The DNA of depression: Australia launches 20,000-person genomics study

Why do some people respond to antidepressant medications, while others gain no symptom relief at all?

That’s just one of many million-dollar questions that confound drug developers and healthcare providers working in the field of mental health. The unknowns complicate clinical trials, treatment decisions, and of course, greatly impact patients.

In an effort to shine some light into the gray skies of depression, Australia has launched a 20,000-person genomics study, funded by the government’s National Health and Medical Research Council.

The resulting data and findings will feed into an international study of 200,000 individuals with depression, the largest-ever undertaking in the field.

It’s just what the doctor ordered.

According to a recent report by the World Health Organization (WHO), depression is now the leading cause of disability worldwide. As of 2015, some 322 million individuals were afflicted — roughly the population of the United States. Global prevalence has soared close to 20 percent in the last decade alone.

In a 2014 Nature article, Steve Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute, called for a large-scale genomics study of over 100,000 patients to bring the field up to speed.

“Progress in other disorders, such as autism and schizophrenia, suggest that the best hope for insights is to identify specific genetic variants associated with the disease,” Hyman wrote. “However, success in depression will require studies of much larger collections of human DNA samples than in other diseases if statistically significant signals are to come through.”

As part of the Australian study, volunteers 18-years and older will be asked to complete a 15-minute online survey. Based on their responses, they may then be asked to submit a saliva sample for genomic analysis. The sample will be sequenced and screened for hundreds of DNA variants through a process known as ‘genome-wide association scans’ (GWAS). The investigators are particularly interested in patients who have taken medications for the disease.

Genomic studies could unlock information about why some individuals – and families – have a greater likelihood of developing depression. The data could inform new drug development and ensure the right patients are recruited into the right trials.

It could also help explain the variable response individuals have to antidepressant medications — a burgeoning field known as pharmacogenomics. Such tests help guide what therapies and doses may work best.

Mayo Clinic startup OneOme has a panel that includes information on what psychotropic drugs, including antidepressants, could be well-tolerated based on the individual’s genetic makeup. Several genes relate to antidepressant efficacy, including HTR2A/GRIK4 and SLC6A4.

“There is a clear need in the psychiatric space for objective biomarkers that allow healthcare providers to tailor treatment – and that’s where pharmacogenomics comes in,” said OneOme CEO Paul Owens in an email forwarded by a company representative. “Since genetic factors account for up to 95 percent of drug-response variability, pharmacogenomics can help physicians identify which psychiatric drugs may work best for individual patients, before they even take them.”

While pharmacogenomics holds wide potential, a lot more information is needed to effectively treat mental illnesses the first time around. Owen also noted that the medical community has been slow to capitalize on the knowledge that does exist.

“Unfortunately, the education and understanding of genomics – let alone pharmacogenomics in routine medical practice – is still in its infancy stage,” he said.

There is a long way to go, but a 200,000-person genomics study is a good place to start. As Hyman wrote in nature, a basic understanding of the biology is still lacking.

“Failures to improve efficacy reflect continued ignorance of the molecular mechanisms of depression,” he said, then noted later on; “The investments will be well worth it.”

Photo: phototechno, Getty Images

In dash to NASH, Immuron targets the gut not the liver

Surprise, surprise; fatty liver disease is associated with a poor Western diet.

That’s not a revelation, but Immuron has an interesting take on exactly how a high fat and high sugar diet help drive the inflammation behind NASH.

Approximately five percent (15.9 million) of Americans are believed to have non-alcoholic steatohepatitis (NASH), but that’s just the tip of the iceberg. It comes as a progression of non-alcoholic fatty liver disease (NAFLD), which affects an estimated 75-100 million Americans. With such solid

With such solid blockbuster potential, startups and Big Pharma are pouring into the field.

Immuron is taking a somewhat radical approach. Its investigational NASH drug called IMM-124E targets bacteria as a key driver of liver inflammation. The formulation is manufactured from bovine colostrum, explained CEO Thomas Liquard in a recent phone interview.

“We’re basically able to engineer colostrum to produce a specific set of antibodies that we can use to target just about any bacteria in the gut, without affecting the rest of the microbiota,” he said.

Headquartered in Melbourne, Australia, Immuron’s proof-of-concept is an over-the-counter product called Travelan, available in the United States, Canada, and a handful of other countries. Based on a small placebo-controlled trial, Travelan prevented new cases of travelers’ diarrhea with 90 percent efficacy, Liquard said. It does this by targeting E. coli, the bacteria responsible for a majority of cases.

The company moved on to two clinical applications: Clostridium difficile (c. diff) infections and NASH, which is now in Phase 2 trials.

IMM-124E is an interesting take on NASH. It accepts that a major contributing factor is the poor quality of the Western diet — but it’s not the long-term build-up of fat that does the damage.

