BOSTON-- Humans are colonized
with thousands of bacterial strains. Researchers are now focused on
genetically modifying such bacteria to enhance their intrinsic
therapeutic properties.
One goal is to develop smart microbes that release therapeutic
payloads at sites of disease, thus maintaining therapeutic efficacy
while limiting many of the side effects that can be associated with the
systemic administration of conventional drugs.
Investigators at Massachusetts General Hospital (MGH), a founding
member of Mass General Brigham (MGB), have engineered a strain of the
probiotic Escherichia coli (E. coli), Nissle 1917, to secrete proteins of therapeutic value into its surroundings.
When engineered to secrete an antibody that blocks inflammation, this “smart microbe”, was
as efficacious as a systemically delivered antibody, the mainstay of
current therapy, in limiting the development of colitis in a mouse model
of inflammatory bowel disease (IBD).
The work is described in the newest issue of Cell Host & Microbe.
One of the challenges of enhancing the therapeutic capabilities of
this beneficial microbe was to enable it to secrete proteins into its
surroundings. E. coli are surrounded by an outer envelope across which 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,” says 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.
Using knowledge gained from fundamental-based research, the lab introduced a version of this secretion machine 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 that was engineered to secrete nanobodies that
bind to and inhibit tumor necrosis factor (TNF) alpha, a
pro-inflammatory cytokine, was as effective in blocking the development
of inflammation in the intestines of mice as an injected monoclonal
antibody that targets the same cytokine.
Monoclonal antibodies that neutralize TNF alpha result in general
suppression of the immune system, which can have unintended effects.
“Patients administered these drugs systemically are at risk for
developing life-threatening infections as well as lymphoma,” says
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.
Engineered E. coli can also be outfitted to secrete
antibodies that block toxins released by harmful strains of bacteria.
Lesser’s team is investigating the microbe’s potential to treat
intestinal infections such as Clostridiodes difficile (C. diff), colitis, and other toxin-driven infections.
E. coli and other bacteria also replicate in solid tumors, so Lesser and others
are researching the use of engineered microbes as anti-cancer agents.
“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,” says Lesser.
Co-authors include Jason P. Lynch, Coral Gonzalez-Prieto, Analise Z.
Reeves, John M. Leong, Charles B. Shoemaker, and Wendy S. Garrett.
This study was supported by the National Institutions of Health, the
Kenneth Rainin Foundation, the Crohn’s & Colitis Foundation, and a
Brit d’Arbeloff research scholar award.
About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts
the largest hospital-based research program in the nation, with annual
research operations of more than $1 billion and comprises more than
9,500 researchers working across more than 30 institutes, centers and
departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.