FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1237745281> ?p ?o ?g. }

• W1237745281 endingPage "1420" @default.
• W1237745281 startingPage "1417" @default.
• W1237745281 abstract "Suicide gene approaches allow the conditional elimination of gene-modified cells and have been applied in cell therapy clinical trials. One such system, based on inducible apoptosis-mediated cell killing by caspase-9 (iC9), which is activated by a nontoxic chemical inducer of dimerization (CID), has now been successfully applied in the context of induced pluripotent stem (iPS) cells.1Yagyu S Hoyos V Del Bufalo F Brenner MK An inducible caspase-9 suicide gene to improve the safety of therapy using human induced pluripotent stem cells.Mol Ther. 2015; 23: 1476-1486Abstract Full Text Full Text PDF Scopus (64) Google Scholar The authors of the study engineered human iPS cells to express inducible caspase-9 (iC9) using lentiviral vectors, and demonstrated rapid CID-dependent apoptotic cell death in the parental iPS cells, in mesenchymal stromal cells differentiated from the iPS cells in vitro, and in teratomas generated in vivo following pluripotent stem cell transplantation in mice. Such a system is of paramount importance for enhancing the safety profiles of iPS cell–based products by elimination of unwanted cells, such as contaminating pluripotent cells or their differentiated progeny with genomic/epigenomic abnormalities having the potential to form teratomas following transplantation. Direct reprogramming of differentiated somatic cells by gene transfer of a small number of defined transcription factors has been shown to yield cells that are highly similar to embryonic stem (ES) cells with respect to gene expression, morphology, pluripotency, and capacity for in vitro differentiation.2Takahashi K Tanabe K Ohnuki M Narita M Ichisaka T Tomoda K et al.Induction of pluripotent stem cells from adult human fibroblasts by defined factors.Cell. 2007; 131: 861-872Abstract Full Text Full Text PDF PubMed Scopus (14964) Google Scholar Due to their plasticity and unlimited capacity for self-renewal, these iPS cells offer exciting possibilities for application in personalized regenerative therapies. In contrast to ES cells, iPS cells can be obtained from autologous, adult somatic cells, obviating both the need for prolonged immunosuppressive therapy in the context of cell transplantation as well as ethical issues with regard to derivation of pluripotent stem cells from human embryos. iPS cells can be genetically modified and can be coaxed to differentiate into endodermal, mesodermal, and ectodermal cell types for transplantation to treat degenerative and/or genetic diseases. Indeed, potential clinical applications such as cellular replacement/transplantation therapies have already been investigated: iPS cells derived from fibroblasts of sickle cell anemia mice were genetically corrected by replacing the mutant β-globin allele with a wild-type allele by means of homologous recombination. This provided a source of iPS cells able to differentiate into disease-free hematopoietic precursors that cured the afflicted mice following transplantation.3Hanna J Wernig M Markoulaki S Sun CW Meissner A Cassady JP et al.Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin.Science. 2007; 318: 1920-1923Crossref PubMed Scopus (1234) Google Scholar Extensive research and development ultimately led to the first clinical trial where iPS cell–derived retinal pigment epithelium cells were implanted into an eye of a patient suffering from age-related macular degeneration, a common eye condition of the elderly that can lead to blindness.4Cyranoski D Japanese woman is first recipient of next-generation stem cells.Nature. 2014; 12https://doi.org/10.1038/nature.2014.15915Crossref Google Scholar However, the possibility for oncogenic transformation remains an obstacle for the safe use of iPS cells in regenerative medicine. The risk of oncogenesis stems from genetic and epigenetic instability during reprogramming and expansion of iPS cells in vitro,5Gore A Li Z Fung HL Young JE Agarwal S Antosiewicz-Bourget J et al.Somatic coding mutations in human induced pluripotent stem cells.Nature. 2011; 471: 63-67Crossref PubMed Scopus (998) Google Scholar,6Laurent LC Ulitsky I Slavin I Tran H Schork A Morey R et al.Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture.Cell Stem Cell. 2011; 8: 106-118Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar,7Lister R Pelizzola M Kida YS Hawkins RD Nery JR Hon G et al.Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells.Nature. 2011; 471: 68-73Crossref PubMed Scopus (1216) Google Scholar,8Mayshar Y Ben-David U Lavon N Biancotti JC Yakir B Clark AT et al.Identification and classification of chromosomal aberrations in human induced pluripotent stem cells.Cell Stem Cell. 2010; 7: 521-531Abstract Full Text Full Text PDF PubMed Scopus (597) Google Scholar,9Pera MF Stem cells: the dark side of induced pluripotency.Nature. 2011; 471: 46-47Crossref PubMed Scopus (234) Google Scholar the presence of partially or abnormally reprogrammed cells in iPS cell populations, or teratoma formation from a small number of pluripotent cells remaining in transplanted iPS cell–derived populations. Therefore, strategies for safeguarding iPS cells and their differentiated progeny is quite likely a critical component for the advance of these cells into clinical applications.10Knoepfler PS Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine.Stem Cells. 2009; 27: 1050-1056Crossref PubMed Scopus (352) Google Scholar The use of “suicide genes” can enable cell killing upon addition of an otherwise nontoxic prodrug. One of the most thoroughly studied and widely used approaches is based on the herpes simplex virus thymidine kinase (HSV-TK), which converts the guanosine analog prodrug ganciclovir (GCV) to a toxic metabolite that causes premature DNA chain termination and apoptosis.11Portsmouth D Hlavaty J Renner M Suicide genes for cancer therapy.Mol Aspects Med. 2007; 28: 4-41Crossref PubMed Scopus (140) Google Scholar Similarly, the nontoxic prodrug 5-fluorocytosine (5-FC) can be converted into a potent antimetabolite, the highly toxic pyrimidine analog 5-fluorouracil (5-FU), by bacterial or yeast cytosine deaminase (CD).12Longley DB Harkin DP Johnston PG 5-fluorouracil: mechanisms of action and clinical strategies.Nat Rev Cancer. 2003; 3: 30-38Crossref Scopus (3513) Google Scholar 5-FU blocks synthesis of thymidine, which is required for DNA replication. Because both the HSV-TK/GCV and the CD/5-FC suicide systems induce cell killing by blocking DNA replication, they are particularly useful in dividing cell populations, such as those found in tumors. Indeed, both systems have been used in clinical trials targeting solid malignant tumors.13Nasu Y Saika T Ebara S Kusaka N Kaku H Abarzua F et al.Suicide gene therapy with adenoviral delivery of HSV-tK gene for patients with local recurrence of prostate cancer after hormonal therapy.Mol Ther. 2007; 15: 834-840Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar,14Chung-Faye GA Chen MJ Green NK Burton A Anderson D Mautner V et al.In vivo gene therapy for colon cancer using adenovirus-mediated, transfer of the fusion gene cytosine deaminase and uracil phosphoribosyltransferase.Gene Ther. 2001; 8: 1547-1554Crossref PubMed Scopus (85) Google Scholar An emerging suicide gene system, iC9, is based on caspase-induced apoptosis.15Jin L Zeng H Chien S Otto KG Richard RE Emery DW et al.In vivo selection using a cell-growth switch.Nat Genet. 2000; 26: 64-66Crossref PubMed Scopus (96) Google Scholar When fused to an activatable dimerization domain such as FKBP12 (Figure 1a), the proapoptotic function of caspase-9 can be conditionally induced with a nontoxic dimerizer drug (AP20187) (Figure 1b). Importantly, iC9-induced apoptosis has been applied to efficiently control T-cell populations16Straathof KC Pulè MA Yotnda P Dotti G Vanin EF Brenner MK et al.An inducible caspase 9 safety switch for T-cell therapy.Blood. 2005; 105: 4247-4254Crossref PubMed Scopus (498) Google Scholar,17Di Stasi A Tey SK Dotti G Fujita Y Kennedy-Nasser A Martinez C et al.Inducible apoptosis as a safety switch for adoptive cell therapy.N Engl J Med. 2011; 365: 1673-1683Crossref PubMed Scopus (1041) Google Scholar as well as endothelial cancer cells.18Song W Dong Z Jin T Mantellini MG Nuñez G Nör JE Cancer gene therapy with iCaspase-9 transcriptionally targeted to tumor endothelial cells.Cancer Gene Ther. 2008; 15: 667-675Crossref PubMed Scopus (15) Google Scholar Yagyu et al.1Yagyu S Hoyos V Del Bufalo F Brenner MK An inducible caspase-9 suicide gene to improve the safety of therapy using human induced pluripotent stem cells.Mol Ther. 2015; 23: 1476-1486Abstract Full Text Full Text PDF Scopus (64) Google Scholar evaluated the iC9 system as a potential safeguard of human iPS cells. They transduced human iPS cells with a lentiviral vector expressing iC9, and established two polyclonal pools of transduced cells from two independent iPS lines. Quite