Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity
Received date: 28 Jul 2011
Accepted date: 08 Sep 2011
Published date: 05 Dec 2011
Copyright
Virus-based vectors are widely used in hematopoietic stem cell (HSC) gene therapy, and have the ability to integrate permanently into genomic DNA, thus driving long-term expression of corrective genes in all hematopoietic lineages. To date, HSC gene therapy has been successfully employed in the clinic for improving clinical outcomes in small numbers of patients with X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficiency (ADA-SCID), adrenoleukodystrophy (ALD), thalassemia, chronic granulomatous disease (CGD), and Wiskott-Aldrich syndrome (WAS). However, adverse events were observed during some of these HSC gene therapy clinical trials, linked to insertional activation of proto-oncogenes by integrated proviral vectors leading to clonal expansion and eventual development of leukemia. Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity, with the aim of developing safer vectors and lower-risk gene therapy protocols. This review will summarize current information on the mechanisms of insertional mutagenesis in hematopoietic stem and progenitor cells due to integrating gene transfer vectors, discuss the available assays for predicting genotoxicity and mapping vector integration sites, and introduce newly-developed approaches for minimizing genotoxicity as a way to further move HSC gene therapy forward into broader clinical application.
Chuanfeng Wu , Cynthia E. Dunbar . Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity[J]. Frontiers of Medicine, 2011 , 5(4) : 356 -371 . DOI: 10.1007/s11684-011-0159-1
| 1 |
Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P, Deist FL, Fischer A. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000; 288(5466): 669–672
|
| 2 |
Hacein-Bey-Abina S, Hauer J, Lim A, Picard C, Wang GP, Berry CC, Martinache C, Rieux-Laucat F, Latour S, Belohradsky BH, Leiva L, Sorensen R, Debré M, Casanova JL, Blanche S, Durandy A, Bushman FD, Fischer A, Cavazzana-Calvo M. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2010; 363(4): 355–364
|
| 3 |
Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, Morecki S, Andolfi G, Tabucchi A, Carlucci F, Marinello E, Cattaneo F, Vai S, Servida P, Miniero R, Roncarolo MG, Bordignon C. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 2002; 296(5577): 2410–2413
|
| 4 |
Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I, Tabucchi A, Carlucci F, Eibl M, Aker M, Slavin S, Al-Mousa H, Al Ghonaium A, Ferster A, Duppenthaler A, Notarangelo L, Wintergerst U, Buckley RH, Bregni M, Marktel S, Valsecchi MG, Rossi P, Ciceri F, Miniero R, Bordignon C, Roncarolo MG. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 2009; 360(5): 447–458
|
| 5 |
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
|
| 6 |
Kang EM, Choi U, Theobald N, Linton G, Long Priel DA, Kuhns D, Malech HL. 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(4): 783–791
|
| 7 |
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
|
| 8 |
Boztug K, Schmidt M, Schwarzer A, Banerjee PP, Díez IA, Dewey RA, Böhm M, Nowrouzi A, Ball CR, Glimm H, Naundorf S, Kühlcke K, Blasczyk R, Kondratenko I, Maródi L, Orange JS, von Kalle C, Klein C. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med 2010; 363(20): 1918–1927
