A Parkinson’s ‘game changer,’ backed by Michael J. Fox, could lead to new diagnostics and, someday, treatments

NEW YORK — Michael J. Fox was sitting in his Upper East Side office surrounded by Emmys and an Oscar — one he received not for his acting but for his Parkinson’s philanthropy. (“Humanitarian stuff,” he said nonchalantly.) He wore blue trousers and a T-shirt, and Adidas sneakers with no socks. His hair, years ago always perfect, was a bit disheveled, and he was in constant movement in his chair, a hallmark of the Parkinson’s disease that has defined half of his life.

This past year has been particularly difficult for Fox. As he sipped Coke Zero through a straw — drinking is hard with Parkinson’s — the 61-year-old icon recounted how he had broken multiple bones in a fall, including some in his hand and his face.

“It’s been a terrible year,” he said.

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But, he added, in some ways he was “feeling better.” He won that Oscar. A new documentary on his life will be coming out in May. And, most importantly, there was the scientific discovery he wanted to talk about.

“This is the thing,” he said. “This is the big reward. This is the big trophy.”

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The trophy is science — and specifically research funded by the Michael J. Fox Foundation for Parkinson’s Research that has resulted in the clearest evidence yet that the presence of a particular misfolded protein, alpha-synuclein, can be used to determine if people have Parkinson’s. It is an advance that may soon be used to develop better diagnostics, but more importantly could rapidly accelerate the search for treatments for the disease.

The new findings, published in The Lancet Neurology, are the result of a 1,123-person study that has cost the Fox Foundation hundreds of millions of dollars since it began in 2010. Right now, alpha-synuclein can only be detected by taking a spinal tap, a difficult and uncomfortable procedure. But scientists say they hope that it could be detected in blood, a skin biopsy, or possibly even in a swab of the nose. An editorial in the medical journal called the test “a game-changer in Parkinson’s disease diagnostics, research, and treatment trials.”

The result is convincing in part because of the unique resource of patient volunteers that Fox was able to bring together, said Vikram Khurana, chair of movement disorders at Brigham & Women’s Hospital.

“It is certainly head and shoulders, in my view, the best resource that we have in the Parkinson’s disease research community to really analyze the behavior and molecular and clinical aspects of our patients,” Khurana said.

Fox, who was diagnosed with a very early case of Parkinson’s at age 29, said that he keeps going back to documentary footage of his childhood. At the time, there was no way to know he would develop the disease; soon, he said, a child like that might be able to simply get a nasal swab at 2 or 3 or 4. “It’s all changed. It can be known and treated early on. It’s huge.”

There is still a long way to go before people can be screened this way. And using the new discovery to craft better drug trials and speed treatments to market could take a decade — although the Fox Foundation, always optimistic and impatient, believes it can do the work in three to five years. But Fox sees the result as the biggest victory yet in a battle that has taken decades and billions of donated dollars.

It’s a battle that Fox feels ready to wage. At 5’4” he prides himself on his toughness; one of his childhood memories is of a day playing on a youth hockey team.

“The guy next to me has a full-on mustache and I’m this little slug,” he recalled. “But I’m a tough son of a bitch. I’ve always been a tough son of a bitch. You can beat me up, but I’ll get one punch in and it will hurt.”

Speaking of the new science, he said, “And I think I got one punch in on Parkinson’s.”

Fox moved from Canada to the U.S. when he was 16, and, he says, he “turned dumpster diving and landlord ducking into a series and became the biggest movie star in the world.” The series was “Family Ties,” in which he played the loveable young Republican scamp Alex P. Keaton. He met his wife of 34 years, Tracy Pollan, on the set of the show. And he starred in “Back to the Future” and its sequels, all of them blockbusters.

But while he was starring in 1991’s “Doc Hollywood,” he was diagnosed with Parkinson’s. For seven years he hid the condition, but in 1998 he went public. “I had to tell people,” he said. “They were going to notice.”

“It turned into this new chapter of my life. It was the foundation.”

He remembers that on New Year’s Eve 2000 he was thinking about whether or not a foundation was the right thing to do. He was swimming with Pollan and their children.

