Gene Therapy with the Sleeping Beauty Transposon System

Kebriaei, Partow; Izsvák, Zsuzsanna; Narayanavari, Suneel A.; Singh, Harjeet; Ivics, Zoltán

doi:10.1016/j.tig.2017.08.008

Cited by 101 publications

(79 citation statements)

References 161 publications

(211 reference statements)

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“…These anti-CD19 CAR T cells demonstrated antitumor activity, persistence (201 days in autologous and 51 days in allogeneic settings), and safety/ feasibility. 77,91,92 Safety switches can be engineered into CAR vectors to allow the opportunity for controlled elimination of CAR T cells in the case of nonspecific cytotoxic activity. Depletion of cells via iCasp9 is caused by application of AP1903, a clinically allowed small molecule dimerizer that activates iCasp9 and thus induces apoptosis of the expres-sing cells.…”

Section: Vector Developments For Carsmentioning

confidence: 99%

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Chimeric Antigen Receptor T Cells: Extending Translation from Liquid to Solid Tumors

Morgan

Schambach

2018

Human Gene Therapy

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Successful translation of chimeric antigen receptor (CAR) T cells designed to target and eradicate CD19+ lymphomas has emboldened scientists and physicians worldwide to explore the possibility of applying CAR T-cell technology to other tumor entities, including solid tumors. Next-generation strategies such as fourth-generation CARs (CAR T cells redirected for universal cytokine killing, also known as TRUCKs) designed to deliver immunomodulatory cytokines to the tumor microenvironment, dual CAR designs to improve tumor control, inclusion of suicide genes as safety switches, and precision genome editing are currently being investigated. One major ongoing goal is to determine how best to generate CAR T cells that modulate the tumor microenvironment, overcome tumor survival mechanisms, and thus allow broader applicability as universal allogeneic T-cell therapeutics. Development of state-of-the-art and beyond viral vector systems to deliver designer CARs coupled with targeted genome editing is expected to generate more effective off-the-shelf CAR T cells with activity against a greater number of cancer types and importantly solid tumors.

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Section: Vector Developments For Carsmentioning

confidence: 99%

“…92 In short, integrating retroviral (including lentiviral) and Sleeping Beauty vectors are suitable systems to transduce primary human T cells, even with complex CAR constructs designed to express suicide genes (e.g., inducible…”

Section: Vector Developments For Carsmentioning

confidence: 99%

Chimeric Antigen Receptor T Cells: Extending Translation from Liquid to Solid Tumors

Morgan

Schambach

2018

Human Gene Therapy

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“…The former require culture of packaging cell lines under GMP conditions for virus production, but have the advantage of very efficient, generally stable transduction of human T cells. Non-viral gene delivery via plasmids, nucleases or transposon-based technologies are cheaper, but efficiency is variable and cell viability can be compromised, depending on the methods used to introduce nucleic acids into therapeutic cells 26 .…”

Section: Car T Cell Manufacturementioning

confidence: 99%

“…These include transposon-based gene transduction such as the sleeping beauty system which facilitate stable transgene expression, have proven feasible for generation of clinical CAR T cell products for patients and are significantly less costly than use of viral transduction 26 . Further advantages include a near-random integration pattern, rather than preferential targeting of highly expressed genes, as is seen with viral transduction methods.…”

Section: Vectorsmentioning

confidence: 99%

“…There is a concern that dysregulated gene expression caused by non-random transgene insertion may lead to oncogenic potential, such as those seen following gene-engineering of haematopoietic stem cells 60,61 , though in practice, there have been no cases of oncogenesis of this type with transduction of mature T cells across CAR T cell or other T cell studies across the globe. Moreover, the cell manipulation and prolonged expansion used with non-viral transduction may impact on the biological fitness of CAR T cells, though prolonged persistence has been documented in early clinical studies of CD19 CAR T cell therapy in the setting of adjunctive allogeneic or autologous stem cell transplantation 26 . Data on disease-related outcomes from these studies are eagerly awaited in order to understand whether their therapeutic efficacy is equivalent to virally-transduced CAR T cells.…”

Section: Vectorsmentioning

confidence: 99%

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Open access? Widening access to chimeric antigen receptor (CAR) therapy for ALL

Ghorashian

Amrolia

Veys

2018

Experimental Hematology

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T cells that are genetically modified to express chimeric antigen receptors (CARs) specific for CD19 show great promise for the treatment of relapsed/refractory acute lymphoblastic leukemia (ALL). The first U.S. Food and Drug Administration approval of a cellular cancer therapy in 2017, Novartis's CD19-targeting CAR T-cell product Kymriah™ within the context of relapsed/refractory pediatric ALL, followed rapidly by approval of Kite's Yescarta™ and, more recently, Kymriah™ for diffuse large B-cell indications in adults, highlights the pace of progress made in this field. In this review, we will consider the latest evidence from CAR T-cell therapy for B-lineage ALL. We discuss the barriers to CAR T-cell therapy for ALL patients and give a perspective on the strategy we have taken to date to widen access to CAR T-cell therapy for UK pediatric patients with high-risk ALL.

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DNA on the move: mechanisms, functions and applications of transposable elements

Schmitz,

Querques

2023

FEBS Open Bio

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Transposons are mobile genetic elements that have invaded all domains of life by moving between and within their host genomes. Due to their mobility (or transposition), transposons facilitate horizontal gene transfer in bacteria and foster the evolution of new molecular functions in prokaryotes and eukaryotes. As transposition can lead to detrimental genomic rearrangements, organisms have evolved a multitude of molecular strategies to control transposons, including genome defense mechanisms provided by CRISPR‐Cas systems. Apart from their biological impacts on genomes, DNA transposons have been leveraged as efficient gene insertion vectors in basic research, transgenesis and gene therapy. However, the close to random insertion profile of transposon‐based tools limits their programmability and safety. Despite recent advances brought by the development of CRISPR‐associated genome editing nucleases, a strategy for efficient insertion of large, multi‐kilobase transgenes at user‐defined genomic sites is currently challenging. The discovery and experimental characterization of bacterial CRISPR‐associated transposons (CASTs) led to the attractive hypothesis that these systems could be repurposed as programmable, site‐specific gene integration technologies. Here, we provide a broad overview of the molecular mechanisms underpinning DNA transposition and of its biological and technological impact. The second focus of the article is to describe recent mechanistic and functional analyses of CAST transposition. Finally, current challenges and desired future advances of CAST‐based genome engineering applications are briefly discussed.

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Gene Therapy with the Sleeping Beauty Transposon System

Cited by 101 publications

References 161 publications

Chimeric Antigen Receptor T Cells: Extending Translation from Liquid to Solid Tumors

Chimeric Antigen Receptor T Cells: Extending Translation from Liquid to Solid Tumors

Open access? Widening access to chimeric antigen receptor (CAR) therapy for ALL

DNA on the move: mechanisms, functions and applications of transposable elements

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