Bile acid-controlled transgene expression in mammalian cells and mice

Rössger, Katrin; Charpin-El-Hamri, Ghislaine; Fussenegger, Martin

doi:10.1016/j.ymben.2013.11.003

Cited by 21 publications

(14 citation statements)

References 67 publications

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“…In the TET systems, Tc responsive transactivators rtTA or tTA bind to tetO with or without TET, respectively, resulting in activation of transcription ( 17 , 39 ). Similarly, in the LightOn system, the light-switchable transactivator GAVPO bound to the UAS G element and activated transcription under blue light ( 26 ).…”

Section: Resultsmentioning

confidence: 99%

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Synthetic dual-input mammalian genetic circuits enable tunable and stringent transcription control by chemical and light

Chen¹,

Li²,

Wang³

et al. 2015

Nucleic Acids Res

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Programmable transcription factors can enable precise control of gene expression triggered by a chemical inducer or light. To obtain versatile transgene system with combined benefits of a chemical inducer and light inducer, we created various chimeric promoters through the assembly of different copies of the tet operator and Gal4 operator module, which simultaneously responded to a tetracycline-responsive transcription factor and a light-switchable transactivator. The activities of these chimeric promoters can be regulated by tetracycline and blue light synergistically or antagonistically. Further studies of the antagonistic genetic circuit exhibited high spatiotemporal resolution and extremely low leaky expression, which therefore could be used to spatially and stringently control the expression of highly toxic protein Diphtheria toxin A for light regulated gene therapy. When transferring plasmids engineered for the gene switch-driven expression of a firefly luciferase (Fluc) into mice, the Fluc expression levels of the treated animals directly correlated with the tetracycline and light input program. We suggest that dual-input genetic circuits using TET and light that serve as triggers to achieve expression profiles may enable the design of robust therapeutic gene circuits for gene- and cell-based therapies.

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Section: Resultsmentioning

confidence: 99%

“…Both systems oppositely respond to the presence of TETs (e.g. doxycycline, Dox), by either activating (Tet-On) or inactivating gene expression (Tet-Off) ( 17 , 39 ). We previously developed a light-switchable transgene expression system termed LightOn, which consists of only one photoactive transactivator GAVPO.…”

Section: Introductionmentioning

confidence: 99%

Synthetic dual-input mammalian genetic circuits enable tunable and stringent transcription control by chemical and light

Chen¹,

Li²,

Wang³

et al. 2015

Nucleic Acids Res

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show abstract

“…HEK‐293 cells cotransfected with the CmeA 2 expression vector and the P CmeON ‐driven SEAP reporter vector exhibited dose‐dependent induction of SEAP expression. The BEAR ON gene switch was further validated in mice, which verified that it could induce SEAP expression in animals treated with bile acids [32].…”

Section: Synthetic Gene Circuits For the Treatment Of Metabolic Disormentioning

confidence: 88%

“…Therefore, increasing numbers of studies have focused on the design of mammalian transgene control devices that form the basis for the assembly of synthetic therapeutic networks in mammalian cells. Most of these control devices are designed to respond to small molecule chemicals [26][27][28][29][30][31][32][33]. Recently, more elegant circuits were developed to use traceless inducers such as light and radio waves to regulate transgene expression [34][35][36].…”

Section: Introductionmentioning

confidence: 99%

Synthetic therapeutic gene circuits in mammalian cells

Fussenegger

2014

FEBS Letters

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a b s t r a c tIn the emerging field of synthetic biology, scientists are focusing on designing and creating functional devices, systems, and organisms with novel functions by engineering and assembling standardised biological building blocks. The progress of synthetic biology has significantly advanced the design of functional gene networks that can reprogram metabolic activities in mammalian cells and provide new therapeutic opportunities for future gene-and cell-based therapies. In this review, we describe the most recent advances in synthetic mammalian gene networks designed for biomedical applications, including how these synthetic therapeutic gene circuits can be assembled to control signalling networks and applied to treat metabolic disorders, cancer, and immune diseases. We conclude by discussing the various challenges and future prospects of using synthetic mammalian gene networks for disease therapy.

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“…First, sensors can enable the regulation of cellular functions through closed-loop control, which confers self-regulating therapeutic functions [7, 8]. Several promising demonstrations of closed-loop control have been reported in which implantable cell-based “devices” were employed to maintain homeostasis via prosthetic gene networks [7–9]. In each of these cases, the presence of an intracellular ligand, which is relevant to the external physiological state, determines whether an engineered transcriptional regulator is recruited to a target DNA sequence encoding a gene that modulates host physiology; thus, such systems achieve real-time monitoring and modulation of the host physiological state.…”

Section: Modalities For Engineering Cells To Interface With Physiomentioning

confidence: 99%

Engineering cell-based therapies to interface robustly with host physiology

Schwarz

Leonard

2016

Advanced Drug Delivery Reviews

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Engineered cell-based therapies comprise a rapidly growing clinical technology for treating disease by leveraging the natural capabilities of cells, including migration, information transduction, and biosynthesis and secretion. There now exists a substantial portfolio of intracellular and extracellular sensors that enable bioengineers to program cells to execute defined responses to specific changes in state or environmental cues. As our capability to construct more sophisticated cellular programs increases, assessing and improving the degree to which cell-based therapies perform as desired in vivo will become an increasingly important consideration and opportunity for technological advancement. In this review, we seek to describe both current capabilities and potential needs for building cell-based therapies that interface with host physiology in a manner that is robust – a phrase we use in this context to describe the achievement of therapeutic efficacy across a range of patients and implementations. We first review the portfolio of sensors and outputs currently available for use in cell-based therapies by highlighting key advancements and current gaps. Then, we propose a conceptual framework for evaluating and pursuing robust clinical performance of engineered cell-based therapies.

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Bile acid-controlled transgene expression in mammalian cells and mice

Cited by 21 publications

References 67 publications

Synthetic dual-input mammalian genetic circuits enable tunable and stringent transcription control by chemical and light

Synthetic dual-input mammalian genetic circuits enable tunable and stringent transcription control by chemical and light

Synthetic therapeutic gene circuits in mammalian cells

Engineering cell-based therapies to interface robustly with host physiology

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