|
| 9 |
Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A, Schmidt M, Krämer A, Schwäble J, Glimm H, Koehl U, Preiss C, Ball C, Martin H, Göhring G, Schwarzwaelder K, Hofmann WK, Karakaya K, Tchatchou S, Yang R, Reinecke P, Kühlcke K, Schlegelberger B, Thrasher AJ, Hoelzer D, Seger R, von Kalle C, Grez M. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med 2010; 16(2): 198–204
|
| 10 |
Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint Basile G, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003; 302(5644): 415–419
|
| 11 |
Leonard WJ. The molecular basis of X-linked severe combined immunodeficiency: defective cytokine receptor signaling. Annu Rev Med 1996; 47: 229–239
|
| 12 |
Sugamura K, Asao H, Kondo M, Tanaka N, Ishii N, Ohbo K, Nakamura M, Takeshita T. The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu Rev Immunol 1996; 14(1): 179–205
|
| 13 |
Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. 20 years of gene therapy for SCID. Nat Immunol 2010; 11(6): 457–460
|
| 14 |
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
|
| 15 |
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
|
| 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 |
Davé UP, Jenkins NA, Copeland NG. Gene therapy insertional mutagenesis insights. Science 2004; 303(5656): 333
|
| 18 |
Woods NB, Bottero V, Schmidt M, von Kalle C, Verma IM. Gene therapy: therapeutic gene causing lymphoma. Nature 2006; 440(7088): 1123
|
| 19 |
Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, Shearer G, Chang L, Chiang Y, Tolstoshev P, Greenblatt JJ, Rosenberg SA, Klein H, Berger M, Mullen CA, Ramsey WJ, Muul L, Morgan RA, Anderson WF. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science 1995; 270(5235): 475–480
|
| 20 |
Kohn DB, Hershfield MS, Carbonaro D, Shigeoka A, Brooks J, Smogorzewska EM, Barsky LW, Chan R, Burotto F, Annett G, Nolta JA, Crooks G, Kapoor N, Elder M, Wara D, Bowen T, Madsen E, Snyder FF, Bastian J, Muul L, Blaese RM, Weinberg K, Parkman R. 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(7): 775–780
|
| 21 |
Cassani B, Montini E, Maruggi G, Ambrosi A, Mirolo M, Selleri S, Biral E, Frugnoli I, Hernandez-Trujillo V, Di Serio C, Roncarolo MG, Naldini L, Mavilio F, Aiuti A. Integration of retroviral vectors induces minor changes in the transcriptional activity of T cells from ADA-SCID patients treated with gene therapy. Blood 2009; 114(17): 3546–3556
|
| 22 |
Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, Urbinati F, Valacca C, Scaramuzza S, Aker M, Slavin S, Cazzola M, Sartori D, Ambrosi A, Di Serio C, Roncarolo MG, Mavilio F, Bordignon C. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest 2007; 117(8): 2233–2240
|
| 23 |
Heyworth PG, Cross AR, Curnutte JT. Chronic granulomatous disease. Curr Opin Immunol 2003; 15(5): 578–584
|
| 24 |
Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol 2007; 3(3): 140–151
|
| 25 |
Yannaki E, Emery DW, Stamatoyannopoulos G. Gene therapy for β-thalassaemia: the continuing challenge. Expert Rev Mol Med 2010; 12: e31
|
| 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 |
Ikeda K, Mason PJ, Bessler M. 3’UTR-truncated Hmga2 cDNA causes MPN-like hematopoiesis by conferring a clonal growth advantage at the level of HSC in mice. Blood 2011; 117(22): 5860–5869