“I’m swimming out in the water, and out of the grass came this big turtle.” He looked like he’d been through a lot — he had visible scars. Fox thought about how this turtle, likely decades before, had made it down the beach, and then managed to survive. “I felt like he was telling me to get on with the fight. I got out of the water and said ‘I’m starting the foundation.’”

(He has a tattoo of a sea turtle on his right arm, with one band of rippled water for every decade of his life. He still needs to get the sixth one drawn in.)

Celebrities often create foundations to try to draw attention to their own illnesses. But from the start the Fox Foundation was something different. Fox was willing to throw himself into the effort almost completely, and also had an amazing ability to pull in both top scientists and big donors. More than that, Fox could communicate with patients and their families, and that turned out to be a much bigger asset than anyone realized. Often what slows down medical research is not a lack of understanding of genes or proteins, but an inability to find people who are willing to sign up for the studies researchers need to know if their hunches will prove out.

As CEO, Fox recruited Deborah Brooks, a Goldman Sachs banker, who remains in the role today. (For a time, she stepped back as executive chairwoman). Among their earliest advisers was Andrew Grove, the former CEO of Intel, who also had Parkinson’s and who helped set a tone of skepticism about science.

“We’d be talking, doing this, doing that, and he’d go ‘Bullshit,’” Fox said, dismissing ideas that were too optimistic. But Fox was amazed to have him there — emailing with Grove, he said, was like talking to Alexander Graham Bell on the telephone.

Photo of Debrah Brooks and Michael J. Fox -- cover from STAT
Michael J. Fox with Deborah Brooks, the CEO of his foundation. The Michael J. Fox Foundation

Fundraising was fast but scientific progress was slow. There were some early, important results but the reality, they quickly learned, was that what needed funding was scientific infrastructure — things like basic research studies that would help scientists understand Parkinson’s well enough that they could start to invent drugs.

The idea for the current study, called the Parkinson’s Progression Markers Initiative, came in 2008. The idea was to follow patients whose Parkinson’s was diagnosed in the earlier stages of the disease in order to better understand how the disease progressed. It was clear from the start that the project would take many years and a great deal of money.

Fox remembers sitting by the pool on vacation and looking at the idea and thinking, “This is a really important step. We’re asking so much of people, we’re not promising anything, but we’re saying this is what it takes.”

Todd Sherer, who took over for Brooks as CEO for a time and is currently the foundation’s chief mission officer, had pointed out that relying on animal systems was part of what was holding Parkinson’s research back. It was better, he argued, to look at what actually happened in people, even if doing so would be difficult and expensive. At that point, the foundation had funded perhaps $25 million of biomarker research. The new study, it was thought, would cost $15 million a year.

Brooks remembers that when this idea was taken to the board, many asked why it was a key priority. And if the study would make it easier for pharmaceutical companies to fund research, why weren’t they funding it.

“Ultimately it was Michael,” Brooks recalled. “He leaned over in the board meeting and said, ‘I don’t know the details. But it sounds like this is something that has to be done. If it’s not us, who?’”

The relationships the Fox Foundation had built with Parkinson’s patients helped make the PPMI study possible. Many patients were eager to volunteer, only to be told that their disease was too advanced. But many had family members sign up to be in the control group — a big sacrifice, given that the study involved regular spinal taps to check the level of alpha-synuclein in spinal fluid. Brooks also joined the control group.

Between July 7, 2010, and July 4, 2019, the study signed up 1,123 patients. Of these 545 had Parkinson’s disease, 163 were healthy people with no evidence of Parkinson’s disease, 54 had evidence of the disease on brain scans, 51 were in the early stages of the disease, and 310 had genetic mutations that should cause Parkinson’s but hadn’t yet done so.

Whether the presence of alpha-synuclein could signal Parkinson’s early was an obvious question. The protein accumulates in clumps in the brain, known as Lewy bodies, that are a hallmark of both Parkinson’s and another disorder, Lewy body dementia. A genetic mutation related to alpha-synuclein had been shown to cause Parkinson’s in a study of Greek and Italian patients in 1997.

The results were stunning. Using synuclein as a test in early Parkinson’s detected the disease 87% of the time. What’s more, in volunteers who did not have Parkinson’s, the test showed the absence of the disease 96% of the time.