important for interpreting some of the findings of the study, the two pools had distinct numbers of genomically integrated vector (for simplicity, they are referred to here as “low” and “high” copy numbers). Impressively, iC9-transduced cells were efficiently eliminated by apoptosis within 24 hours of exposure to nanomolar AP20817 in vitro. Importantly, CID itself in the absence of iC9 was not toxic to iPS cells. To investigate whether the procedure is also effective in differentiated progeny, the authors generated mesenchymal stromal cells in vitro. Highly efficient cell death was again observed in the presence of nanomolar concentrations of CID, suggesting that the suicide system remains active and potent following differentiation of iPS cells. Finally, the authors tested the efficacy of their system in iPS cell–derived teratomas in mice. Although analysis was done at a relatively early time point after systemic CID administration, histological examinations indicated that the teratomas displayed signs of apoptosis and necrosis, accompanied by a reduction of tumor volume. The iC9 safety switch may therefore be useful to eliminate or reduce adverse effects of human iPS cells and their differentiated progeny, potentially improving the safety profile of patient-derived iPS cells in clinical trials. Potential advantages of the iC9 system over other suicide strategies include its rapid kinetics, effectiveness in both dividing and nondividing cell populations, and lack of immunogenicity in humans. The study also raises important questions that are relevant to fine-tuning and future designs of the system. First, a small subpopulation of cells was apparently resistant to induced apoptosis. Potential explanations include (i) carryover of contaminating, nontransduced cells in the experimental cell pools, (ii) silencing of the iC9 transgene in some of the cells, and/or (iii) emergence of resistance to apoptosis in a small fraction of cells during culture in vitro by unknown mechanisms. Importantly, the fraction of cells that were resistant to apoptosis was different in the two iPS cell populations: ~1% in the “high” copy number line and ~6% in the “low” copy number line. One possible explanation for this observation is that cells that express higher levels of iC9 are more effectively killed, suggesting dose-dependent iC9 cell killing. A second consideration that future designs will probably address is whether to target the iPS cells, their differentiated progeny, or both (Figure 1c). Both the level of iC9 required for effective cell killing as well as a need for flexibility in targeting different cell types for apoptosis suggest that promoter choice for driving iC9 expression will be key. Yagyu et al. wisely settled for the promoter of the housekeeping gene human elongation factor-1 alpha (EF1α) in their study, because it provides fairly robust transgene expression in a wide range of cell types.1Yagyu S Hoyos V Del Bufalo F Brenner MK An inducible caspase-9 suicide gene to improve the safety of therapy using human induced pluripotent stem cells.Mol Ther. 2015; 23: 1476-1486Abstract Full Text Full Text PDF Scopus (64) Google Scholar Other promoter elements providing cell type–specific expression may be considered in the future; for example, promoters exclusively active in pluripotent stem cells would allow selective elimination of iPS cells from heterogeneous cell populations, including both iPS cells and their differentiated progeny (Figure 1c). Furthermore, as the field moves toward integration-free technologies to generate iPS cells,19Schlaeger TM Daheron L Brickler TR Entwisle S Chan K Cianci A et al.A comparison of non-integrating reprogramming methods.Nat Biotechnol. 2015; 33: 58-63Crossref PubMed Scopus (344) Google Scholar the need for several lentiviral vector integrations to efficiently express iC9 would clearly compromise the otherwise integration-free production of iPS cells by generating an unwanted, and unpredictable mutagenic load. Thus, the safety of the iC9 system for future clinical testing will probably rest on technologies of precision genome engineering that allow targeted knock-in of iC9 expression cassettes into genomic safe harbors,20Lombardo A Cesana D Genovese P Di Stefano B Provasi E Colombo DF et al.Site-specific integration and tailoring of cassette design for sustainable gene transfer.Nat Methods. 2011; 8: 861-869Crossref PubMed Scopus (263) Google Scholar followed by selection of well-defined, CID-responsive clonal cell populations." @default.
