Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC25710.15690/vramn.v67i10.417SHORT MESSAGESКРАТКИЕ СООБЩЕНИЯSAFETY OF RETROVIRAL VECTORS IN GENE THERAPYБЕЗОПАСНОСТЬ ИСПОЛЬЗОВАНИЯ РЕТРОВИРУСНЫХ ВЕКТОРОВ В ГЕННОЙ ТЕРАПИИBogoslovskayaE. V.БогословскаяЕ. В.
Russian Federation

кандидат медицинских наук, старший научный сотрудник отдела молекулярной диагностики и эпидемиологии ФБУН ЦНИИ эпидемиологии Роспотребнадзора Адрес: 111123, Москва, ул. Новогиреевская, д. 3А Тел.: (495) 974-96-46, факс: (495) 305-54-23

elena.bogoslovskaya@pcr.ruGlazkovaD. V.ГлазковаД. В.
Russian Federation

кандидат биологических наук, научный сотрудник отдела молекулярной диагностики и эпидемиологии ФБУН ЦНИИ эпидемиологии Роспотребнадзора Адрес: 111123, Россия, Москва, ул. Новогиреевская, д. 3А Тел.: (495) 974-96-46, (916) 958-09-57, факс: (495) 305-54-23

glazkova@pcr.ruShipulinG. A.ШипулинГ. А.
Russian Federation

кандидат медицинских наук, заведующий отделом молекулярной диагностики и эпидемиологии ФБУН ЦНИИ эпидемиологии Роспотребнадзора Адрес: 111123, Россия, Москва, ул. Новогиреевская, д. 3А Тел.: (495) 974-96-46, факс: (495) 305-54-23

german@pcr.ruPokrovskiiV. V.ПокровскийВ. В.
Russian Federation

доктор медицинских наук, академик РАМН, заместитель директора ФБУН ЦНИИ эпидемиологии Роспотребнадзора по научной работе Адрес: 111123, Россия, Москва, ул. Новогиреевская, д. 3А Тел.: (495) 974-96-46, факс: (495) 305-54-23

info@pcr.ruCentral Research Institute of Epidemiology, MoscowЦентральный научно-исследовательский институт эпидемиологии, Москва101020126710Вестник Российской академии медицинских наук556107082015Copyright ©; 2012, "Paediatrician" Publishers LLCCopyright ©; 2012, Издательство "Педиатръ"2012"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/257

Retroviral vectors are widely used in gene therapy and found to be an effective tool for the delivery of genetic constructs into cells. A unique feature of these vectors is the ability to incorporate therapeutic genes into a chromosome that ensures its passage to all progeny cells and enables to cure the diseases requiring genetic correction of dividing cells such as hematopoietic cells or skin cells. Retroviral vectors have been successfully used in gene therapy clinical trials for the treatment of 2 forms of severe combined immunodeficiencies and some other hereditary blood disorders. However, the integration of the vector into the chromosome was accompanied by genotoxicity and caused development of hematologic malignancies in several patients. Later it was shown that genotoxicity is not a general feature of retroviral vectors but it depends on many factors. In the present article we discuss safety issues concerning the use of different retroviral vectors in gene therapy. The description of modern vectors which designed to avoid the genotoxicity and other possible side effects are given.

Ретровирусные векторы широко используют в генотерапевтических исследованиях, они признаны эффективным инструментом для доставки генетических конструкций в клетки. Уникальной особенностью данных векторов является способность эффективно встраивать терапевтические гены в хромосому, что обеспечивает передачу генов дочерним клеткам и позволяет лечить заболевания, требующие генетической коррекции активно делящихся клеток, таких как гемопоэтические клетки или клетки кожи. Ретровирусные векторы были успешно использованы в клинических испытаниях препаратов, направленных на лечение 2 форм тяжелых комбинированных иммунодефицитов и некоторых других врожденных заболеваний крови. Однако в нескольких случаях интеграция вектора в хромосому сопровождалась генотоксичностью и привела к развитию онкогематологического заболевания. В дальнейшем было показано, что генотоксичность не является неотъемлемой чертой всех ретровирусных векторов, а зависит от многих факторов. В настоящей статье рассматриваются вопросы безопасности применения различных ретровирусных векторов в генной терапии. Приведено описание современных векторов, обладающих свойствами, позволяющими избежать генотоксичности и других возможных побочных эффектов.

