Christensella: the key to unlocking gut microbiome-based drug discovery?

Progress in sequencing and metagenomics has made it possible to identify more than 2,000 new bacteria that inhabit the human microbiome, many of which have major therapeutic potential in the treatment of diseases and health conditions. However, only 20% of the bacteria identified are cultured due to the complex environment of the digestive tract.

In 2012, a new species of anaerobic bacteria was cultivated from human faeces: Christensenella minuta, named in honour of microbiologist Henrik Christensen. Research shows that more than any other microbe, its presence in our intestinal flora is strongly determined by our genes, and it also influences our weight – Christensenella is more common in slim people, and has been shown to reduce weight gain in mice.

In addition, Christensenella appears to support an ecosystem of beneficial bacteria. Several studies have shown the presence of Christensenella is aligned with the beneficial bacterium Oscillospira, which is associated with greater diversity of the gut microbiota, a biomarker of healthiness. The Christensenella family is emerging as the cornerstone of healthy human intestinal microbiota.

It is hoped that in the near future a drug candidate developed from Christensenella will transform the management of obesity, metabolic disorders and other high-impact diseases. This recently discovered family of bacteria represents a major opportunity in microbiome modulation, with the potential to unlock a wide range of therapeutic applications.

The millions of microbes that exist in symbiosis in our gut have very specific functions and interact with our cells to drive signals along the brain and gut axis. In simple terms, a healthy microbiome signals to the brain that all is well, so the immune system is not activated.

However, many factors such as malnutrition, antibiotic use, and ingestion of pollutants can harm our gut microbiome, reducing essential keystone bacteria which provide the positive cues to our human cells. As a result, the immune system is activated which can result in the onset of certain diseases and health issue.

“The permeability of our gut increases and many nutrients and lipids and other things that aren’t supposed to go through get into our system, and it’s then a vicious circle that our metabolism has to cope with,” explains Dr Georges Rawadi, CEO of LNC Therapeutics. “One of the ways of correcting this is to supplement the gut with the right microbes and this is what we will be trying to do, to provide living bacteria such as Christensenella to the patient with the expectation that this living bacteria will help establish a healthy ecosystem and reverse the situation.”

Founded in 2010, LNC Therapeutics is a French biotech company specialising in gut microbiome-based drug discovery. All of the company's projects include basic research, preclinical research and clinical trials. With a total of €16.5m raised since it was founded, including €1.5m in grants from BPIfrance and the Nouvelle Aquitaine region, LNC Therapeutics pursues ambitious research and development programmes.

“The microbiome has become an area of intense innovation and discovery,” continues Rawadi. “It was thought to just be involved in the absorption of nutrients, but crucially in the last decade it was discovered to be associated with metabolic, inflammatory and neurogenic diseases and recently linked to cancer development.”

The company is aiming to become a major player in biotechnologies and plans to continue building its intellectual property portfolio, and developing industry partnerships with research teams working on microbiome-related topics.

“Scientific data showed that the absence of Christensenella was highly associated in human patients with obesity as well as some inflammatory, metabolic and other diseases. Through our own activity at LNC we also made this link and filed patents in that space,” continues Rawadi.

“Since then the company has been focused on developing Christensenella as a Live Biotherapeutic Product. To do this we wanted the freedom to operate on this specific family of bacteria and we knew that Cornell University had also filed a patent family in 2014 to cover the use of Christensenella as a specialist area of interest.”

LNC has now secured exclusive commercial rights from Cornell University and controls multiple patents covering the development of Christensenella to treat obesity and associated metabolic diseases.

Initially Symflor, a Europe-based company which had not been active for some time, held the IP. Symflor facilitated the agreement, but LNC now has a direct agreement with Cornell University.

“We now have the freedom to operate as a key player in that space,” says Rawadi. “There was an upfront payment involved as part of a traditional licence agreement and it was important that this was exclusive and worldwide for us. If other pharma and biotech want to develop in that space they will now have to obtain a licence from us as a third party.”

From gastric bands to dietary management, treatments so far developed to control obesity have often had safety issues or lacked efficacy or sustainability. The hope is that microbiome products will have the ability to treat obesity at source, with a much higher success rate.

“Treating obesity by controlling certain receptors, or by controlling appetite or surgery, can generate other complications and these approaches are not always sustainable,” confirms Rawadi. “We will be able to treat obesity and all metabolic diseases at the starting point using a natural process of restoring the microbiome.”

If all goes to plan, LNC intends to run its first clinical trial of Christensenella by 2020.

“The average time for a drug to reach market is about seven years, so if all goes well with Christensenella then we are looking at the horizon of 2027-2028 to get a product out there,” says Rawadi.

LNC is also dissecting the mechanism of this family of bacteria to understand how it operates and interacts with host cells.

"We strongly believe that Christensenella has a wide therapeutic potential that goes beyond obesity and metabolic disorders,” adds Rawadi. “We are therefore considering the possibility of broadening our fields of application, potentially exploring other disease areas.”