Could the gut microbiome be a key to improved drug efficacy with less toxicity?

Microorganisms may get a bad rap in a setting like a hospital, but in the world of research, they’re offering fascinating new insights into human health and disease.

One group of researchers, for example, has linked microbial changes in the gut to the dose-limiting gastrointestinal side effects of certain drugs, and under a newly formed startup called Symberix, they’re testing an inhibitor they think could reduce those effects.

The story starts in the lab of University of North Carolina professor of chemistry Matt Redinbo. A colleague’s battle with cancer, and the gruesome side effects of her treatment, led him to take interest in the cancer drug irinotecan (CPT-11), a chemotherapy agent used against solid tumors, often colorectal and pancreatic cancers. It’s a very effective drug, as most chemotherapy drugs are, he said, but its efficacy can sometimes be limited by severe diarrhea.


“We know a lot about how to kill cancer cells,” Redinbo said. “The thing that we struggle with is how to kill the cancer cells without killing the healthy cells.”

Redinbo formulated a hypothesis that — simply put — the side effects were the result of how the drug affected a microbial enzyme called beta-glucuronidase in the intestines. Tests done in his lab supported that hypothesis and led to the identification of inhibitors that target those bacterial enzymes without killing other bacteria in the gut that are essential for health. An animal study that was published in Science in 2010 demonstrated that oral dosing of an inhibitor hit its target molecule in mice and nearly eliminated the occurrence of diarrhea.

After the initial paper was published, Redinbo heard from Urs Boelsterli, a researcher at the University of Connecticut. Boelsterli was working with a compound in the nonsteroidal, anti-inflammatory drug (NSAID) family — one that’s also commonly associated with GI side effects — called diclofenac (DCF). He wondered if those side effects might have the same ties to the microbiome.

So, together they began exploring whether the inhibitors identified in Redinbo’s lab would be effective in eliminating the upper GI toxicity associated with that drug.

“The larger questions we’re trying to unravel are what roles do the microbiome play in drug efficacy and toxicity, and can we modulate those roles for therapeutic gains?” Redinbo said. What they found was that, in a mouse study, the same oral dosing of the inhibitor given with DCF significantly reduced ulcerations in the small intestine.

By the summer of 2012, the researchers felt confident they had the early workings of a platform that they could move forward with. So, Symberix came to life, comprising collaborators from UNC, Albert Einstein College of Medicine and the University of Connecticut as well as business leaders from Research Triangle Park.

It’s still in its early stages, but the company is continuing preclinical work on the oral compound as part of the Carolina KickStart program. Long-term, the goal is to develop drugs that would improve the efficacy of a range of therapeutics.

[Photo from University if North Carolina]

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