Tuneable Conditional Control of Engineered Bacterial Therapeutics

ended

Engineered microbes are attractive platforms for the diagnosis and treatment of several diseases. For example, bacteria can selectively target tumors and are ideal vehicles for in situ delivery of therapeutic agents. However, as of today, no engineered living bacterial therapeutics in clinical trials have the ability for conditional control of therapeutic activity. This lack of reliable control over the timing and dosage of effector molecule production limits the specificity, safety, and efficacy of current bacterial therapies. In this project, I will use of a generalizable synthetic receptor platform to control the in vivo therapeutic activity of engineered bacteria using an externally administered molecules. As a proof of concept, I will use a receptor responding to a molecule found in the diet to control therapeutic release in tumors. I will use a safe probiotic, E. coli Nissle 1917, with demonstrated tumor targeting properties. In a first research line, I will characterize the dose-response and kinetics of synthetic receptors implemented in bacteria colonizing an in vitro 3D tumor spheroids model. I will then evaluate the therapeutic activity of strains producing cytolytic molecules in response to external inducer. In a second research line, I will characterize conditional control of gene expression and then therapeutic release in tumor mice model, using cytolytic and immunotherapeutic effectors. My work will deliver robust, safe, and efficient frameworks for conditional control of bacterial cancer therapy. By enabling in situ drug delivery with a highly-precise dosage and timing, it will allow physicians and ultimately the patients to finely control bacterial therapeutic activity. Because of its modularity my platform will be further engineerable to detect other conditional inducers. This system will be reusable for the treatment of many other pathologies, including autoimmune and infectious diseases.