• W1237745281 created "2016-06-24" @default.
• W1237745281 creator A5066552100 @default.
• W1237745281 date "2015-09-01" @default.
• W1237745281 modified "2023-10-05" @default.
• W1237745281 title "Self-Destruct Genetic Switch to Safeguard iPS Cells" @default.
• W1237745281 cites W1589194933 @default.
• W1237745281 cites W1589789540 @default.
• W1237745281 cites W1984197757 @default.
• W1237745281 cites W1984328540 @default.
• W1237745281 cites W1991107962 @default.
• W1237745281 cites W1995061082 @default.
• W1237745281 cites W2019229253 @default.
• W1237745281 cites W2037338370 @default.
• W1237745281 cites W2059378220 @default.
• W1237745281 cites W2065653704 @default.
• W1237745281 cites W2066099080 @default.
• W1237745281 cites W2070823657 @default.
• W1237745281 cites W2081808845 @default.
• W1237745281 cites W2097175022 @default.
• W1237745281 cites W2104978512 @default.
• W1237745281 cites W2122465970 @default.
• W1237745281 cites W2134491303 @default.
• W1237745281 cites W2138977668 @default.
• W1237745281 cites W2163404991 @default.
• W1237745281 doi "https://doi.org/10.1038/mt.2015.139" @default.
• W1237745281 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4817888" @default.
• W1237745281 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26321184" @default.
• W1237745281 hasPublicationYear "2015" @default.
• W1237745281 type Work @default.
• W1237745281 sameAs 1237745281 @default.
• W1237745281 citedByCount "6" @default.
• W1237745281 countsByYear W12377452812019 @default.
• W1237745281 countsByYear W12377452812020 @default.
• W1237745281 countsByYear W12377452812021 @default.
• W1237745281 countsByYear W12377452812022 @default.
• W1237745281 countsByYear W12377452812023 @default.
• W1237745281 crossrefType "journal-article" @default.
• W1237745281 hasAuthorship W1237745281A5066552100 @default.
• W1237745281 hasBestOaLocation W12377452811 @default.
• W1237745281 hasConcept C144133560 @default.
• W1237745281 hasConcept C155202549 @default.
• W1237745281 hasConcept C2780771206 @default.
• W1237745281 hasConcept C86803240 @default.
• W1237745281 hasConcept C95444343 @default.
• W1237745281 hasConceptScore W1237745281C144133560 @default.
• W1237745281 hasConceptScore W1237745281C155202549 @default.
• W1237745281 hasConceptScore W1237745281C2780771206 @default.
• W1237745281 hasConceptScore W1237745281C86803240 @default.
• W1237745281 hasConceptScore W1237745281C95444343 @default.
• W1237745281 hasIssue "9" @default.
• W1237745281 hasLocation W12377452811 @default.
• W1237745281 hasLocation W12377452812 @default.
• W1237745281 hasLocation W12377452813 @default.
• W1237745281 hasLocation W12377452814 @default.
• W1237745281 hasOpenAccess W1237745281 @default.
• W1237745281 hasPrimaryLocation W12377452811 @default.
• W1237745281 hasRelatedWork W1965643020 @default.
• W1237745281 hasRelatedWork W2018697625 @default.
• W1237745281 hasRelatedWork W2094017463 @default.
• W1237745281 hasRelatedWork W2349278934 @default.
• W1237745281 hasRelatedWork W2354541802 @default.
• W1237745281 hasRelatedWork W2356776069 @default.
• W1237745281 hasRelatedWork W2360630526 @default.
• W1237745281 hasRelatedWork W2732372545 @default.
• W1237745281 hasRelatedWork W2766662140 @default.
• W1237745281 hasRelatedWork W2954358882 @default.
• W1237745281 hasVolume "23" @default.
• W1237745281 isParatext "false" @default.
• W1237745281 isRetracted "false" @default.
• W1237745281 magId "1237745281" @default.
• W1237745281 workType "article" @default.