gene therapysafetyretroviral vectorinsertion mutagenesisgenotoxicityгенная терапиябезопасностьретровирусный векторинсерционный мутагенезгенотоксичность1. Glazkova D.V., Bogoslovskaya E.V., Shipulin G.A., Pokrovskii V.I. Progress in gene therapy. Terapevticheskii arkhiv = Therapeutic Archives. 2011; 8: 62–69.2. Available at: http://www.wiley.com/legacy/wileychi/genmed/clinical/3. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrère F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Bougnères P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009; 326 (5954): 818–823.4. Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, Vogel AN, Kalos M, Riley JL, Deeks SG, Mitsuyasu RT, Bernstein WB, Aronson NE, Levine BL, Bushman FD, June CH. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 2012; 4 (132): 132–153.5. Westwood J.A., Kershaw M.H. Genetic redirection of T cells for cancer therapy. J. Leukoc. Biol. 2010; 87 (5): 791–803.6. von Laer D., Baum C., Protzer U. Antiviral gene therapy. Handb. Exp. Pharmacol. 2009; 189: 265–297.7. De Luca M., Pellegrini G., Mavilio F. Gene therapy of inherited skin adhesion disorders: A critical overview. Br. J. Dermatol. 2009; 161: 19–24.8. Sakuma T., Barry M.A., Ikeda Y. Lentiviral vectors: basic to translational. Biochem. J. 2012; 443 (3): 603–618.9. Donahue RE, Kessler SW, Bodine D, McDonagh K, Dunbar C, Goodman S, Agricola B, Byrne E, Raffeld M, Moen R Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer. J. Exp. Med. 1992; 176 (4): 1125–1135.10. Maetzig T., Galla M., Baum C., Schambach A. Gammaretroviral vectors: biology, technology and application. Viruses. 2011; 3 (6): 677–713.11. Somia N., Verma I.M. Gene therapy: trials and tribulations. Nat. Rev. Genet. 2000; 1 (2): 91–99.12. Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, Clappier E, Caccavelli L, Delabesse E, Beldjord K, Asnafi V, MacIntyre E, Dal Cortivo L, Radford I, Brousse N, Sigaux F, Moshous D, Hauer J, Borkhardt A, Belohradsky BH, Wintergerst U, Velez MC, Leiva L, Sorensen R, Wulffraat N, Blanche S, Bushman FD, Fischer A, Cavazzana-Calvo M. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Invest. 2008; 118 (9): 3132–3142.13. Aiuti A., Roncarolo M.G. Ten years of gene therapy for primary immune deficiencies. Hematology Am. Soc. Hematol. Educ. Program. Book 2009; 682–689.14. Hacein-Bey-Abina S., Hauer J., Lim A. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 2010; 363 (4): 355–364.15. Gaspar HB, Parsley KL, Howe S, King D, Gilmour KC, Sinclair J, Brouns G, Schmidt M, Von Kalle C, Barington T, Jakobsen MA, Christensen HO, Al Ghonaium A, White HN, Smith JL, Levinsky RJ, Ali RR, Kinnon C, Thrasher AJ. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet. 2004; 364 (9452): 2181–2187.16. Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M, Kempski H, Brugman MH, Pike-Overzet K, Chatters SJ, de Ridder D, Gilmour KC, Adams S, Thornhill SI, Parsley KL, Staal FJ, Gale RE, Linch DC, Bayford J, Brown L, Quaye M, Kinnon C, Ancliff P, Webb DK, Schmidt M, von Kalle C, Gaspar HB, Thrasher AJ. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J. Clin. Invest. 2008; 118 (9): 3143–3150.17. Trobridge G.D. Genotoxicity of retroviral hematopoietic stem cell gene therapy. Expert Opin. Biol. Ther. 2011; 11 (5): 581–593.18. Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kühlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Lüthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat. Med. 2006; 12 (4): 401–409.19. Westwood J.A., Kershaw M.H. Genetic redirection of T cells for cancer therapy. J. Leuk. Biol. 2010; 87 (5): 791–803.20. Montini E, Cesana D, Schmidt M, Sanvito F, Ponzoni M, Bartholomae C, Sergi Sergi L, Benedicenti F, Ambrosi A, Di Serio C, Doglioni C, von Kalle C, Naldini L. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat. Biotechnol. 