Editors' ChoiceMetabolism

Treating phenylketonuria now Phe-sible with engineered bacteria?

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Science Translational Medicine  29 Aug 2018:
Vol. 10, Issue 456, eaau8878
DOI: 10.1126/scitranslmed.aau8878

Abstract

Engineered bacteria are capable of converting phenylalanine and may serve as a potential therapy for phenylketonuria.

Phenylketonuria, or PKU, is an inborn error of metabolism that is included in many newborn screening programs worldwide. The disease is caused by an inability to metabolize the amino acid phenylalanine (Phe). When left untreated, the accumulation of Phe can cause severe neurological disease, but early detection followed by a strict low-protein diet can mitigate these symptoms. Compliance with the diet is difficult, however, and the low-protein diet can lead to a failure to thrive. Alternative treatments are therefore eagerly awaited.

Isabella and colleagues engineered bacteria capable of converting Phe, thereby reducing the plasma Phe load. They used an Escherichia coli Nissle strain into which the phenylalanine transporter and the phenylalanine ammonia lyase enzyme were introduced, allowing these bacteria to take up and metabolize Phe. Treating PKU mice with this strain, called SYNB1618, led to markedly increased urinary excretion of the Phe breakdown product hippuric acid, confirming that Phe was indeed metabolized. Moreover, SYNB1618 treatment largely prevented plasma Phe accumulation levels after Phe challenge.

To bridge the gap to human application, the authors extended their studies to nonhuman primates. As no PKU primate model is available, they challenged healthy primates with a peptide bolus that increased plasma Phe levels. SYNB1618 attenuated plasma Phe accumulation following the bolus and was accompanied by increased urinary hippuric acid levels. This indicated that the engineered E. coli were successful in metabolizing dietary Phe and preventing its plasma accumulation.

Although SYNB1618 consistently reduced plasma Phe, it is unclear whether these probiotics lead to clinical improvement in any of the models. It is tempting, however, to think of these engineered bacteria as a possible supplement that could allow patients to be more lenient in their restrictive diets. Moreover, it is worth speculating that using custom engineered bacterial strains might be a suitable strategy for correcting other inborn errors of metabolism.

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