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Engineered Microbe Blocks Ammonia Blood Poisoning

Ammonia molecule

Ammonia molecule (Ben Mills, Wikimedia Commons)

18 Jan. 2019. A genetically engineered bacterial strain is shown in tests with animals to stop ammonia poisons in the gut from reaching the blood stream, as well as be safe for humans in a clinical trial. Findings from the lab tests and clinical trial, conducted by biotechnology company Synlogic Inc. in Cambridge, Massachusetts, appear in the 16 January issue of Science Translational Medicine (paid subscription required).

A team led by Paul Miller, Synlogic’s chief scientist, is seeking better treatment options for hyperammonemia, a condition where the body’s metabolic system fails to clear ammonia from the gut, allowing ammonia to build up in the blood. The accumulation of ammonia often results in neurological disorders ranging from lethargy and irritability to seizures and Reye’s syndrome, swelling of the liver and brain. Treating hyperammonemia today usually involves managing its symptoms, although a liver transplant can sometimes correct the disorder.

Miller and colleagues tested a solution developed by Synlogic, an engineered form of Escherichia coli, or E. coli, bacteria in the gut that removes ammonia before it reaches the blood stream. While E. coli is often associated with food poisoning, the species includes many benign strains, including one called E. coli Nissle, a probiotic form used to treat colon inflammation, such as ulcerative colitis. Synlogic genetically engineers E. coli Nissle to perform another task: stop ammonia from building up in the colon. In this case, the modified E. coli Nissle bacteria absorb ammonia and convert it to arginine, an amino acid used by the body to produce proteins that dilate blood vessels, and marketed to treat conditions such as hypertension and erectile dysfunction.

Synlogic code-names its engineered microbe SYNB1020, which it tested in lab mice, monkeys, and humans. In lab mice bred to express a genetic condition that results in hyperammonemia, the researchers fed the animals a high-protein diet to produce high blood ammonia levels. Mice randomly assigned to receive feedings of SYNB1020 were found with lower ammonia levels in their blood, less liver damage, and longer survival times than other mice fed a deactivated substitute. The tests also show test mice tolerated feedings of SYNB1020, cleared it quickly from the gastrointestinal tract, and showed no signs of the engineered bacteria elsewhere in the body. Tests with lab monkeys show similar results in tolerating SYNB1020 and clearing it from the body.

The team then tested the safety of SYNB1020 in an early-stage clinical trial with 52 healthy volunteers. Participants were assigned to receive single, then multiple doses of SYNB1020 or a placebo for 14 days looking primarily for signs of adverse effects. The results show participants generally tolerated the daily doses of SYNB1020 with mild to moderate nausea or vomiting exhibited by some participants to higher doses. No serious adverse effects were reported.

The trial also checked for signs of SYNB1020 activity in the body. The results show recipients of SYNB1020 had traces of nitrate, an indicator of SYNB1020 in blood and urine samples, and arginine in fecal samples, while placebo recipients did not. Fecal samples from SYNB1020 recipients found no signs of of the bacteria after 14 days.

“These data demonstrate that we can engineer bacteria to carry out a specific function, deliver them to humans and that they perform as designed,” says Miller in a Synlogic statement. He adds, “The compelling data in this publication encouraged us to advance SYNB1020 into additional clinical studies and we look forward to presenting data from our trial, designed to evaluate the potential of SYNB1020 to lower ammonia in patients with cirrhosis, in mid-2019.”

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