|
| 28 |
Ochman H, Gerber AS, Hartl DL. Genetic applications of an inverse polymerase chain reaction. Genetics 1988; 120(3): 621–623
|
| 29 |
Kim HJ, Tisdale JF, Wu T, Takatoku M, Sellers SE, Zickler P, Metzger ME, Agricola BA, Malley JD, Kato I, Donahue RE, Brown KE, Dunbar CE. Many multipotential gene-marked progenitor or stem cell clones contribute to hematopoiesis in nonhuman primates. Blood 2000; 96(1): 1–8
|
| 30 |
Suzuki T, Minehata K, Akagi K, Jenkins NA, Copeland NG. Tumor suppressor gene identification using retroviral insertional mutagenesis in Blm-deficient mice. EMBO J 2006; 25(14): 3422–3431
|
| 31 |
Mueller PR, Wold B. In vivo footprinting of a muscle specific enhancer by ligation mediated PCR. Science 1989; 246(4931): 780–786
|
| 32 |
Kustikova OS, Baum C, Fehse B. Retroviral integration site analysis in hematopoietic stem cells. Methods Mol Biol 2008; 430: 255–267
|
| 33 |
Kustikova O, Fehse B, Modlich U, Yang M, Düllmann J, Kamino K, von Neuhoff N, Schlegelberger B, Li Z, Baum C. Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking. Science 2005; 308(5725): 1171–1174
|
| 34 |
Schmidt M, Schwarzwaelder K, Bartholomae CC, Glimm H, von Kalle C. Detection of retroviral integration sites by linear amplification-mediated PCR and tracking of individual integration clones in different samples. Methods Mol Biol 2009; 506: 363–372
|
| 35 |
Schmidt M, Zickler P, Hoffmann G, Haas S, Wissler M, Muessig A, Tisdale JF, Kuramoto K, Andrews RG, Wu T, Kiem HP, Dunbar CE, von Kalle C. Polyclonal long-term repopulating stem cell clones in a primate model. Blood 2002; 100(8): 2737–2743
|
| 36 |
Schmidt M, Schwarzwaelder K, Bartholomae C, Zaoui K, Ball C, Pilz I, Braun S, Glimm H, von Kalle C. High-resolution insertion-site analysis by linear amplification-mediated PCR (LAM-PCR). Nat Methods 2007; 4(12): 1051–1057
|
| 37 |
Hematti P, Hong BK, Ferguson C, Adler R, Hanawa H, Sellers S, Holt IE, Eckfeldt CE, Sharma Y, Schmidt M, von Kalle C, Persons DA, Billings EM, Verfaillie CM, Nienhuis AW, Wolfsberg TG, Dunbar CE, Calmels B. Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells. PLoS Biol 2004; 2(12): e423
|
| 38 |
Harkey MA, Kaul R, Jacobs MA, Kurre P, Bovee D, Levy R, Blau CA. Multiarm high-throughput integration site detection: limitations of LAM-PCR technology and optimization for clonal analysis. Stem Cells Dev 2007; 16(3): 381–392
|
| 39 |
Gabriel R, Eckenberg R, Paruzynski A, Bartholomae CC, Nowrouzi A, Arens A, Howe SJ, Recchia A, Cattoglio C, Wang W, Faber K, Schwarzwaelder K, Kirsten R, Deichmann A, Ball CR, Balaggan KS, Yáñez-Muñoz RJ, Ali RR, Gaspar HB, Biasco L, Aiuti A, Cesana D, Montini E, Naldini L, Cohen-Haguenauer O, Mavilio F, Thrasher AJ, Glimm H, von Kalle C, Saurin W, Schmidt M. Comprehensive genomic access to vector integration in clinical gene therapy. Nat Med 2009; 15(12): 1431–1436
|
| 40 |
Margulies M, Egholm M, Altman WE, Attiya S, Bader JS, Bemben LA, Berka J, Braverman MS, Chen YJ, Chen Z, Dewell SB, Du L, Fierro JM, Gomes XV, Godwin BC, He W, Helgesen S, Ho CH, Irzyk GP, Jando SC, Alenquer ML, Jarvie TP, Jirage KB, Kim JB, Knight JR, Lanza JR, Leamon JH, Lefkowitz SM, Lei M, Li J, Lohman KL, Lu H, Makhijani VB, McDade KE, McKenna MP, Myers EW, Nickerson E, Nobile JR, Plant R, Puc BP, Ronan MT, Roth GT, Sarkis GJ, Simons JF, Simpson JW, Srinivasan M, Tartaro KR, Tomasz A, Vogt KA, Volkmer GA, Wang SH, Wang Y, Weiner MP, Yu P, Begley RF, Rothberg JM. Genome sequencing in microfabricated high-density picolitre reactors. Nature 2005; 437(7057): 376–380
