A Synthetic Mammalian Therapeutic Gene Circuit for Sensing and Suppressing Inflammation

Smole, Anže; Lainšček, Duško; Bezeljak, Urban; Horvat, Simon; Jerala, Roman

doi:10.1016/j.ymthe.2016.10.005

Cited by 44 publications

(30 citation statements)

References 65 publications

(64 reference statements)

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“…This channel is bound by antibodies coated with ferrous oxide nanoparticles, which are heated with radio waves to trigger channel opening, leading to subsequent Ca 2+ influx (Stanley et al, 2012). Smole et al (2017) reported an exemplary case of a fully synthetic network that can sense an inflammatory signal in mice and produce a response to suppress this signal (Fig. 7).…”

Section: B Box 2 Synthetic Regulatory Open-and Closeloop Circuitsmentioning

confidence: 99%

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Synthetic Switches and Regulatory Circuits in Plants

2019

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Synthetic biology is an established but ever-growing interdisciplinary field of research currently revolutionizing biomedicine studies and the biotech industry. The engineering of synthetic circuitry in bacterial, yeast, and animal systems prompted considerable advances for the understanding and manipulation of genetic and metabolic networks; however, their implementation in the plant field lags behind. Here, we review theoretical-experimental approaches to the engineering of synthetic chemical-and light-regulated (optogenetic) switches for the targeted interrogation and control of cellular processes, including existing applications in the plant field. We highlight the strategies for the modular assembly of genetic parts into synthetic circuits of different complexity, ranging from Boolean logic gates and oscillatory devices up to semi-and fully synthetic open-and closed-loop molecular and cellular circuits. Finally, we explore potential applications of these approaches for the engineering of novel functionalities in plants, including understanding complex signaling networks, improving crop productivity, and the production of biopharmaceuticals.

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Section: B Box 2 Synthetic Regulatory Open-and Closeloop Circuitsmentioning

confidence: 99%

“…Exogenous application of doxycycline inhibits the activation of the sensor, amplifier, and effector modules by binding to their upstream tetO motifs, thus deactivating the system. (Adapted from Smole et al, 2017. ) Figure 8.…”

Section: B Box 2 Synthetic Regulatory Open-and Closeloop Circuitsmentioning

confidence: 99%

Synthetic Switches and Regulatory Circuits in Plants

2019

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“…An appealing feature of this approach is that stem cells can be differentiated to manifest this desired feedback control in mature cell types for disease-specific applications. In a similar approach, sensing and countering pro-inflammatory cues was implemented using a synthetic gene expression program that is induced by NF-κB (a TF activated downstream of many receptors for pro-inflammatory cues) to drive secretion of an anti-inflammatory protein [20]. The circuit was designed using network motifs that amplify the sensing event, threshold the responsiveness to NF-κB, and provide a small molecule-inducible OFF switch.…”

Section: Building New Therapeutic Functional Modalitiesmentioning

confidence: 99%

Building with intent: Technologies and principles for engineering mammalian cell-based therapies to sense and respond

Muldoon

Donahue

Dolberg

et al. 2017

Current Opinion in Biomedical Engineering

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The engineering of cells as programmable devices has enabled therapeutic strategies that could not otherwise be achieved. Such strategies include recapitulating and enhancing native cellular functions and composing novel functions. These novel functions may be composed using both natural and engineered biological components, with the latter exemplified by the development of synthetic receptor and signal transduction systems. Recent advances in implementing these approaches include the treatment of cancer, where the most clinical progress has been made to date, and the treatment of diabetes. Principles for engineering cell-based therapies that are safe and effective are increasingly needed and beginning to emerge, and will be essential in the development of this new class of therapeutics.

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“…Novel genetic tools built by synthetic biologists have transformed how cells can be reprogrammed that include genetic programs to introduce switching (5)(6)(7)(8)(9)(10)(11)(12), oscillations (13)(14)(15)(16)(17)(18), logic gates (19)(20)(21), and biosensing (22)(23)(24)(25)(26)(27)(28) behaviours into cells. Assembling simple genetic parts into more complex gene circuits can reliably and predictably control cell behaviours (29,30).…”

Section: Introductionmentioning

confidence: 99%

Rosa26 docking sites for investigating genetic circuit silencing in stem cells

Fitzgerald

Livingston

Gibbs

et al. 2019

Preprint

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Approaches in mammalian synthetic biology have transformed how cells can be programmed to have reliable and predictable behaviour. The majority of mammalian synthetic biology has been accomplished using immortalized cell lines that are easy to grow, and easy to transfect. Additionally, genetic circuits that integrate into the genome of these immortalized lines remain functional for many generations, often for the lifetime of the cells. However, when genetic circuits are integrated into the genome of stem cells, gene silencing is observed within a few generations. To investigate the stability of genetic circuits and their propensity to silence in stem cells, the Rosa26 locus of mouse pluripotent stem cells was modified to contain docking sites for site-specific integration of genetic circuits. We show that the silencing of genetic circuits can be reversed with the addition of sodium butyrate, a histone deacetylase inhibitor. These findings demonstrate an approach to stabilize the function of genetic circuits in pluripotent stem cells to ensure robust function over many generations. Altogether, this work introduces an approach to overcome silencing of genetic circuits in pluripotent stem cells that enable the possibility of leveraging synthetic biology in pluripotent stem cells to meet therapeutic needs.

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A Synthetic Mammalian Therapeutic Gene Circuit for Sensing and Suppressing Inflammation

Cited by 44 publications

References 65 publications

Synthetic Switches and Regulatory Circuits in Plants

Synthetic Switches and Regulatory Circuits in Plants

Building with intent: Technologies and principles for engineering mammalian cell-based therapies to sense and respond

Rosa26 docking sites for investigating genetic circuit silencing in stem cells

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