2006; 24 (6): 687–696.21. Montini E, Cesana D, Schmidt M, Sanvito F, Bartholomae CC, Ranzani M, Benedicenti F, Sergi LS, Ambrosi A, Ponzoni M, Doglioni C, Di Serio C, von Kalle C, Naldini L. 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): 964–975.22. Baum C. Insertional mutagenesis in gene therapy and stem cell biology. Curr. Opin. Hematol. 2007; 14 (4): 337–342.23. Sinn P.L., Sauter S.L., McCray P.B., Jr. Gene therapy progress and prospects: development of improved lentiviral and retroviral vectors — design, biosafety, and production. Gene Ther. 2005; 12 (14): 1089–1098.24. Modlich U, Bohne J, Schmidt M, von Kalle C, Knöss S, Schambach A, Baum C. Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity. Blood. 2006; 108 (8): 2545–2553.25. Modlich U, Navarro S, Zychlinski D, Maetzig T, Knoess S, Brugman MH, Schambach A, Charrier S, Galy A, Thrasher AJ, Bueren J, Baum C. Insertional transformation of hematopoietic cells by self-inactivating lentiviral and gammaretroviral vectors. Mol. Ther. 2009; 17 (11): 1919–1928.26. Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, Down J, Denaro M, Brady T, Westerman K, Cavallesco R, Gillet-Legrand B, Caccavelli L, Sgarra R, Maouche-Chrétien L, Bernaudin F, Girot R, Dorazio R, Mulder GJ, Polack A, Bank A, Soulier J, Larghero J, Kabbara N, Dalle B, Gourmel B, Socie G, Chrétien S, Cartier N, Aubourg P, Fischer A, Cornetta K, Galacteros F, Beuzard Y, Gluckman E, Bushman F, Hacein-Bey-Abina S, Leboulch P. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature. 2010; 467 (7313): 318–322.27. DiGiusto DL, Krishnan A, Li L, Li H, Li S, Rao A, Mi S, Yam P, Stinson S, Kalos M, Alvarnas J, Lacey SF, Yee JK, Li M, Couture L, Hsu D, Forman SJ, Rossi JJ, Zaia JA. RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma. Sci. Transl. Med. 2010; 2 (36): 36–43.28. Deichmann A, Hacein-Bey-Abina S, Schmidt M, Garrigue A, Brugman MH, Hu J, Glimm H, Gyapay G, Prum B, Fraser CC, Fischer N, Schwarzwaelder K, Siegler ML, de Ridder D, Pike-Overzet K, Howe SJ, Thrasher AJ, Wagemaker G, Abel U, Staal FJ, Delabesse E, Villeval JL, Aronow B, Hue C, Prinz C, Wissler M, Klanke C, Weissenbach J, Alexander I, Fischer A, von Kalle C, Cavazzana-Calvo M. Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy. J. Clin. Invest. 2007; 117 (8): 2225–2232.29. Biffi A., Aubourg P., Cartier N. Gene therapy for leukodystrophies. Hum. Mol. Genet. 2011; 20 (1): 42–53.30. Biffi A, Bartolomae CC, Cesana D, Cartier N, Aubourg P, Ranzani M, Cesani M, Benedicenti F, Plati T, Rubagotti E, Merella S, Capotondo A, Sgualdino J, Zanetti G, von Kalle C, Schmidt M, Naldini L, Montini E. Lentiviral-vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection. Blood. 2011; 117 (20): 5332–5339.31. Radic M. Armed and accurate: engineering cytotoxic T cells for eradication of leukemia. BMC Biotechnol. 2012; 12: 6.32. Tebas P, Stein D, Zifchak L, Seda A, Binder G, Aberra F, Collman R, McGarrity G, Levine B, June C. Prolonged control of viremia after transfer of autologous CD4 T Cells genetically modified with a lentiviral vector expressing long antisense to HIV env (VRX496). 17th CROI Conference on Retroviruses and Opportunistic Infections. San-Francisco CA. February 16–19, 2010.33. Suerth JD, Maetzig T, Galla M, Baum C, Schambach A. Self-inactivating alpharetroviral vectors with a split-packaging design. J. Virol. 2010; 84 (13): 6626–6635.34. Lindemann D., Rethwilm A. Foamy virus biology and its application for vector development. Viruses. 2011; 3 (5): 561–585.35. Mussolino C., Cathomen T. TALE nucleases: tailored genome engineering made easy. Curr. Opin. Biotechnol. 2012; 23(5):644-5036. Palpant N.J., Dudzinski D.M. Zinc-finger nucleases: looking toward translation. Gene Ther. 2012. In press.37. Silva G, Poirot L, Galetto R, Smith J, Montoya G, Duchateau P, Pâques F. Meganucleases and other tools for targeted genome engineering: perspectives and challenges for gene therapy. Curr. Gene Ther. 2011; 11 (1): 11–27.