|
| 41 |
Wang GP, Garrigue A, Ciuffi A, Ronen K, Leipzig J, Berry C, Lagresle-Peyrou C, Benjelloun F, Hacein-Bey-Abina S, Fischer A, Cavazzana-Calvo M, Bushman FD. DNA bar coding and pyrosequencing to analyze adverse events in therapeutic gene transfer. Nucleic Acids Res 2008; 36(9): e49
|
| 42 |
Pule MA, Rousseau A, Vera J, Heslop HE, Brenner MK, Vanin EF. Flanking-sequence exponential anchored-polymerase chain reaction amplification: a sensitive and highly specific method for detecting retroviral integrant-host-junction sequences. Cytotherapy 2008; 10(5): 526–539
|
| 43 |
Brady T, Roth SL, Malani N, Wang GP, Berry CC, Leboulch P, Hacein-Bey-Abina S, Cavazzana-Calvo M, Papapetrou EP, Sadelain M, Savilahti H, Bushman FD. A method to sequence and quantify DNA integration for monitoring outcome in gene therapy. Nucleic Acids Res 2011; 39(11): e72
|
| 44 |
Schröder AR, Shinn P, Chen H, Berry C, Ecker JR, Bushman F. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002; 110(4): 521–529
|
| 45 |
Trobridge GD, Miller DG, Jacobs MA, Allen JM, Kiem HP, Kaul R, Russell DW. Foamy virus vector integration sites in normal human cells. Proc Natl Acad Sci USA 2006; 103(5): 1498–1503
|
| 46 |
Mitchell RS, Beitzel BF, Schroder AR, Shinn P, Chen H, Berry CC, Ecker JR, Bushman FD. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol 2004; 2(8): e234
|
| 47 |
Wu X, Li Y, Crise B, Burgess SM. Transcription start regions in the human genome are favored targets for MLV integration. Science 2003; 300(5626): 1749–1751
|
| 48 |
Narezkina A, Taganov KD, Litwin S, Stoyanova R, Hayashi J, Seeger C, Skalka AM, Katz RA. Genome-wide analyses of avian sarcoma virus integration sites. J Virol 2004; 78(21): 11656–11663
|
| 49 |
Trobridge GD. Genotoxicity of retroviral hematopoietic stem cell gene therapy. Expert Opin Biol Ther 2011; 11(5): 581–593
|
| 50 |
Biasco L, Ambrosi A, Pellin D, Bartholomae C, Brigida I, Roncarolo MG, Di Serio C, von Kalle C, Schmidt M, Aiuti A. 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(2): 89–101
|
| 51 |
Wang GP, Ciuffi A, Leipzig J, Berry CC, Bushman FD. HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res 2007; 17(8): 1186–1194
|
| 52 |
Brady T, Agosto LM, Malani N, Berry CC, O’Doherty U, Bushman F. HIV integration site distributions in resting and activated CD4+ T cells infected in culture. AIDS 2009; 23(12): 1461–1471
|
| 53 |
Lewinski MK, Yamashita M, Emerman M, Ciuffi A, Marshall H, Crawford G, Collins F, Shinn P, Leipzig J, Hannenhalli S, Berry CC, Ecker JR, Bushman FD. Retroviral DNA integration: viral and cellular determinants of target-site selection. PLoS Pathog 2006; 2(6): e60
|
| 54 |
Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J Biol Chem 2003; 278(1): 372–381
|
| 55 |
Llano M, Delgado S, Vanegas M, Poeschla EM. Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase. J Biol Chem 2004; 279(53): 55570–55577
|
| 56 |
