Safety issues of gene therapy
Abstract
By present time safety problems of gene therapy are widely discussed among scientists of all world. In this review results of clinical researches are summarized; explanations concerning side effects of vectors integration are given; factors that can cause genotoxicity are discussed. Approaches which can save or increase clinical efficacy of gene therapy with use as targets hematopoietic stem cells, thus significantly reduced risk of leukemia development and other side effects related to vectors including in genome, are presented.
About the Authors
S. E. Ipatov
Federal Research Center of Pediatric Hematology, Oncology and Immunology
Russian Federation
Russian Federation
Moscow
S. A. Roumiantsev
Federal Research Center of Pediatric Hematology, Oncology and Immunology
Russian Federation
Russian Federation
Moscow
References
1. Larochelle A., Dunbar C. E. Genetic manipulation of hematopoietic stem cells. Semin Hematol 2004; 41: 257—71.
2. Cavazzana-Calvo M., Hacein-Bey S., de Saint Basile G. et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000; 288: 669—72.
3. 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.
4. Gaspar H. B., Parsley K. L., Howe S. et al. Gene therapy of Xlinked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 2004; 364: 2181—7.
5. Hacein-Bey-Abina S., von Kalle C., Schmidt M. et al. A serious adverse event after successful gene therapy for Xlinked severe combined immunodeficiency. N Engl J Med 2003; 348: 255—6.
6. 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.
7. Fischer A., Hacein-Bey-Abina S., Le Deist F. et al. Gene therapy for human severe combined immunodeficiencies. Immunity 2001; 15: 1—4.
8. Hacein-Bey-Abina S., Le Deist F., 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.
9. Blaese R. M., Culver K. W., Miller A. D. et al. T-lymphocyte directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 1995; 270: 475—80.
10. Kohn D. B., Weinberg K. I., Nolta J. A. et al. Engraftment of genemodified umbilical cord blood cells in neonates with adenosine deaminase deficiency. Nat Med 1995; 1: 1017—23.
11. Kohn D. B., Hershfield M. S., Carbonaro D. et al. T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates. Nat Med 1998; 4: 775—80.
12. Nam C. H., Rabbitts T. H. The role of LMO2 in development and in T cell leukemia after chromosomal translocation or retroviral insertion. Mol Ther 2006; 13: 15—25.
13. Dave U. P., Jenkins N. A., Copeland N. G. Gene therapy insertional mutagenesis insights. Science 2004; 303: 333.
14. Woods N. B., Bottero V., Schmidt M. et al. Gene therapy: therapeutic gene causing lymphoma. Nature 2006; 440: 1123.
15. Thrasher A. J., Gaspar H. B., Baum C. et al. Gene therapy: XSCID transgene leukaemogenicity. Nature 2006; 443: 5—6.
16. Donahue R. E., Kessler S. W., Bodine D. et al. Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer. J Exp Med 1992; 176: 1125—35.
17. Cornetta K., Morgan R. A., Anderson W. F. Safety issues related to retroviral-mediated gene transfer to humans. Hum Gene Ther 1991; 2: 5—14.
18. Schroder A. R., Shinn P., Chen H. et al. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002; 110: 521—9.
19. Wu X., Li Y., Crise B., Burgess S. M. Transcription start regions in the human genome are favored targets for MLV integration. Science 2003; 300: 1749—51.
20. Hematti P., Hong B. K., Ferguson C. et al. Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells. PLoS Biol 2004; 2: 2183—90.
21. Schwarzwaelder K., Howe S. J., 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.
22. 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.
23. 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.
24. Li Z., Dullmann J., Schiedlmeier B. et al. Murine leukemia induced by retroviral gene marking. Science 2002; 296: 497.
25. Seggewiss R., Pittaluga S., Adler R. L. et al. Acute myeloid leukemia is associated with retroviral gene transfer to hematopoietic progenitor cells in a rhesus macaque. Blood 2006; 107: 3865—7.
26. Mitchell R. S., Beitzel B. F., Schroder A. R. et al. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol 2004; 2: 234.
27. Urnov F. D., Miller J. C., Lee Y. L. et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 2005; 435: 646—51.
28. Chalberg T. W., Portlock J. L., Olivares E. C. et al. Integration specificity of phage phiC31 integrase in the human genome. J Mol Biol 2006; 357: 28—48.
29. Wang G. P., Ciuffi A., Leipzig J. et al. HIV integration site selection: Analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res 2007; 17: 1186—94.
30. Hacker C. V., Vink C. A., Wardell T. W. et al. The integration profile of EIAV-based vectors. Mol Ther 2006; 14: 536—45.
31. Themis M., Waddington S. N., Schmidt M. et al. Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal and neonatal mice. Mol Ther 2005; 12: 763—71.
32. Yant S. R., Wu X., Huang Y. et al. High-resolution genome-wide mapping of transposon integration in mammals. Mol Cell Biol 2005; 25: 2085—94.
33. Nakai H., Wu X., Fuess S. et al. Large-scale molecular characterization of adeno-associated virus vector integration in mouse liver. J Virol 2005; 79: 3606—14.
34. Donsante A., Vogler C., Muzyczka N. et al. Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther 2001; 8: 1343—6.
35. Bell P., Wang L., Lebherz C. et al. No evidence for tumorigenesis of AAV vectors in a large-scale study in mice. Mol Ther 2005; 12: 299—306.
36. Suzuki T., Shen H., Akagi K. et al. New genes involved in cancer identified by retroviral tagging. Nat Genet 2002; 32: 166—74.
37. Calmels B., Ferguson C., Laukkanen M. O. et al. Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells. Blood 2005; 106: 2530—3.
38. Ott M. G., 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.
39. Du D., Copeland N. G. Insertional mutagenesis identifies genes that promote the immortalization of primary murine bone marrow progenitor cells. Blood 2005; 106: 3932—9.
40. Buonamici S., Chakraborty S., Senyuk V., Nucifora G. The role of EVI1 in normal and leukemic cells. Blood Cells Mol Dis 2003; 31: 206—12.
41. Barjesteh van Waalwijk van Doorn-Khosrovani S., Erpelinck C., van Putten W. L. et al. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood 2003; 101: 837—45.
42. Kustikova O., Fehse B., Modlich U. et al. Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking. Science 2005; 308: 1171—4.
43. Modlich U., Kustikova O. S., Schmidt M. et al. Leukemias following retroviral transfer of multidrug resistance 1 (MDR1) are driven by combinatorial insertional mutagenesis. Blood 2005; 105: 4235—46.
44. 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.
45. 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.
46. Evans-Galea M. V., Wielgosz M. M., Hanawa H. et al. Suppression of clonal dominance in cultured human lymphoid cells by addition of the cHS4 insulator to a lentiviral vector. Mol Ther 2007; 15: 801—9.
47. Trobridge G. D., Miller D. G., Jacobs M. A. et al. Foamy virus vector integration sites in normal human cells. Proc Natl Acad Sci USA 2006; 103: 1498—503.
Review
For citations:
Ipatov S.E., Roumiantsev S.A. Safety issues of gene therapy. Oncohematology. 2010;(1):57-63. (In Russ.)
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