Disruption in the gut microbiome is linked to a wide range of health problems in newborn babies and patients with cancer. Persephone Biosciences is studying stool samples from these populations to devise bacterial treatments that improve gut health.
Research into the gut microbiome has advanced a long way in the last decades. One major boost for the field came in the early 2010s, when fecal microbiota transplants became increasingly common to treat infections by the bacteria Clostridium difficile. A new generation of targeted, industrially processed microbiome therapeutics is poised to enter the market, with Ferring and Rebiotix leading the way.
Nevertheless, there is still a lot to learn before the industry can harness the full power of the gut microbiome in human health.
“We see a lack of true industrialization of the microbiome,” said Stephanie Culler, co-founder and CEO of the San Diego-based company Persephone Biosciences. “We’re just scratching the surface and there has to be a lot more innovation to understand it and really leverage it.”
From industrial biotechnology to the microbiome
The co-founders of Persephone Biosciences initially worked at the industrial biotechnology company Genomatica, which engineers microbes as sustainable mini-factories for industrial chemicals. They left to form Persephone Biosciences in 2017, and focused their research on the microbiome.
“Many of the other companies in the microbiome [field] come from traditional drug development,” explained Culler.
While drug development elements are needed, the field is still in its infancy. Companies need to be able to screen thousands upon thousands of different combinations of bacterial strains, and to broaden the limited range of drug targets in the field.
“The background that we have in industrial biotechnology — how to create platforms to screen microbes and microbial strains for new products — is what’s really needed here,” Culler said.
Boosting the immune system against tumors
One big part of Persephone’s strategy is to collect reams of data that map out the microbiome and identify which types of bacteria are present. In collaboration with Janssen, Persephone is enrolling up to 4,000 participants in a clinical study to screen the gut microbiota of patients with solid tumors.
The goal of the clinical study is to identify people at high or low risk of developing specific tumors and profile their gut microbiota. The firm will then research biomarkers that could signal how to better treat and even prevent the cancer. The first patient was enrolled in September 2022, and the study could run for up to eight years.
With the information gleaned from the clinical study, Persephone plans to develop a microbiome therapeutic that can treat cancer. The bacterial therapy is genetically engineered to produce key metabolites that can restore the gut to a healthy state and boost the immune system against the tumor.
“We want to develop a medicine that works for everybody and recognize that clinical trials historically haven’t had accurate representation of certain populations,” said Culler. “We try to have a large balance of ethnic and racial minorities in our data set. In some cases, we actually overrepresent them so that we can fully account for them.”
Unlocking secrets in baby poop
In addition, Persephone is working to improve gut health in babies. Infants often lack bacterial strains, such as Bifidobacterium longum bv. Infantis, in their microbiome that are key for the development of a healthy digestive and immune system. This can lead to allergies and gastrointestinal problems later in life.
“We see a multi-generational problem in infants, and I think many people don’t know about this,” said Culler. Factors that drive the problem include performing a cesarean section at birth, a poor maternal diet, and the use of baby formula and antibiotics.
To fight this crisis, Persephone is developing a probiotic consumer product. The aim is to restore the gut flora of newborn babies to a healthy state and combat health problems caused by premature births and low birth weight. Unlike the microbiome therapeutic for cancer, the probiotic won’t contain genetically engineered microbes.
The development of the product will be guided by what Persephone dubs the largest study to map the microbiome of infants under the age of two months. The company collects donated baby poop from parents participating in the study, and plans to complete the study by the end of 2022.
“We chose that time window because that’s actually when the immune system makes the choice to go down the right path for development or go down a path that can lead to food allergies,” said Culler.
Bacterial therapies bring challenges
One of the main technical hurdles for Persephone Biosciences to overcome is the fact that many microbes in the gut don’t rely on oxygen to survive. There is less knowledge about the genetics of these so-called anaerobic bacteria than aerobic bacteria, and there are fewer genetic toolkits to engineer them.
“Many of them we don’t even know if we can engineer,” said Culler. “We decided to have a partnership with Ginkgo Bioworks to develop some of these flagship toolkits. It’s the first of its kind in the industry.”
Another obstacle for the company to tackle is the regulatory process. While the U.S. Food and Drug Administration (FDA) appears to be open-minded regarding the use of genetically engineered organisms in clinical trials, Culler noted that further regulations could appear as the technology becomes more established.
Persephone Biosciences in the microbiome landscape
To finance its research, Persephone raised $15 million in a seed round in July 2022. The round was led by First Bight Ventures and Propel Bio Partners.
A group of other synthetic biology companies is also raising big cash to develop microbiome therapeutics. For example, Novome Biotechnologies raised $43.5 million in a Series B round in September 2022 to fund a phase 2a trial testing a live biotherapeutic for the treatment of the metabolic disorder hyperoxaluria. And in March 2022, the U.K. firm Microbiotica bagged £50 million ($67 million) in a Series B round to finance its own microbiome therapeutics.
According to Culler, Persephone Biosciences has an advantage with its data collection projects, building the largest real-world database for any of the indications that they are chasing.
What’s next for the microbiome
Though microbiome research has been running for decades, the field is still at an early stage, with no industrially processed microbiome therapeutics yet in the market. While early research has focused on applying genomics to map the microbiome, Culler sees the field changing gear in the coming years.
“The next phase of microbiome for everybody is function,” said Culler. “It’s great to know what is there in the microbiome, but ideally we have to know what they are doing so that we can develop effective interventions for patients with unmet needs.”