Emiliani S, Mousnier A, Busschots K, Maroun M, Van Maele B, Tempé D, Vandekerckhove L, Moisant F, Ben-Slama L, Witvrouw M, Christ F, Rain JC, Dargemont C, Debyser Z, Benarous R. Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication. J Biol Chem 2005; 280(27): 25517–25523
|
| 57 |
Ciuffi A, Llano M, Poeschla E, Hoffmann C, Leipzig J, Shinn P, Ecker JR, Bushman F. A role for LEDGF/p75 in targeting HIV DNA integration. Nat Med 2005; 11(12): 1287–1289
|
| 58 |
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
|
| 59 |
Du Y, Jenkins NA, Copeland NG. Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells. Blood 2005; 106(12): 3932–3939
|
| 60 |
Zychlinski D, Schambach A, Modlich U, Maetzig T, Meyer J, Grassman E, Mishra A, Baum C. Physiological promoters reduce the genotoxic risk of integrating gene vectors. Mol Ther 2008; 16(4): 718–725
|
| 61 |
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
|
| 62 |
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
|
| 63 |
Li Z, Düllmann J, Schiedlmeier B, Schmidt M, von Kalle C, Meyer J, Forster M, Stocking C, Wahlers A, Frank O, Ostertag W, Kühlcke K, Eckert HG, Fehse B, Baum C. Murine leukemia induced by retroviral gene marking. Science 2002; 296(5567): 497
|
| 64 |
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
|
| 65 |
Lund AH, Turner G, Trubetskoy A, Verhoeven E, Wientjens E, Hulsman D, Russell R, DePinho RA, Lenz J, van Lohuizen M. Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. Nat Genet 2002; 32(1): 160–165
|
| 66 |
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
|
| 67 |
Drake AC, Khoury M, Leskov I, Iliopoulou BP, Fragoso M, Lodish H, Chen J. Human CD34+ CD133+ hematopoietic stem cells cultured with growth factors including Angptl5 efficiently engraft adult NOD-SCID Il2rγ-/- (NSG) mice. PLoS ONE 2011; 6(4): e18382
|
| 68 |
Frecha C, Fusil F, Cosset FL, Verhoeyen E. In vivo gene delivery into hCD34+ cells in a humanized mouse model. Methods Mol Biol 2011; 737: 367–390
|
| 69 |
Joseph A, Zheng JH, Chen K, Dutta M, Chen C, Stiegler G, Kunert R, Follenzi A, Goldstein H. Inhibition of in vivo HIV infection in humanized mice by gene therapy of human hematopoietic stem cells with a lentiviral vector encoding a broadly neutralizing anti-HIV antibody. J Virol 2010; 84(13): 6645–6653
|
| 70 |
Spraul CW, Roth HJ, Gäckle H, Lang GE, Lang GK. Influence of special-effect contact lenses (Crazy Lenses) on visual function. CLAO J 1998; 24(1): 29–32
|
| 71 |
Trobridge GD, Kiem HP. Large animal models of hematopoietic stem cell gene therapy. Gene Ther 2010; 17(8): 939–948
|
| 72 |
Felsburg PJ, Somberg RL, Perryman LE. Domestic animal models of severe combined immunodeficiency: canine X-linked severe combined immunodeficiency and severe combined immunodeficiency in horses. Immunodefic Rev 1992; 3(4): 277–303
|
| 73 |
Spellacy E, Shull RM, Constantopoulos G, Neufeld EF. A canine model of human alpha-L-iduronidase deficiency. Proc Natl Acad Sci USA 1983; 80(19): 6091–6095
|
| 74 |
Kijas JM, Bauer TR Jr, Gäfvert S, Marklund S, Trowald-Wigh G, Johannisson A, Hedhammar A, Binns M, Juneja RK, Hickstein DD, Andersson L. A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency. Genomics 1999; 61(1): 101–107
|
| 75 |
Beard BC, Kiem HP. Canine models of gene-modified hematopoiesis. Methods Mol Biol 2009; 506: 341–361
|
| 76 |