“The high levels of sugar and fat in our diet, especially glucose, creates an overgrowth of Gram-negative bacteria in the gut,” Liquard explained.

Not all Gram-negative bacteria are bad, he noted. They do, however, all share a common feature known as a lipopolysaccharide (LPS) receptor. According to Liquard, when the bacteria dies or sheds, pro-inflammatory byproducts of LPS enter the bloodstream.

“LPS is not the pathway per se, it’s a trigger of inflammation,” he said. It causes injury, which leads to the development of NASH.

Because the liver is right next to the intestines and stomach, it takes the biggest hit when the gut bacteria shed LPS into the bloodstream. By targeting certain Gram-negative bacteria, IMM-124E is designed to prevent the overflow of LPS into the liver. 

“We’re not an antibiotic, so we don’t kill the bacteria,” Liquard explained. “We block that overgrowth of bacteria in the gut without destroying the rest of the microbiota.”

There are a number of benefits to this approach. With its novel mechanism, IMM-124E would likely pair well with any future NASH therapies — or drugs for the many comorbidities found in this patient population, such as heart disease and metabolic syndrome. Targeting the Gram-negative gut bacteria could also cut down on LPS-driven inflammation and damage in other organs such as the pancreas, which Liquard said was demonstrated in the Phase 1 trial.

There also seems to be some sort of feed-forward effect beyond the LPS suppression as the body gets a handle on the inflammation.

“Because you decrease the levels of LPS within the gut, you see an anti-inflammatory response from patients,” Liquard said. “In all of our studies, you see the cytokines going down, you see regulatory T-cells – which are the T-cells that regulate inflammation – go down. The type of regulatory T-cells that decreases inflammation goes up.”

A microbiota approach also has the ability to treat a wide range of patients. That differs from any other companies, he said, which target specific pathways that may only apply to a subset of patients. With a lack of biomarkers, it’s hard to know who to treat.

The challenge of treating a sick population is also front of mind for the FDA. Any potential therapies need to be suitable for chronic use in patients with obesity-related comorbidities. An investigational NASH drug from Intercept Pharmaceuticals, for example, appears to increase LDL-cholesterol levels, a major concern in this patient population.

For Immuron, the broad applicability of IMM-124E may pose a novel hurdle. Where to start?

“We need to be very strategic in terms of how we bite that NASH apple,” Liquard said. “To make sure we don’t bite off more than we can chew.”

Photo: pagadesign, Getty Images

5 startups from the SXSW Accelerator that you should meet

Sound Scouts, an Australian-based business that developed a DIY hearing test app that parents can download and run for their children, emerged as the winner of the SXSW Accelerator pitch competition in the digital health and wearables track, according to an emailed announcement from the organizers. The test is cleverly disguised as a game designed to create a more interactive experience for kids but alert parents to any hearing problems that warrant attention from healthcare professionals.

It wasn’t immediately clear what Sound Scouts’ plans for the U.S. market are, but Founder Carolyn Mee said during her initial presentation that she wants to make the product available to adults and children around the world.

Although there was only one dedicated health track, the technology behind a few of the other startup winners have direct or indirect applications for healthcare as well.

Enterprise and Smart Data

Deep 6 AI developed technology to make it easier to match patients with appropriate clinical trials through natural language processing and artificial intelligence. The clinical trial recruitment process is one of the most time consuming and costly aspects of drug development and Deep 6 AI is one of several companies to take up the gauntlet of creating a more streamlined process. Wout Brusselaers is the founder and CEO.

Security and Privacy

UnifyID uses data collected by sensors from an individual’s mobile devices such as GPS, accelerometer, gyroscope, magnetometer, barometer, ambient light, and WiFi and Bluetooth signal telemetries to figure out what makes the owner unique, according to the San Francisco company’s website. The data is kept on the local device, is encrypted and anonymized. UnifyID’s approach can also be applied to desktop and laptop computers. Given the cybersecurity concerns in healthcare over the theft of personal health data it seems like UnifyID’s approach could have useful applications in this sector.

Innovative World

Thimble.io in Buffalo, New York wants customers to discover their inner engineer, their inner maker. A monthly subscription gives users an electronics kit each month that teaches them how to code, hack and construct electronic devices. By playing the long game, stimulating young and older minds to use these kits as stepping stones towards realizing their creative interests, they could help create a new generation of software developers and biomedical engineers wherever they might be.

Augmented and Virtual Reality

Lampix shuns the goggles and other head gear that tends to be associated with augmented and virtual reality. Instead, it takes a more subtle approach. The company’s product lets users adopt flat surfaces like a table to project a computer screen and interact with the screen projection as if it’s a touchscreen. As for healthcare applications, Lampix’s platform could be used as another approach to gaming technology for cognitive assessment to expanding health literacy delivery tools.