Numerous bacterium types have taken up residence in humans. Currently, research is concentrated on genetically modifying these bacteria to increase their inherent therapeutic qualities.
One objective is to create intelligent microbes that deliver therapeutic payloads at disease sites, keeping therapeutic effectiveness while reducing many of the adverse effects that can be connected to the systemic delivery of conventional medications.
Probiotic Escherichia coli (E. coli) strain Nissle 1917 has been modified by researchers at Massachusetts General Hospital (MGH), a founding member of Mass General Brigham (MGB), to release therapeutically useful proteins into its environment.
This “smart microbe: was equally effective as a systemically delivered antibody, the cornerstone of current treatment, at preventing the formation of colitis in a mouse model of inflammatory bowel disease (IBD) when it was designed to produce an antibody that inhibits inflammation.
The latest edition of Cell Host & Microbe contains a description of the study.
One of the difficulties in improving this helpful microbe’s therapeutic powers was allowing it to secrete proteins into its environment. E. coli is encased in an outer membrane through which only a few proteins are transported.
Many pathogenic relatives of E. coli directly transport bacterial proteins across their outer envelope into human cells using a syringe-like machine.”
Cammie F. Lesser MD, PhD, Study Senior Author and Physician Investigator, Infectious Disease, Massachusetts General Hospital
Dr Lesser is also an associate professor of Medicine at Harvard Medical School and d’Arbeloff MGH Research Scholar.
For more than two decades, Lesser’s team at MGH has been investigating these complicated protein secretion systems with the eventual aim of reengineering them as drug delivery systems.
The team used basic research to introduce a version of this secretion machine into beneficial E. coli and modify it to secrete proteins into its environment.
They also designed several types of therapeutic proteins to be recognized as secreted proteins of this machine. The resulting customizable platform is known as PROT3EcT for probiotic type III secretion E. coli.
Lesser and her coworkers examined the engineered E. coli in a mouse model of inflammatory bowel disease to show the possible therapeutic utility of PROT3EcT.
PROT3EcT, which was designed to secrete nanobodies that bind to and suppress tumor necrosis factor (TNF) alpha, a pro-inflammatory cytokine, was as effective as an injected monoclonal antibody targeting the same cytokine in inhibiting the onset of inflammation in the intestines of mice.
Monoclonal antibodies that neutralize TNF alpha cause general immune system suppression, which can have unexpected consequences.
Dr Lesser further added, “Patients administered these drugs systemically are at risk for developing life-threatening infections as well as lymphoma. 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 creating bacterial strains that release therapeutic proteins in reaction to particular circumstances, such as when inflammation in the stomach starts developing.
It is also possible to modify engineered E. coli to produce antibodies that prevent the toxins emitted by dangerous bacterial strains. The possibility of using the microbe to treat intestinal infections like colitis, Clostridiodes difficile (C. diff), and other diseases caused by toxins is being studied by Lesser’s team.
Lesser and others are investigating the use of engineered bacteria as anti-cancer drugs since solid tumors can also reproduce E. coli and other bacteria.
Lesser concluded, “We hope to advance these strains towards the treatment of a variety of human diseases by outfitting them to secrete a variety of proteins of therapeutic value.”
Lynch, J. P., et al. (2023). Engineered Escherichia coli for the in situ secretion of therapeutic nanobodies in the gut. Cell Host & Microbe. doi.org/10.1016/j.chom.2023.03.007