An Ottawa scientist's discovery offers rare hope for patients with devastating genetic disease

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As a child, Michael Rudnicki liked to dismantle clocks. He would take them apart, piece by piece, to see what made them tick.

That curiosity has been a driving force throughout the celebrated Ottawa stem cell researcher’s career. ?The 65-year-old scientist, who directs the regenerative medicine program and the Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute, has long been driven by trying to better understand what makes stem cells — the body’s repair system — work.

In doing so, his work has become a disruptive force in the understanding of and potential treatment for Duchenne muscular dystrophy, a devastating muscle-wasting disease that affects hundreds of boys and young men in Canada and hundreds of thousands around the world.

A decade ago Rudnicki and his team made a discovery about stem cells that is changing the understanding of Duchenne muscular dystrophy. Today, treatment based on that discovery and developed by a company Rudnicki co-founded is in the early phase of clinical testing.

There are still months, possibly years, of testing ahead before the value of the drug is fully understood. But if it works as Rudnicki believes it will, it could change lives.

The aha moment happened in the lab when Rudnicki and his team found that Duchenne muscular dystrophy affects muscle stem cells in addition to muscle fibres, which compromises the body’s ability to repair ongoing damage. The finding set the stage for the development of a drug and, hopefully, seeing that treatment make a difference. If all goes according to plan, it would also be extraordinary in the normally slower-moving world of scientific discovery.

“Scientists working in fields like stem cells can work a lifetime and make discoveries that are large, but not have the ability to see that in real life. Not everyone gets to see their work go from discovery to possibly impacting clinical practice and changing and helping patients. That would be tremendously satisfying.”

Still, he and others involved in the drug development remain cautious as the treatment begins crucial phases of testing. “We don’t want to overpromise and raise false hope.”

Duchenne, one of the most severe forms of muscular dystrophy, affects about one out of every 3,600 boys. The inherited rare disease on the X chromosome is caused by a genetic defect and it primarily affects boys.? It impairs the body’s ability to produce dystrophin, a protein that acts as a shock absorber for muscles.

It leads to progressive muscle degeneration, loss of mobility, a need for ventilator support and eventually death, usually before the age of 30.? Children are usually diagnosed between the ages of two and four.

For affected children, young men and their families, life follows a series of negative milestones marked by loss of mobility and physical function along with daily struggles. Children with Duchenne muscular dystrophy typically lose the ability to walk by age 12.

There is no cure for Duchenne muscular dystrophy. A focus of potential treatment has long been on fixing or replacing the defective gene that causes the disease. One genetic treatment has been approved by the U.S. Food and Drug Administration, but it costs millions; its longevity is uncertain; and people who have been exposed to the viral vector used to deliver it don’t qualify. Crucially, patients only get one shot at it.

Many other researchers are working on potential gene therapies. So far, Rudnicki says, the results are not promising.

The discovery made by Rudnicki and his team showed that Duchenne muscular dystrophy (DMD) is also a stem cell disease. Patients with DMD have a defect in their muscle stem cells that impairs the normal regenerative process, meaning muscles do not repair themselves.

Not only did that finding — published in the journal Nature in 2015 – go against the grain of conventional thinking about the disease, but it opened the possibility of new treatments.

Stem cells have been part of Canada’s scientific history since University of Toronto scientists James Till and Ernest McCulloch stunned the scientific world with their discovery of transplantable stem cells in 1961. They made the discovery while studying the effect of radiation on bone marrow, paving the way for the growing field of stem cell research.

Rudnicki, who also teaches at the University of Ottawa, is at the leading edge of the burgeoning field of stem cell research and regenerative medicine, said Cate Murray, president and CEO of Canada’s Stem Cell Network.

“This builds on the Canadian story of James Till and Ernest McCulloch,” Murray said. “They were the pioneers who proved the existence of stem cells although the odds were against them. They opened a whole new area of research activity through regenerative medicine. Michael (Rudnicki) is another great among them.”

Rudnicki calls the discovery a paradigm shift in the understanding of the devastating disease — something that could be a game changer for boys and young men living with the disease.

It was hailed by some experts as a long-awaited breakthrough. In 2022, Rudnicki was admitted as a fellow of the Royal Society, the world’s most prestigious scientific institution whose members include Charles Darwin and Isaac Newton. That honour, he says, was largely based on his Duchenne muscular dystrophy discovery.

Rudnicki’s discovery challenged the theory that Duchenne muscular dystrophy is solely caused by a genetic mutation that affects production of the protein dystrophin that acts as a shock absorber, protecting the muscles from injury.

But Frank Gleeson, who, with Rudnicki, co-founded the company to develop drugs based on the research, said the shock absorber theory doesn’t fully explain why muscles disappear over time in people living with Duchenne muscular dystrophy.

“It would be like saying your car is missing a shock absorber and therefore the tires disappeared,” said Gleeson. “(Muscles) are getting damaged and they are not repairing themselves. Eventually, the damage and the lack of repairing itself gets worse and worse and goes into a death spiral … that is how muscle disappears.

