Synchronized Lysis Circuit (SLC) Technology

The development of live biotherapeutic products (LBPs) is progressing rapidly. Recent advances in synthetic biology and biosystems engineering have made it possible to design and construct engineered live biotherapeutics for a range of human clinical applications. Engineered bacterial strains can be designed to sense and respond to environmental signals within the body, including those in the gastrointestinal tumors tract or the microenvironment of solid. With over 10 years of custom LBP experience, Creative Biolabs can help you from the very first idea, by providing expert consultancy in the design of your study.

Design of Engineered Therapeutic Strains for Solid Tumors

Solid tumors show abnormal vascular structure, leading to the development of hypoxic areas and necrotic cores, which can serve as suitable habitats for obligate and facultative anaerobe. Preferential colonization of tumors upon administration in mice has been demonstrated for many bacterial genera, including Bifidobacterium, Clostridium, Salmonella, and Escherichia. Engineering strains designed for tumor treatment are crucial in several aspects, including the regulation of engineering circuits, the selection of therapeutic effectors, safety and biological containment, and delivery methods. Chemically inducible promoters, including tetracycline inducible (Tet) promoters, are widely used in the research of regulatory engineering circuits because of their easy use and titratable expression. Another way to regulate engineering circuits is through quorum sensing molecules, such as N-acyl-homoserine lactones (AHL), which have been widely studied in Salmonella strains.

A gene circuit for a transcriptional program regulating bacterial activities at the population level.Fig.1 A gene circuit for a transcriptional program regulating bacterial activities at the population level. (Zhou, 2018)

Synchronized Cycles of Bacterial Lysis for In Vivo Delivery

To control population levels and facilitate drug delivery using bacteria, scientists engineered a synchronized lysis circuit (SLC) using coupled positive and negative feedback loops. The genetic circuit contains a common promoter (pLuxI) that drives the expression of LuxI, producing the quorum sensing molecule acyl homoserine lactone (AHL) that further activates the promoter by binding the activator LuxR. AHL can spread to neighboring cells and thus provides an intercellular synchronization mechanism. The bacterial population dynamics caused by SLC can be understood as the slow accumulation of signaling molecules (AHL) to a threshold level, followed by cleavage events that rapidly clear the population and allow the release of bacterial contents. After lysis, the few remaining bacteria begin to re-produce AHL, making the "integrate and fire" cycle repeat.

Construction and characterization of the SLC.Fig.2 Construction and characterization of the SLC. (Din, 2016)

The SLC exemplifies a methodology for leveraging the tools of synthetic biology to exploit the ability of certain bacteria to colonize disease sites. In contrast to most drug delivery strategies, the SLC does not require drug pre-loading or additional secretion mechanisms. The circuit can adjust the frequency and amplitude of the population cycle to achieve a new bacterial drug delivery strategy.

Creative Biolabs prides itself on being an innovator and problem solver in the LBP development. If you are interested in our SLC technology, please contact us for more detail.

References

  1. Zhou, S.; et al. Tumour-targeting bacteria engineered to fight cancer. Nat Rev Cancer. 2018, 18: 727-743.
  2. Din, M.O.; et al. Synchronized cycles of bacterial lysis for in vivo delivery. Nature. 2016, 536: 81-85.

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