In silico Simulation to Predict Activity of a Synthetic Biotic, SYNB8802, in Healthy Volunteers and Patients with Enteric Hyperoxaluria

Enteric Hyperoxaluria is an acquired metabolic disorder caused by increased absorption of dietary oxalate, which is present in many common foods including leafy greens, nuts, and chocolate. Enteric Hyperoxaluria often occurs as a result of a primary insult to the bowel, such as inflammatory bowel disease, Crohn’s disease, short bowel syndrome, or as a result of surgical procedures such as Roux-en-Y bariatric weight-loss surgery. Enteric Hyperoxaluria results in dangerously high levels of urinary oxalate, which causes progressive kidney damage, kidney stone formation, and nephrocalcinosis. There are an estimated 250,000 patients with Enteric Hyperoxaluria in the United States and no approved treatment options. SYNB8802 is an engineered non-pathogenic strain of E. coli(Nissle), using Synlogic’s Synthetic Biotic platform, designed to consume oxalate in the GI tract and lower urinary oxalate levels, potentially reducing kidney damage due to Enteric Hyperoxaluria. We present an approach for in silico simulation (ISS) of SYNB8802 activity based on in vitro gastrointestinal simulations and the relevant disease biology. This computational framework considers the dynamics of metabolite availability and microenvironmental conditions to predict the capacity of SYNB8802 for consumption of dietary oxalate and subsequently reduction of plasma absorption and urinary excretion of oxalate. For Enteric Hyperoxaluria patients consuming a reasonable dietary intake of oxalate, ISS predicts a dose-dependent lowering of urinary oxalate excretion at a clinically meaningful level. Along with in vitro gut simulations and animal models, the ISS approach contributes to a physiologically based understanding of SYNB8802’s therapeutic potential for Enteric Hyperoxaluria patients.