Modified bacteria could fight this brain-damaging genetic disease

Modified bacteria could fight this brain-damaging genetic disease

Cambridge-based biotech Synlogic’s bacteria-based treatment for phenylketonuria (PKU) has shown positive results in a small phase 2 trial, the company announced in October – proof of concept for the idea of ​​using modified strains of beneficial bacteria to treat disease.

“Diseases like PKU are good fruit at hand to answer the first question, which is whether the bacteria can do anything that benefits the individual,” said the UC gastroenterologist. San Diego Amir Zarrinby Emily Mullin of WIRED.

More and more researchers are turning to bacteria as potential therapies lately.

Biotech Synlogic’s bacteria-based treatment for phenylketonuria (PKU) showed positive results in a small phase 2 trial.

MIT and Harvard have modified a strain of bacteria used in cheese making to help protect the ecosystem of beneficial bacteria in the gut, called the microbiome, which can be devastated by drugs and potentially lead to infections.

Researchers at the University of Georgia designed E.coli to produce L-DOPA, a proven therapy for Parkinson’s disease whose short half-life they hope to overcome by turning bacteria into little L-DOPA factories.

What is the PCU? Patients with PKU (“phenyl-keto-nuria”) cannot break down an amino acid called phenylalanine, or PHE, which is typically found in protein-rich foods. Eating too much protein — or the sugar sub-aspartame — causes PHE to build up to toxic levels, which can cause serious brain damage.

As a result, patients must be placed on a severely restricted diet for most of their lives; it’s serious enough that babies in the United States and many other countries are screened for PKU soon after birth.

“The types of foods they can eat are extremely limited,” Jessica Kopesky, a Wisconsin children’s clinical dietitian who sees patients with PKU, told Mullin.

“Any new medical advances that can help reduce Phe levels and potentially allow them to eat even a little more protein from food will have a big impact on the types of foods these patients can eat and on the flexibility available to them in their day-to-day life.”

Engineering E.coli: For its drug candidate, Synlogic turned to a strain of gut bacteria called E. coli Nissle, which naturally protects against dysentery. These beneficial bacteria have been modified to also reduce PHE levels, picking up where the body left off.

“Similar to how you might program a computer, we can tinker with the DNA of bacteria and make them do things like produce a drug at the right time and in the right place, or in this case, break down a toxic metabolite,” Synlogic co-founder Timothy Lu told Mullin.

The bacteria was able to reduce levels of an amino acid that can cause brain damage in PKU patients when it builds up.

The small, 28-day, open-label phase 2 trial – designed to test the safety, tolerability and efficacy of two different bacterial candidates – recruited 20 patients with phenylketonuria, who drank a liquid mixture of either other bacteria.

Both strains showed reductions in blood PHE levels that Synlogic deemed “clinically significant” by day 14 – a 20% reduction in baseline PHE for one bacterial strain (SYNB1618) and a 34% reduction for the other (SYNB1934).

These results were similar for those taking sapropterin, a phenylketonuria drug that also helps break down PHE, suggesting the two may one day work in concert, Synlogic said.

Adverse events were mild or moderate, the biotech said, and tended to be related to the gastrointestinal system.

Full results have not yet been published in a peer-reviewed journal; Synlogic will present the full data at upcoming medical meetings and submit it for review and publication.

The more promising of the two strains, SYNB1934, will enter a phase 3 trial expected to begin in 2023, with the goal of gathering enough data to file for approval.

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