Ting-De Ravin SS, Kennedy DR, Naumann N, Kennedy JS, Choi U, Hartnett BJ, Linton GF, Whiting-Theobald NL, Moore PF, Vernau W, Malech HL, Felsburg PJ. Correction of canine X-linked severe combined immunodeficiency by in vivo retroviral gene therapy. Blood 2006; 107(8): 3091–3097
|
| 77 |
Bauer TR Jr, Hai M, Tuschong LM, Burkholder TH, Gu YC, Sokolic RA, Ferguson C, Dunbar CE, Hickstein DD. Correction of the disease phenotype in canine leukocyte adhesion deficiency using ex vivo hematopoietic stem cell gene therapy. Blood 2006; 108(10): 3313–3320
|
| 78 |
Beard BC, Keyser KA, Trobridge GD, Peterson LJ, Miller DG, Jacobs M, Kaul R, Kiem HP. Unique integration profiles in a canine model of long-term repopulating cells transduced with gammaretrovirus, lentivirus, or foamy virus. Hum Gene Ther 2007; 18(5): 423–434
|
| 79 |
Kiem HP, Sellers S, Thomasson B, Morris JC, Tisdale JF, Horn PA, Hematti P, Adler R, Kuramoto K, Calmels B, Bonifacino A, Hu J, von Kalle C, Schmidt M, Sorrentino B, Nienhuis A, Blau CA, Andrews RG, Donahue RE, Dunbar CE. Long-term clinical and molecular follow-up of large animals receiving retrovirally transduced stem and progenitor cells: no progression to clonal hematopoiesis or leukemia. Mol Ther 2004; 9(3): 389–395
|
| 80 |
Seggewiss R, Pittaluga S, Adler RL, Guenaga FJ, Ferguson C, Pilz IH, Ryu B, Sorrentino BP, Young WS 3rd, Donahue RE, von Kalle C, Nienhuis AW, Dunbar CE. Acute myeloid leukemia is associated with retroviral gene transfer to hematopoietic progenitor cells in a rhesus macaque. Blood 2006; 107(10): 3865–3867
|
| 81 |
Calmels B, Ferguson C, Laukkanen MO, Adler R, Faulhaber M, Kim HJ, Sellers S, Hematti P, Schmidt M, von Kalle C, Akagi K, Donahue RE, Dunbar CE. Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells. Blood 2005; 106(7): 2530–2533
|
| 82 |
Kim YJ, Kim YS, Larochelle A, Renaud G, Wolfsberg TG, Adler R, Donahue RE, Hematti P, Hong BK, Roayaei J, Akagi K, Riberdy JM, Nienhuis AW, Dunbar CE, Persons DA. Sustained high-level polyclonal hematopoietic marking and transgene expression 4 years after autologous transplantation of rhesus macaques with SIV lentiviral vector-transduced CD34+ cells. Blood 2009; 113(22): 5434–5443
|
| 83 |
Sellers S, Gomes TJ, Larochelle A, Lopez R, Adler R, Krouse A, Donahue RE, Childs RW, Dunbar CE. Ex vivo expansion of retrovirally transduced primate CD34+ cells results in overrepresentation of clones with MDS1/EVI1 insertion sites in the myeloid lineage after transplantation. Mol Ther 2010; 18(9): 1633–1639
|
| 84 |
Hu J, Renaud G, Gomes TJ, Ferris A, Hendrie PC, Donahue RE, Hughes SH, Wolfsberg TG, Russell DW, Dunbar CE. Reduced genotoxicity of avian sarcoma leukosis virus vectors in rhesus long-term repopulating cells compared to standard murine retrovirus vectors. Mol Ther 2008; 16(9): 1617–1623
|
| 85 |
Hu J, Ferris A, Larochelle A, Krouse AE, Metzger ME, Donahue RE, Hughes SH, Dunbar CE. Transduction of rhesus macaque hematopoietic stem and progenitor cells with avian sarcoma and leukosis virus vectors. Hum Gene Ther 2007; 18(8): 691–700
|
| 86 |
Deeks SG, Wagner B, Anton PA, Mitsuyasu RT, Scadden DT, Huang C, Macken C, Richman DD, Christopherson C, June CH, Lazar R, Broad DF, Jalali S, Hege KM. A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy. Mol Ther 2002; 5(6): 788–797
|
| 87 |
