Engineering Living Medicines for Chronic Diseases

As the molecular mechanisms underlying the associations between the microbiome and diseases are discovered, delivering defined activities to gut will become an increasingly important therapeutic modality. A key challenge for microbiome therapeutics is delivering predictable, high doses of therapeutics strains despite widely varying patient microbiomes. We have developed a suite of synthetic biology tools that enable the programing of therapeutic activities into the most abundant genus of gut bacteria, Bacteroides. Our therapeutic Bacteroides strains are engineered to consume a rare carbohydrate, porphyran, so that even within a complex community we can exclusively feed them with a prebiotic. By creating this exclusive niche, we can colonize diverse, and even resistant, microbiotas at a predictable level that is tunable with porphyran dosing. To avoid the uncontrolled release of engineered strains we have further modified the strains to rely on porphyran for function of essential genes, so that strains are only viable in the subject during porphyran dosing. We are applying our platform for robustly and reversibly colonizing the gut with engineered bacteria to treating enteric hyperoxaluria, a chronic disease where over absorption of oxalate in the colon can result in recurrent kidney stones. Inspired by natural oxalate degrading bacteria often found in the gut at low levels, we have engineered rapid oxalate degradation into our robustly colonizing Bacteroides strain. When introduced in rat and pig models of enteric hyperoxaluria, our strain successfully reduces urine oxalate. We are currently working to bring this therapeutic into the clinic and are investigating treatment of other microbiome associated disease.