Editor’s summary
The gut #microbiota has long been an aspirational target for clinical delivery of therapeutics. Successful therapy by this route depends on ensuring engraftment of the therapeutic organisms and their clearance after treatment. Whitaker et al. have engineered a strain of Bacteroides vulgatus, which is commonly found in the gut of healthy humans, with two genetic modules. One is therapeutic to rectify oxalate metabolism for preventing kidney stone formation, and the second adds multiple biosafety promoters that make the organism reliant on an essential nutrient, in this case porphyrin. Although the approach is very promising therapeutically, so far it is still encountering problems with horizontal gene transfer creating “biosafety escape” mutants. —Caroline Ash
Abstract
Precision microbiome programming for therapeutic applications is limited by challenges in achieving reproducible colonic colonization. Previously, we created an exclusive niche that we used to engraft engineered bacteria into diverse microbiota in mice by using a porphyran prebiotic. Building on this approach, we have now engineered conditional attenuation into a porphyran-utilizing strain of Phocaeicola vulgatus by replacing native essential gene regulation with a porphyran-inducible promoter to allow reversible engraftment. Engineering a five-gene oxalate degradation pathway into the reversibly engrafting strain resulted in a therapeutic candidate that reduced hyperoxaluria, a cause of kidney stones, in preclinical models. Our phase 1/2a clinical trial demonstrated porphyran dose–dependent abundance and reversible engraftment in humans, reduction of oxalate in the urine, and characterized genetic stability challenges to achievinglong-term treatment.
2 Medical News 