Mitsuyasu RT, Anton PA, Deeks SG, Scadden DT, Connick E, Downs MT, Bakker A, Roberts MR, June CH, Jalali S, Lin AA, Pennathur-Das R, Hege KM. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood 2000; 96(3): 785–793
|
| 88 |
Walker RE, Bechtel CM, Natarajan V, Baseler M, Hege KM, Metcalf JA, Stevens R, Hazen A, Blaese RM, Chen CC, Leitman SF, Palensky J, Wittes J, Davey RT Jr, Falloon J, Polis MA, Kovacs JA, Broad DF, Levine BL, Roberts MR, Masur H, Lane HC. Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. Blood 2000; 96(2): 467–474
|
| 89 |
Newrzela S, Cornils K, Li Z, Baum C, Brugman MH, Hartmann M, Meyer J, Hartmann S, Hansmann ML, Fehse B, von Laer D. Resistance of mature T cells to oncogene transformation. Blood 2008; 112(6): 2278–2286
|
| 90 |
Persons DA. Lentiviral vector gene therapy: effective and safe? Mol Ther 2010; 18(5): 861–862
|
| 91 |
Nowrouzi A, Dittrich M, Klanke C, Heinkelein M, Rammling M, Dandekar T, von Kalle C, Rethwilm A. Genome-wide mapping of foamy virus vector integrations into a human cell line. J Gen Virol 2006; 87(Pt 5): 1339–1347
|
| 92 |
Nienhuis AW, Dunbar CE, Sorrentino BP. Genotoxicity of retroviral integration in hematopoietic cells. Mol Ther 2006; 13(6): 1031–1049
|
| 93 |
Dorrell C, Gan OI, Pereira DS, Hawley RG, Dick JE. Expansion of human cord blood CD34(+)CD38(-) cells in ex vivo culture during retroviral transduction without a corresponding increase in SCID repopulating cell (SRC) frequency: dissociation of SRC phenotype and function. Blood 2000; 95(1): 102–110
|
| 94 |
Williams DA. Ex vivo expansion of hematopoietic stem and progenitor cells—robbing Peter to pay Paul? Blood 1993; 81(12): 3169–3172
|
| 95 |
Dunbar CE, Takatoku M, Donahue RE. The impact of ex vivo cytokine stimulation on engraftment of primitive hematopoietic cells in a non-human primate model. Ann N Y Acad Sci 2001;938: 236–244; discussion 244–245
|
| 96 |
Spencer DM. Developments in suicide genes for preclinical and clinical applications. Curr Opin Mol Ther 2000; 2(4): 433–440
|
| 97 |
Lupo-Stanghellini MT, Provasi E, Bondanza A, Ciceri F, Bordignon C, Bonini C. Clinical impact of suicide gene therapy in allogeneic hematopoietic stem cell transplantation. Hum Gene Ther 2010; 21(3): 241–250
|
| 98 |
Ciceri F, Bonini C, Gallo-Stampino C, Bordignon C. Modulation of GvHD by suicide-gene transduced donor T lymphocytes: clinical applications in mismatched transplantation. Cytotherapy 2005; 7(2): 144–149
|
| 99 |
Bonini C, Bondanza A, Perna SK, Kaneko S, Traversari C, Ciceri F, Bordignon C. The suicide gene therapy challenge: how to improve a successful gene therapy approach. Mol Ther 2007; 15(7): 1248–1252
|
| 100 |
Frank O, Rudolph C, Heberlein C, von Neuhoff N, Schröck E, Schambach A, Schlegelberger B, Fehse B, Ostertag W, Stocking C, Baum C. Tumor cells escape suicide gene therapy by genetic and epigenetic instability. Blood 2004; 104(12): 3543–3549
|
| 101 |
Uckert W, Kammertöns T, Haack K, Qin Z, Gebert J, Schendel DJ, Blankenstein T. Double suicide gene (cytosine deaminase and herpes simplex virus thymidine kinase) but not single gene transfer allows reliable elimination of tumor cells in vivo. Hum Gene Ther 1998; 9(6): 855–865
|
| 102 |
Straathof KC, Pulè MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, Heslop HE, Spencer DM, Rooney CM. An inducible caspase 9 safety switch for T-cell therapy. Blood 2005; 105(11): 4247–4254