“Diseases of this level of devastation are often extremely complex. There are many factors that create the conditions that people live with. We are trying to address one of those factors, which we think is the most dominant factor,” Gleeson added.

But moving that discovery to a possible treatment hasn’t been easy.

The concept was initially met with resistance and skepticism.

“It truly was a paradigm shift in our understanding of the disease, so it was slow to be accepted and there was pushback,” said Rudnicki. “Ten years later, it is mostly accepted.”

A second paper published by Rudnicki’s lab showed that satellite cells could be restored in mice with Duchenne muscular dystrophy, improving their outcomes. Based on that work, Rudnicki and Gleeson, a biotechnology entrepreneur and former chairman of the board of Canada’s Stem Cell Network, founded a company called Satellos in 2018. The aim was to develop drugs that could be taken orally and would act on stem cells inside the body.

“That was the beginning of our journey to see if we could take his discovery and turn it into a treatment for children with this disease,” said Gleeson.

Drug development is both costly and difficult. Scientific funding agencies, such as the Canadian Institutes of Health Research and organizations like the Stem Cell Network support discovery-based scientific research. However, the multi-million dollar cost of translating that research into drug development and testing requires other sources of money.

But when Satellos went looking for private sector investors, the reception was sometimes cautious, often unreceptive and even harsh.

“A brand new idea that challenges convention, as this one does, can be met in a number of ways. Some people meet it with disbelief, but open arms. Some people meet it with disbelief, but cynicism. We’ve experienced all of them,” said Gleeson.

“Over 10 years, we have lived the gamut of people slamming doors in our faces.”

Among other things, Gleeson said some people doubted the findings could be true, saying “How could we all have missed it?” Either that or they were skeptical the company could figure out how to develop a drug to treat it.

“This is one of those radical scientific ideas. Radical ideas being met with cynicism or skepticism is not new.”

But angel investors initially and professional biotechnology institutional investors later became interested in the small bioscience startup backed by encouraging results in animal models. The company — which Rudnicki said has financially “run on fumes at times” — has now raised $73 million.

It has designed and produced a drug to stimulate the body’s ability to repair its own muscle damage.

Among other things, the drug was tested on laboratory dogs in a pilot study. After four months, the dogs were back to nearly normal muscle strength. The number of dogs involved was too small to be statistically significant. Still, pictures of their muscles going from damaged to nearly normal “floored” Rudnicki.

The Phase 1 clinical trial of the drug therapy is taking place in Australia where it is being tested on healthy volunteers to determine whether it is safe.

By next year, if all goes as planned, the treatment – in the form of a single pill taken daily – is expected to be tested for efficacy on children with muscular dystrophy around the world in Phase 2 clinical trials. The potential treatment received orphan drug designation from the U.S. Food and Drug Administration earlier this year, which could expedite some research.

Gleeson said the company’s objective is to get approval for the drug by 2027. “That is what we are trying to make happen.”

Rudnicki and Gleeson receive letters from parents around the world who are desperate for treatment to improve the quality of their children’s lives.

“These families are in unbearable pain. The parents want to know whether they can enroll their sons in a clinical trial. When you talk to these families, they want to be hopeful and they want there to be something for their boys,” said Gleeson.

“We tell them the truth. We are working as fast as we can and trying to be as open as we can and to run as many clinical trials as we can. We are one little company trying to help as many people as possible as quickly as possible.”

The current standard of care for Duchenne muscular dystrophy is treatment with steroids and physical therapy, which helps children remain ambulatory for an extra two to three more years. Rudnicki is hopeful that the Satellos therapy, if approved, can give patients as many as 10-15 more years before relying on a wheelchair.

“What motivates all of us in the company is to do something for these boys and their families. Many people who have joined the team have personal connections to people living with Duchenne muscular dystrophy. It is very moving to see what their daily struggles entail,” said Rudnicki.

Among those watching Satellos’ progress is Elijah Stacy, a 23-year-old patient advocate living with Duchenne muscular dystrophy in Southern California. Stacy was diagnosed when he was six and lost his ability to walk at age 11. At 15, he founded the not-for-profit organization called Destroy Duchenne. He acts as a patient consultant to five biotech companies, including Satellos.

Stacy says his condition is progressively worsening.

“It is a lot harder in a wheelchair now that I can’t really use my arms. Even sleeping is harder, which I didn’t expect. I used to get out of bed myself.”

Stacy is excited about the possibilities of the drug therapy being developed by Satellos, especially after seeing the results the treatment had on affected dogs.

“They were stronger than they ever were. If I could be stronger than I ever was … I don’t know what that would be like.”

Amid the buzz about the possibilities of the approach to treating Duchenne muscular dystrophy, Rudnicki remains realistic.

“If this works the way we hope it will, we could see patients walking for many years longer than normal. Maybe it will only be a few years. Maybe it won’t work,” he said.? “But we really think it will have a significant impact on the muscles’ ability to maintain themselves through regenerative response.

“And if these patients can walk for several more years, it will utterly transform their lives.”

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