Endogenous Transposase Source in Human Cells Mobilizes piggyBac Transposons

Ivics, Zoltán

doi:10.1038/mt.2016.76

Cited by 15 publications

(11 citation statements)

References 30 publications

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“…Thus, despite the vast evolutionary distance between PGBD5 and insect PB transposons, there appears to be a cross-reaction between a catalytically active endogenous human transposase and transposon vector sequences that are exogenously delivered into human cells by gene transfer. The findings have potential implications for the genomic stability of PB vector insertions in human applications [81].…”

Section: Glossarymentioning

confidence: 91%

Gene Therapy with the Sleeping Beauty Transposon System

et al. 2017

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Section: Glossarymentioning

confidence: 91%

Gene Therapy with the Sleeping Beauty Transposon System

et al. 2017

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“…Vice versa, human cells do not express proteins that could re-mobilize a genomically integrated Sleeping Beauty or Tol2 vector. In contrast, the human PGBD5 transposase-derived protein was reported to mobilize piggyBac transposon vectors in human cells [278], thereby presenting potential implications for human applications [279].…”

Section: Dna Transposons As Tools For Genetic Engineering Of Stem Cellsmentioning

confidence: 99%

The impact of transposable element activity on therapeutically relevant human stem cells

et al. 2019

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Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use, including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome, and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for the biosafety of stem cells to be used for substitutive and regenerative cell therapies.

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“…The findings suggest that there may be stability issues for applications involving PB vectors in human cells expressing PGBD5. 62 To estimate the genotoxic potential of different vector types and designs, it is important to characterize the properties that influence their selection of target sites. 63 A comparative study was previously carried out of the target site selection properties of the SB and PB transposons, as well as MLV-derived gammaretroviral and HIVderived lentiviral systems in primary human CD4 + T cells.…”

Section: Safety Aspects Of Sb Transpositionmentioning

confidence: 99%

Wide Awake and Ready to Move: 20 Years of Non-Viral Therapeutic Genome Engineering with the Sleeping Beauty Transposon System

et al. 2017

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Gene therapies will only become a widespread tool in the clinical treatment of human diseases with the advent of gene transfer vectors that integrate genetic information stably, safely, effectively, and economically. Two decades after the discovery of the Sleeping Beauty (SB) transposon, it has been transformed into a vector system that is fulfilling these requirements. SB may well overcome some of the limitations associated with viral gene transfer vectors and transient non-viral gene delivery approaches that are being used in the majority of ongoing clinical trials. The SB system has achieved a high level of stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, representing crucial steps that may permit its clinical use in the near future. This article reviews the most important aspects of SB as a tool for gene therapy, including aspects of its vectorization and genomic integration. As an illustration, the clinical development of the SB system toward gene therapy of age-related macular degeneration and cancer immunotherapy is highlighted.

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Endogenous Transposase Source in Human Cells Mobilizes piggyBac Transposons

Cited by 15 publications

References 30 publications

Gene Therapy with the Sleeping Beauty Transposon System

Gene Therapy with the Sleeping Beauty Transposon System

The impact of transposable element activity on therapeutically relevant human stem cells

Wide Awake and Ready to Move: 20 Years of Non-Viral Therapeutic Genome Engineering with the Sleeping Beauty Transposon System

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