Researchers at Massachusetts General Hospital (MGH) have engineered a strain of the probiotic Escherichia coli (E. coli), Nissle 1917, to secrete proteins of therapeutic value into its surroundings. The engineered strain has the potential to treat intestinal-based diseases.

Their findings are published in Cell Host & Microbe in an article titled, “Engineered Escherichia coli for the in situ secretion of therapeutic nanobodies in the gut.”

“Drug platforms that enable the directed delivery of therapeutics to sites of diseases to maximize efficacy and limit off-target effects are needed,” wrote the researchers. “Here, we report the development of PROT3EcT, a suite of commensal E. coli engineered to secrete proteins directly into their surroundings.

“Many pathogenic relatives of E. coli directly transport bacterial proteins across their outer envelope into human cells using a syringe-like machine,” said senior author Cammie F. Lesser, MD, PhD, a physician-scientist in the infectious disease division at MGH, associate professor of medicine at Harvard Medical School, and d’Arbeloff MGH research scholar.

Lesser’s lab at MGH has been studying these complex protein secretion systems for more than two decades with the ultimate goal of reengineering them as drug delivery systems.

The lab introduced a version of this secretion system into beneficial E. coli and modified it to secrete proteins into its surroundings. They also engineered a variety of proteins of therapeutic value to be recognized as secreted proteins of this machine. The resulting programmable platform is referred to as PROT3EcT for probiotic type III secretion E. coli.

As proof of the potential therapeutic value of PROT3EcT, Lesser and her colleagues tested the engineered E. coli in a mouse model of inflammatory bowel disease.

PROT3EcT was engineered to secrete nanobodies that bind to and inhibit tumor necrosis factor (TNF) alpha, a pro-inflammatory cytokine, and was as effective in blocking the development of inflammation in the intestines of mice as an injected monoclonal antibody that targets the same cytokine.

“Patients administered these drugs systemically are at risk for developing life-threatening infections as well as lymphoma,” said Lesser. “By using engineered bacteria, it should be possible to deliver these anti-inflammatory antibodies and limit immunosuppression directly to where inflammation is present.”

Lesser and her colleagues are now working on engineering bacterial strains that will secrete therapeutic proteins in response to specific conditions, such as when inflammation begins developing in the gut.

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