SBIR Phase I: Establishing a Synthetic Niche to Reliably Colonize the Human Gut with Engineered Bacterial Therapeutics

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) project is to harness the power of engineered gut microbes for treating disease through the development of tools for controlling their abundance in patients. The underlying technology platform utilizes engineered gut bacteria that respond to gastrointestinal conditions to deliver new therapeutic activities to specific sites in the gut at the appropriate dose and time. This SBIR project will improve the reliability of these cell-based therapies by allowing for precise control over the abundance of engineered bacteria in the gut. Such control is key to ensuring a consistent therapeutic effect across different patient diets and microbiomes. Engineered bacteria have been used to deliver anti-inflammatory proteins to the gut to treat mice with a model of inflammatory bowel disease (IBD). IBD is a chronic disease with no cure and low response rates to current treatments, affecting 1.4 million Americans at an annual cost of $6.3 billion in the US alone. In addition to solving a critical remaining challenge in bringing this IBD therapy to the clinic, this SBIR project will enable broader application of engineered gut bacteria to treat additional diseases such as heart-disease, obesity and colorectal cancer. This SBIR Phase I project proposes to develop the first means of achieving reliable colonization of the gut by an engineered therapeutic microbe. Reliable colonization will be accomplished by engineering into a therapeutic strain the ability to grow on a control molecule that is safe for humans to consume, is rarely consumed by other gut bacteria, and will not be absorbed by the intestinal tissue. First, all genes that are suspected to be involved in growth on the control molecule will be systematically removed from a natural isolate to determine those that are required. Next, these genes will be transferred to a non-consuming strain to introduce the ability to grow on the control molecule. Finally, this newly engineered strain that was modified to grow on the control molecule will be introduced into mice that harbor a human microbiota, and the ability to get reliable colonization of these mice by feeding the mice the control molecule will be tested. This project will employ recent insights into the mechanisms governing microbiota structure to develop a key missing tool from current cell-based therapeutic approaches to achieve more predictable therapeutic outcomes.