Efeyan, A, Criado, LM, Martín-Caballero, J, Flores, JM et al. (2004). Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging. Genes Dev 18: 2736-2746
41. Ciampi, R, Knauf, JA, Kerler, R, Gandhi, M, Zhu, Z, Nikiforova, MN et al. (2005). Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 115: 94-101
42. Palanisamy, N, Ateeq, B, Kalyana-Sundaram, S, Pflueger, D, Ramnarayanan, K, Shankar, S et al. (2010). Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med 16: 793-798
43. Clark, AM, Reynolds, SH, Anderson, M and Wiest, JS (2004). Mutational activation of the MAP3K8 protooncogene in lung cancer. Genes Chromosomes Cancer 41: 99-108
44. Miyoshi, J, Higashi, T, Mukai, H, Ohuchi, T and Kakunaga, T (1991). Structure and transforming potential of the human cot oncogene encoding a putative protein kinase. Mol Cell Biol 11: 4088-4096
45. Jeong, JH, Bhatia, A, Toth, Z, Oh, S, Inn, KS, Liao, CP et al. (2011). TPL2/COT/ MAP3K8 (TPL2) activation promotes androgen depletion-independent (ADI) prostate cancer growth. PLoS ONE 6: E16205
46. Carver, BS, Tran, J, Gopalan, A, Chen, Z, Shaikh, S, Carracedo, A et al. (2009). Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet 41: 619-624
47. Di Cristofano, A, Pesce, B, Cordon-Cardo, C and Pandolfi, PP (1998). Pten is essential for embryonic development and tumour suppression. Nat Genet 19: 348-355
48. Nardella, C, Chen, Z, Salmena, L, Carracedo, A, Alimonti, A, Egia, A et al. (2008). Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events. Genes Dev 22: 2172-2177
49. Lombardo, A, Genovese, P, Beausejour, CM, Colleoni, S, Lee, YL, Kim, KA et al. (2007). Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nat Biotechnol 25: 1298-1306
50. Schmidt, M, Schwarzwaelder, K, Bartholomae, C, Zaoui, K, Ball, C, Pilz, I et al. (2007). High-resolution insertion-site analysis by linear amplification-mediated PCR (LAMPCR). Nat Methods 4: 1051-1057.