Mutated bacteria help metabolize phenylalanine

People with phenylketonuria (PKU), a genetic disease characterized by a lack of the enzyme needed to break down the amino acid phenylalanine, are often hungry. Because phenylalanine can cause severe neurological damage if it builds up in the brain, people with PKU can’t consume much of the amino acid, which is found in meat, fish, milk, and eggs. While existing treatments can help some patients manage the disease—in combination with a restricted diet—they come with adverse side effects. Scientists at the company Synlogic hope to offer a new PKU therapy using genetically modified bacteria called SYNB1618, which is currently being evaluated in Phase I clinical trials. SYNB1618 is derived from a safe strain of bacteria called Escherichia coli Nissle that doesn’t colonize well in the gut. Researchers designed the bacteria to break down phenylalanine via two pathways (shown). In one pathway, phenylalanine ammonia lyase (PAL) converts phenylalanine to trans-cinnamate. In the other, l-amino acid deaminase (LAAD) produces phenylpyruvate. Synlogic researchers injected phenylalanine in mice missing the phenylalanine-metabolizing enzyme. The mice that were then administered SYNB1618 had 38% lower phenylalanine blood concentration than those that didn’t receive the treatment (Nat. Biotechnol. 2018, DOI: 10.1038/nbt.4222). The team also demonstrated SYNB1618’s ability to break down deuterium-labeled phenylalanine in monkeys, whose physical and kinetic digestion resembles humans’ more closely than the mouse digestion system does.