Development of a Synthetic Biotic for the Treatment of Enteric Hyperoxaluria David Lubkowicz, Nick Horvath, Lauren Renaud, Chris Bergeron, Michael James, Pat Cantarella, Ron Shmueli, JR Gao, Vincent Isabella, Mylene Perreault, and Mark R. Charbonneau* Synlogic, Cambridge, MA. *Presenting author 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 (EH) often occurs as a result of inflammatory bowel disease or as a result of surgical procedures, including bariatric weight-loss surgery. EH results in high levels of urinary oxalate, which can lead to kidney stone formation, progressive kidney damage, and nephrocalcinosis. There are an estimated 250,000 patients with EH in the United States and limited available treatment options. SYNB8802 is an engineered bacterial therapeutic (Synthetic Biotic) derived from Escherichia coli Nissle 1917 that has been designed to degrade oxalate throughout the human gastrointestinal tract. Inoculation of SYNB8802 into simulated intestinal fluids showed significant consumption of oxalate as compared to the unengineered bacterial strain. When administered concomitantly with 13C-oxalate to healthy mice, SYNB8802 decreased the urinary recovery of 13C-oxalate, which is indicative of its ability to consume oxalate in vivo. In addition, for healthy non-human primates (NHP) administered approximately 400 mg of oxalate in the form of a spinach smoothie, SYNB8802 dose-dependently lowered the urinary recovery of oxalate and 13C-oxalate as compared to vehicle. Lastly, we have developed a mathematical model of SYNB8802 function in the human gastrointestinal tract that predicts clinically meaningful reductions in urinary. In summary, SYNB8802 represents a promising novel approach for the treatment of enteric hyperoxaluria.
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