A Hotchkiss Brain Institute (HBI) trainee looking for the next big discovery in multiple sclerosis (MS) research got a surprise break while on a ski trip to Banff with some new friends — unveiling a new approach to repair damaged nerve cells.
MS is a neurological disease that attacks myelin, the protective covering surrounding nerve cells. It can leave the patient with devastating symptoms such as extreme fatigue, lack of co-ordination, weakness, tingling, impaired sensation, vision problems, bladder problems, cognitive impairment and mood changes. The disease affects 100,000 Canadians and approximately 340 out of every 100,000 Albertans.
Michael Keough, a joint MD-PhD student in the Leaders in Medicine program at the Cumming School of Medicine, was searching for better therapies for patients with MS, when he hit a roadblock. Keough, who works in the lab of V. Wee Yong, PhD, was investigating the regeneration of myelin.
He found that he couldn’t move forward in his project without a cheaper supply of a compound that he thought would promote regeneration of damaged nerve cells. It wasn’t until he ran into a chemistry student while carpooling to Sunshine Village that he got his big break. The chance meeting proved extremely valuable.
“As we talked about our respective research, I was shocked to learn she was from a lab that could do exactly what I needed,” Keough recalls. “Soon after, I paid a visit to the chemistry department where I met Chang-Chun Ling, PhD. And a collaboration was born.”
Led by Keough, with Yong’s overall guidance and supported by a talented cadre of trainees, the team published an innovative study identifying a mechanism by which myelin can repair itself in MS lesions. Their discovery was published on April 26 in the prestigious journal Nature Communications.
The finding represents an important step forward in a new approach to MS research — clearing a path for the body to heal itself.
Identifying molecules that inhibit the body’s natural repair mechanism
Keough’s team began their investigation by identifying a group of molecules called chondroitin sulfate proteoglycans (CSPGs). While these molecules play an important role in the developing brain, they are also present in the scarring that results from brain injury, such as in MS lesions. When CSPGs appear in lesions, they create an inhibitory environment that prevents the lesion from repairing itself.
Normally, cells called oligodendrocyte precursor cells (OPCs) will differentiate to create new myelin. “This is perhaps the best example of a regenerative event in the brain,” explains Keough. “Myelin, if given the right environment, actually can regenerate and heal itself.”
One of the problems in MS, as Keough and his colleagues hypothesize, is that the CSPGs in MS lesions are preventing the OPCs from doing their job.
The team started by painstakingly testing a library of 245 drugs, looking for something that would help the OPCs grow in the presence of CSPGs. When they found that none of the drugs had a substantial effect, they recognized the need for a fresh approach.
“Rather than adding a drug to help the cells grow in the presence of an inhibitory environment,” says Keough, “we started to ask what if we could prevent the inhibition from happening in the first place?”
Collaboration key to testing a unique approach
Keough thought back to something he remembered reading about in the literature — a chemical compound that could reduce the synthesis of CSPGs. The problem was that the compound was extraordinarily expensive and he would need a lot of it if he were to properly test it.
The serendipitous ski trip to Banff provided exactly the kind of breakthrough Keough needed. As it turned out, the chemists he had bumped into were specialists in making exactly the kind of molecule that he had been looking for.
“It was amazing,” says Keough of the symbiotic partnership that followed. “They were across campus making these compounds but weren’t set up to test them in cells and we were five minutes away with the ability to test compounds that we couldn’t make ourselves.”
With the newly synthesized drug, which they called fluorosamine, Keough was excited to find his hunch was correct. When added to cells, the drug resulted in fewer inhibitory CSPGs and more myelin-repairing OPCs. Not only that, but the OPCs were also more differentiated, meaning they were further down the path towards making new myelin.
From cells to an animal model — removing the barrier to repair
Armed with these encouraging results, the team took their experiments out of the petri dish.
“We then looked at two animal models of MS and found that when we gave the animals fluorosamine we saw fewer CSPGs in lesion scars, accelerated myelin repair and the animals had improved sensorimotor functioning — they got healthier," says Keough.
This type of approach is new to the field of MS. Current therapies offered to MS patients work by targeting — and in some cases, completely obliterating — the immune system.
“We’re at a real turning point in the field right now," says Keough. “By altering the inhibitory environment, we are essentially clearing the path for the body to heal itself; it’s a completely new way to look at treating MS.”
The team’s supervisor V. Wee Yong, PhD, co-leader of the HBI’s Multiple Sclerosis NeuroTeam, is clearly proud as he emphasizes the value of collaboration within his lab.
“I am blessed with a group of very strong trainees," says Yong. "My job is to create the environment and then step back and allow them to interact with one another. The work that emerges is of the highest quality.”
This discovery has implications far beyond this study. Not only can this approach be applied to MS, but it also has potential for other neurological conditions such as traumatic brain injury, spinal cord injury and even stroke.
“We’re at the forefront of the next wave,” says Keough. “There is real potential here to do a lot of good for patients and we’re always looking for new ways, new approaches and new targets to do that. We’ve come a long way, but we’re nowhere near slowing down.”
Led by the HBI, Brain and Mental Health is one of six strategic research themes guiding the University of Calgary toward its Eyes High goals.
This study was funded by operating grants from the Multiple Sclerosis Society of Canada, the Alberta Innovates — Health Solutions (AIHS) Alberta/Pfizer Translational Research Fund Opportunity, and the AIHS Collaborative Research and Innovation Opportunities Team program.