Turning brain disorder research on its head

New Frontiers in Research Fund | Published: 2023-07-10 10:00 AM (eastern)

A research team will upend the way research is done in pursuit of new drugs to treat brain disorders such as Alzheimer’s and Parkinson’s. The cross-Canada, multidisciplinary team was awarded a $24 million grant from the Government of Canada to build an innovative open science platform to share research findings and knowledge with the wider scientific community.

“This will reinvigorate and accelerate drug discovery in the neurosciences in Canada and globally,” says Western University’s Schulich School of Medicine and Dentistry Professor Ravi Menon. “We expect that within six years, we will be able to predict one or more drugs that are going to be very successful in a human clinical trial.”

Menon is the nominated principal investigator on TRIDENT (TRanslational Initiative to DE-risk NeuroTherapeutics), one of six projects to be awarded a New Frontiers in Research Fund Transformation grant in recognition of its transformational potential. It brings together researchers from institutions including The University of British Columbia (UBC), Western University, the University of Toronto and McGill University, whose expertise spans stem cells, cognitive testing, next-generation animal models, computation and imaging techniques, and the impact of sex and gender on neurodegenerative disorders.

Among the other renowned researchers on the TRIDENT team are professors in the Brain and Mind Institute at Western University, Lisa Saksida (one of the team’s principal investigators) and Tim Bussey (another principal investigator), who invented the cross-species touchscreen cognition testing system now used in over 500 academic and commercial entities. UBC Centre for Brain Health neurology professor Neil Cashman (a co-applicant) has developed a promising vaccine for Parkinson’s disease that is at the right stage to proceed through the TRIDENT testing model.

“The conversations over the decisions we will be making to determine what drug moves forward through the process are going to be really, really interesting,” says Liisa Galea, another principal investigator and neuroscientist at the Centre for Addiction and Mental Health, who is a world-recognized expert in sex hormone influences on brain and behaviour.

Menon agrees that the team’s multidisciplinary expertise is “our secret sauce.”

“This is a multi-trillion-dollar global problem. No individual is ever going to solve this problem.”

Brain disorders have emerged as one of the most pressing public health and policy challenges in Canada, particularly as the country’s population ages. Brain disorders will affect 1 in 3 Canadians over their lifetimes, impairing people’s learning, memory, and judgement. By 2031, the Public Health Agency of Canada expects that annual healthcare costs for Canadians affected by dementia will reach $16.6 billion, doubling what was spent two decades earlier.

“We are at a pivotal moment in history. We have a pressing unmet need that will overwhelm our economies and health care systems,” Menon says.

A key reason why there are no effective treatments yet is that neuroscience drug development is expensive and risky. It costs between $50 million and $100 million to identify a promising therapeutic candidate at the preclinical stage. The cost to take that drug through all phases of human clinical trials totals more than $1 billion. And, after all that, clinical trials on promising compounds fail to reach final approval more than 90% of the time.

“Over the past 30 years, this conventional approach has resulted in over $230 billion dollars wasted on failed clinical trials for drugs to treat neurodegeneration. And no cures,” Menon says. “What we are missing is a way to get from discovery to drug in the shortest time, at the lowest cost, and with the highest confidence. TRIDENT bridges that gap in a way that has never been possible.”

The team believes that by using less expensive and more accurate preclinical research instead of clinical trials to predict treatments that will fail, those treatments will “fail fast” and save companies 80-90% of the costs of these trials. Furthermore, by putting all this information into the public sphere, other researchers can see what is working and what isn’t. Right now, that’s top-secret, meaning more than one research team can go down the same dead-end road of inquiry and not realize it. Similarly, because of a conventional team’s narrower area of expertise, connections could be missed—such as a drug that doesn’t end up working for Parkinson’s but could be useful against Alzheimer’s disease.

Another factor that makes drug discovery in the neurosciences particularly challenging is the vast number of cell types in the brain and the complex interactions between them, further complicated by sex or hormones. This has an enormous impact on women, who make up two-thirds of Alzheimer’s disease patients. Yet, sex and gender are rarely part of the preclinical drug analysis. A direct result of this is that many of the drugs on the market have more side effects for women, or do not work as well in women as in men.

Galea says she’s excited about TRIDENT because sex and gender analysis is going to be baked in at every level. She believes this project may deliver something that’s never been done before—identify separate drugs that are best used for either males or females.

“I think this is the way forward that we’ve been looking for,” Galea says. “I think the reason so many clinical trials fail is because we’re not investigating whether sex and gender play a role in the outcomes. Plus, any new therapeutics that make it into approvals have more unwanted side effects in female patients, suggesting a lack of analyses of sex and gender is problematic. I see that time and time again; sex and gender are ignored in drug discovery. And that’s a huge problem.”

Building and growing a globally unique preclinical testing platform is going to put Canada on the map when it comes to brain disorders, Menon predicts. The platform and training opportunities alone will spur more pharmaceutical research and development and create more manufacturing jobs.

“This could make Canada the destination of choice in the neurosciences,” says Menon.