Design of Engineered Therapeutic Strains

With the development of efficient DNA techniques for manipulating microbial genomes and increasing knowledge of the molecular basis of disease, it is possible to design bacteria specifically to treat human diseases. A new live biotherapeutics consisting of engineered microbes could tackle specific mechanisms of disease. 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. Creative Biolabs is a complete live biotherapeutic product (LBP) solutions provider, we deliver LBP services and products of unparalleled quality.

Synthetic Biology Approaches Improving Bacterial Therapies

Synthetic biology aims to rationally design bacteria for therapeutic and other applications by developing computational tools and techniques for extreme genetic manipulation. Through these methods, designed biological modules, devices, and regulatory circuits for predictable behavior can be integrated into the bacterial chassis genome through strict biological control measures. Ideally engineered bacteria for treatment should be sensitive to antibiotics and free of mobile elements such as transposons and plasmids. In addition, engineered bacteria must have their containment strategies to resist environmental replenishment, mutagenesis drift, and horizontal gene transfer.

Fig.1 Synthetic bacteria for biomedical applications. (Piñero-Lambea, 2015)

Testing Strategies for Engineered Therapeutic Organisms

Environmental conditions, including pH, the concentration of oxygen, and nutrient availability, are the major determinant of strain viability and metabolism, The first tests of engineered biotherapeutic organisms can reproduce the physiological conditions of the target environment using predictable, high-throughput in vitro models. Engineering bacterium function of in vitro model has many advantages, including high flux and relatively low cost, but they are simplified representations of the host and its associated microbiome. Therefore, animal models will remain a key component of testing strategies for engineered bacterial therapies in the context of various diseases.

Fig.2 Strategy for the development of engineered live bacterial therapeutic clinical candidates. (Charbonneau, 2020)

Engineered Live Bacterial Therapeutic Services at Creative Biolabs

Many studies have linked dysbiosis to diseases such as infections, inflammation, allergy, asthma, obesity, cancer, and even neurological disorders. Therefore, targeting the microbiome with specific microorganisms will help develop therapies for such diseases. These intentional administrations with natural bacteria have been mostly performed with strains of lactic acid bacteria (e.g. Lactobacillus, Bifidobacterium) but also with Escherichia coli strains, such as E. coli Nissle 1917.

• Recombinant Lactobacillus Expression Strain Construction

Lactic acid bacteria are commonly found in the intestines of humans and most animals and play beneficial roles in a variety of gastrointestinal and inflammatory diseases. Therefore, lactic acid bacteria have emerged as a potential carrier of oral bacteria that can deliver DNA and proteins. It has been shown that the production of bacteriocins may be regulated via quorum-sensing mechanisms based on secreted peptide pheromones with no or little bacteriocin activity. Using these regulatory mechanisms, several inducible gene expression systems have been developed for efficient and regulated overproduction of heterologous proteins in lactic acid bacteria, using, for example, Lactococcus lactis, Lactobacillus brevis, Streptococcus thermophilus, or Lactobacillus sakei and Lactobacillus plantarum as expression hosts.

• Synchronized Lysis Circuit

Some bacteria have evolved to preferentially grow in disease-infested environments, providing a natural platform for the development of engineered therapies. The bacterial population dynamics caused by a synchronized lysis circuit can be understood as the slow accumulation of signaling molecules (AHL) to a threshold level, followed by lysis 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 "integration and combustion" cycle repeat.

• Engineered Escherichia coli Nissle 1917

Escherichia coli Nissle 1917 (EcN) is a commonly used probiotic in clinical practice. Genetic engineering has enhanced the utility of EcN in several vaccines and pharmaceutical preparations and can be engineered as a bacteria-based microrobot for molecular imaging, drug delivery, and gene delivery.

Synthetic biology is providing modular parts and gene circuits that can be used to program the designed bacterial chassis to precisely control the expression and delivery of therapeutic proteins, the adhesion of the engineered bacteria to target cells or modify their chemotactic behavior. Creative Biolabs is a USA biotech company. We have specialized in providing custom LBP development services for researchers around the world. Our experts can help you from the very first idea, by providing expert consultancy in the design of your study. We are happy to discuss your objectives. If you are interested in our services and products, please contact us for more detail.

References

1. Piñero-Lambea, C.; et al. Engineered bacteria as therapeutic agents. Current opinion in biotechnology. 2015, 35: 94-102.
2. Charbonneau, M.R.; et al. Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nature Communications. 2020, 11(1): 1-11.

For Research Use Only. Not intended for use in food manufacturing or medical procedures (diagnostics or therapeutics). Do Not Use in Humans.