“This changes things in many ways in a positive direction,” said Ken Marek, the president of the Institute for Neurodegenerative Disorders in New Haven, Conn. and principal investigator of the PPMI study. “It enables us to be more clear for individuals who might have or who have what we now think of as Parkinson’s disease.”

One of the big surprises was that not all patients had the same biology. For instance, mutations in one particular gene, known as LRRK2, were known to cause Parkinson’s. One of the more promising experimental drugs against Parkinson’s, which is being developed by the biotech firm Denali Therapeutics, is being tested particularly in people with the LRRK2 mutation.

Yet 30% of people with the LRRK2 mutation, which causes a disease that looks like Parkinson’s, do not have alpha-synuclein. They appear to have a different biological disease, Marek said. Meanwhile in another group — those who have lost their sense of smell, which is a hallmark of Parkinson’s — the test detected the disease 98.6% of the time.

Those differences, Marek said, could be a key clue to treating Parkinson’s. Perhaps an LRRK2 drug works in the people who have synuclein — in Marek’s formulation, who have Parkinson’s. Until now, it was not clear that researchers should look.

Carole Ho, the chief medical officer of Denali Therapeutics, which is testing a medicine that target LRRK2, disagreed with the idea that LRRK2 patients have something other than Parkinson’s. She also pointed out that it was known Parkinson’s patients with this condition do not always have measurable alpha-synuclein. Khurana, the Brigham and Women’s researcher, said that seeing such definitive numbers would still have an impact on the field.

In the near term, Marek said, the result will have practical implications for cases in which doctors are not sure if they are dealing with Parkinson’s or not. A commercial test is already available. Testing whether the assay can be used for screening will take longer, and will involve learning how to test for levels of synuclein in blood, skin, or on nasal swabs.

When Fox started his foundation, some people he talked to told him that there was hope he could have an impact in five years — something he calls “naive” now. Back then, he notes, scientists were often talking about results in fruit flies. Now they are dealing with results in human brains.

“Now this is the newest chapter, which is, we got something done, something that is fundamentally going to change the world,” Fox said. “I don’t say that lightly. I don’t say it with any credit. It’s the way it worked out.”

That, Fox said, could “open the floodgates.” The Fox Foundation is already beginning studies to use DNA sequencing data collected from these patients to understand how different genes might affect Parkinson’s progression. Another target will be to see if instead of just viewing alpha synuclein as an on-off switch, researchers can look at levels of the protein to determine how advanced Parkinson’s is and even to see if drugs can lower concentrations of the protein.

Outside researchers and drug industry experts agree with that potential — and also see big hurdles to reaching it. Showing the assay can work is a “tour de force,” said David Eidelberg, a neurologist at the Feinstein Institutes for Medical Research.

But what’s not clear is how quickly someone who tests positive for alpha-synuclein will develop Parkinson’s. Will it be months or years? The lack of that information will make it more difficult to use the test to design clinical trials.

Still, the existence of a test makes possible studies that would not have been possible before. Ho, the Denali executive, said that it is now possible to conduct trials early in the disease. “This is the first time that there has been an identification of a biochemical assay that can predict the likelihood that somebody has Parkinson’s disease,” she said.

Frank D’Amelio, who was the chief financial officer of Pfizer for 15 years, recently joined the Fox Foundation’s board. “Hopefully this could lead to better clinical trial design, faster clinical trial execution, and hopefully at some point medicines that can actually slow down the progression of the disease.” Putting on his “financial hat,” he added that that could make Parkinson’s a more appealing disease for drug companies to target, because faster trials mean that treatments are on the market longer before their patents expire.

Many researchers said that they hoped the research would be similar to Alzheimer’s, where the ability to identify patients with particular abnormal peptides has led to drugs that have at least some efficacy against the disease.

Fox knows not to expect it will happen fast.

“At a personal level I’d love to see this happen before I get on the bus and head to the next parking lot,” he said.

He is thrilled by the results so far. To present them to him, Brooks flew to Los Angeles and Sherer joined via Zoom. When the presentation was done, Fox kissed Sherer’s forehead on the computer screen.

“I just feel like I’m in a unique position,” Fox said. “I steered the ship but I have no idea about the workings on the deck.”

Source: STAT