SBIR-STTR Award

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.

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project will be to advance the use of engineered cell-based therapeutics in the human gut through the development of technologies for the reliable and reversible colonization of the gut with therapeutic bacterial strains. Engineered cellular therapeutics are poised to become the next major driver of pharmaceutical innovation due to their potential for sophisticated behavior and modular design. The gut is an ideal entry point for deploying engineered therapeutic cells, as it serves as our body's natural interface with foreign genetic material. A key impediment to bacterial drug development for the gut is the lack of strategies for achieving predictable colonization across the wide range of gut environments that patients can harbor. Furthermore, tools for on-demand clearance of therapeutic strains to ensure safety do not currently exist. The proposed innovation will overcome these challenges and allow the potential of engineered bacterial cells as therapies to be fully realized.This SBIR Phase II project will develop the technologies necessary to achieve predictable colonization of, and targeted clearance from, the human gut by engineered bacterial strains. Predictable colonization will be achieved through the use of a therapeutic strain that has been modified to consume a privileged prebiotic substrate that can be dosed alongside the strain to precisely control its abundance by giving it a competitive advantage. To ensure containment and enable targeted clearance, the therapeutic strain will be further modified such that it only can grow in environments where the prebiotic is present. This will allow for the generation of a robust synthetic niche within the gut that can be manipulated solely through the administration of this prebiotic control molecule. In addition, to enable the commercial deployment of these novel technologies, manufacturing protocols will be developed to ensure that a fully integrated therapeutic strain can be produced in sufficient quantities and stably formulated.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.