|
| 103 |
Tey SK, Dotti G, Rooney CM, Heslop HE, Brenner MK. Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation. Biol Blood Marrow Transplant 2007; 13(8): 913–924
|
| 104 |
Quintarelli C, Vera JF, Savoldo B, Giordano Attianese GM, Pule M, Foster AE, Heslop HE, Rooney CM, Brenner MK, Dotti G. Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes. Blood 2007; 110(8): 2793–2802
|
| 105 |
Zhong B,Watts KL,Gori JL,Wohlfahrt ME,Enssle J,Adair JE, Kiem H P. Safeguarding nonhuman primate iPS cells with suicide genes. Mol Ther, 2011; 19:1667-1675
|
| 106 |
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126(4): 663–676
|
| 107 |
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131(5): 861–872
|
| 108 |
Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007; 318(5858): 1920–1923
|
| 109 |
Raya A, Rodríguez-Pizà I, Guenechea G, Vassena R, Navarro S, Barrero MJ, Consiglio A, Castellà M, Río P, Sleep E, González F, Tiscornia G, Garreta E, Aasen T, Veiga A, Verma IM, Surrallés J, Bueren J, Izpisúa Belmonte JC. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 2009; 460(7251): 53–59
|
| 110 |
Kane NM, Nowrouzi A, Mukherjee S, Blundell MP, Greig JA, Lee WK, Houslay MD, Milligan G, Mountford JC, von Kalle C, Schmidt M, Thrasher AJ, Baker AH. Lentivirus-mediated reprogramming of somatic cells in the absence of transgenic transcription factors. Mol Ther 2010; 18(12): 2139–2145
|
| 111 |
Winkler T, Cantilena A, Métais JY, Xu X, Nguyen AD, Borate B, Antosiewicz-Bourget JE, Wolfsberg TG, Thomson JA, Dunbar CE. No evidence for clonal selection due to lentiviral integration sites in human induced pluripotent stem cells. Stem Cells 2010; 28(4): 687–694
|
| 112 |
Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 2011; 471(7336): 68–73
|
| 113 |
Hussein SM, Nagy K, Nagy A. Human induced pluripotent stem cells: the past, present, and future. Clin Pharmacol Ther 2011; 89(5): 741–745
|
| 114 |
Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008; 322(5903): 949–953
|
| 115 |
Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K. Induced pluripotent stem cells generated without viral integration. Science 2008; 322(5903): 945–949
|
| 116 |
Sommer CA, Stadtfeld M, Murphy GJ, Hochedlinger K, Kotton DN, Mostoslavsky G. Induced pluripotent stem cell generation using a single lentiviral stem cell cassette. Stem Cells 2009; 27(3): 543–549
|
| 117 |
Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009; 458(7239): 771–775
|
| 118 |
Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan C, Schlaeger TM, Rossi DJ. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 2010; 7(5): 618–630
|
| 119 |
Papapetrou EP, Lee G, Malani N, Setty M, Riviere I, Tirunagari LM, Kadota K, Roth SL, Giardina P, Viale A, Leslie C, Bushman FD, Studer L, Sadelain M. Genomic safe harbors permit high β-globin transgene expression in thalassemia induced pluripotent stem cells. Nat Biotechnol 2011; 29(1): 73–78
|
| 120 |
Zou J, Sweeney CL, Chou BK, Choi U, Pan J, Wang H, Dowey SN, Cheng L, Malech HL. Oxidase-deficient neutrophils from X-linked chronic granulomatous disease iPS cells: functional correction by zinc finger nuclease-mediated safe harbor targeting. Blood 2011; 117(21): 5561–5572
|
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