Ideas

The beginning of the end? The race for a Parkinson’s cure

GLOBE PHOTO ILLUSTRATION; Library of Congress Prints and Photographs Division

Dad told me he had Parkinson’s disease over broccoli and beef at the Chinese restaurant in Lincoln, Neb. He was 45. I was a senior in college.

He operated a retirement home in Omaha, so he had seen the disease. He spared me the details then, but he knew it well enough from the over-60 set — the tremors, a stiffening of limbs, and eventually, the wheelchair.

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The symptoms vary, but often it delivers you to a nursing home, maybe with a dollop of dementia and struggling to swallow. Still, it’s not usually Parkinson’s that kills you. By taking your sense of balance, it gives you a push down the stairs, or it flings open the door to other predators, like pneumonia.

It’s not a new story. The disease was first classified and deemed worthy of study by British physician James Parkinson in his “Essay on the Shaking Palsy” 198 years ago. But all I knew then was it meant a death sentence for my dad. I drove back to my apartment, and sobbed just that to my roommate, whose totally appropriate response was to give me a drink.

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That was in 1997, and little has changed since then for Parkinson’s patients. To this day, the only way to get diagnosed — really diagnosed, as opposed to a doctor’s declaration based on your symptoms — is a look at your brain after you’re dead. More importantly, the primary treatment for the disease remains a drug from the 1960s, called levodopa, or Sinemet in commercial form.

That long inertia may finally be breaking, though the solutions are so new — still in early stages of clinical testing — that most of those afflicted have likely heard nothing about it. And, of course, much to my dismay and that of others who live in a world shaped by Parkinson’s disease, the trials could end in failure and the search for a cure will be 198 years and counting.

The potential breakthrough comes from a recent focus on alpha synuclein, a protein found mainly in nerve cells. It is so biologically obscure that scientists aren’t even sure of its purpose. What they do know is that the protein can deform, or what scientists call misfold, and gum up into clumps called Lewy bodies, which litter the transportation system that nerves rely on. The nerves die. If enough die, your body stops producing the dopamine necessary for normal functioning. You have Parkinson’s disease.

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Grim though it is, the discovery has given scientists a target for therapy. Their new weapon? Vaccines, or more generally, immunotherapy — an approach that has kickstarted the kind of outbreak you can cheer for: loads of biotech investment and clinical studies.

“The alpha-synuclein story has energized the entire movement-disorder community,” says Lawrence Elmer, a professor of neurology at the University of Toledo and the director of its Center for Neurological Health. “I think it’s going to be the beginning of the end of Parkinson’s disease as we know it.”

At least three biotech companies — AFFiRiS, Prothena, and Biogen — are now running competing trials of immunotherapy: developing vaccines that would spur antibodies to destroy the toxic alpha synuclein (while sparing the healthy) or developing the antibodies directly, thereby cleaning out the gunk and, with luck, restoring functionality.

The therapy would be unlike current pharmacological treatments that only alleviate the symptoms of Parkinson’s. “There’s been nothing to slow the course of the disease,” says Dale Schenk, the CEO of Prothena and an immunotherapy research scientist. “This offers an opportunity to change the direction of the disease.” In other words, this is a shot at a cure.

Scientists are working on targeting Lewy bodies, which are deformed clumps of protein associated with Parkinson’s.

Scientists are working on targeting Lewy bodies, which are deformed clumps of protein associated with Parkinson’s.

A year ago, I launched a quest for answers after being jolted into action by a dream. That night, I had seen my dad as he was before the disease ate away at his size and swagger, possessed his right hand with tremors, stole his job. In the dream, I was at Mass. I turned away from the priest to behold my dad standing next to me, young, trim, and square shouldered. He gave me a grin. His light brown hair was moppish, like he used to wear it when I was a kid in the ’80s, and raked to the side. He looked amused, cocky. Like he knew the score. I woke and wept for my dad a second time.

I discovered the trials through nights of online searches. Dad was too far along to qualify. Still, I told him about the research and learned he hadn’t heard of alpha synuclein, probably because he was diagnosed in 1997, when the medical community itself was very unsure of the protein’s role.

His understanding from his neurologist was broader, but probably no less true: He likely got Parkinson’s from the farm as a kid. In Iowa, in the ’50s and ’60s, he sat on the back of a tractor, spraying herbicide across the corn and making the mistake of breathing the whole time. In the hog barn, he scooped powdered pesticide from a bag at the door, cast it through the air, and watched hundreds of flies drop dead. Then he continued his chores.

He likely got Parkinson’s from the farm as a kid. He sat on the back of a tractor, spraying herbicide across the corn and making the mistake of breathing the whole time.

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But, like so much else with the disease, even the cause has been elusive. For generations, the conventional wisdom was that Parkinson’s was hereditary, akin to such terrors as Huntington’s disease.

Still, some people suspected an environmental component. In 1982, that was confirmed when several young addicts in a garage in northern California injected synthetic, home-brewed heroin. Within days, they had “frozen into living statues,” as described in a Time report. Neurologist William Langston identified the symptoms as similar to advanced Parkinson’s disease. Analysis of the drug showed the toxin MPTP, which killed neurons in the part of their brains that controls movement, the substantia nigra — the same area attacked by Parkinson’s disease.

“Once it was discovered that it was MPTP, it was discovered that you could get Parkinson’s disease from the environment,” says Carrollee Barlow, the CEO of the Parkinson’s Institute and Clinical Center that Langston later founded. “And everything started changing.”

Sure enough, new studies proved an association between exposure to some pesticides and Parkinson’s disease — increasing risk by a factor of two to six. Not surprisingly, farmers are more prone to the disease. Throw it on the list of dangers for what is already one of our most dangerous occupations.

But in the late ’90s, genetic factors came back into play with the discovery of an Italian family now spread across the old and new worlds, in which Parkinson’s ran rampant. Researchers discovered a mutation in their gene that instructs the creation of alpha synuclein, causing it to aggregate into Lewy bodies. The role of genetics was reinforced with a similar Parkinson’s-afflicted family in Iowa that carried an extra copy of the alpha synuclein gene, imbuing them with high levels of the protein.

Further complicating the search for the cause in the early 2000s, German husband-wife duo Heiko Braak and Kelly Del Tredici thought to look beyond the brain and found alpha synuclein clumped in the gut, too. “Once they identified that, it was like all the lights went on,” Elmer says. “Everything you eat and drink passes through intestines. So it is factored by the environment.”

Hence, Parkinson’s is environmental. Or it is hereditary. Or it is both at the same time. Folks who get the disease from the environment often have a genetic disposition to the disease that is triggered by certain toxins. In every instance, however, the toxic clumps of alpha synuclein are the culprit. “That’s why there’s so much excitement,” says Todd Sherer, the CEO of the Michael J. Fox Foundation. “An alpha synuclein therapy should work for any of those individuals.”

The idea of the therapy is to use antibodies to attack the bad protein, as if it were a foreign invader like a virus or bacteria. That can mean antibodies cooked up in a lab and injected into a person or a vaccine that instigates the test subject’s own immune system to go to war.

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The immunotherapy approach tracks a similar breakthrough in an even deadlier neurological disease, Alzheimer’s disease. The aforementioned Biogen has seen its stock price skyrocket in anticipation of a new, designer antibody (also known as passive immunization) now entering a late-stage study. Early results showed a 71 percent decline in the Clinical Dementia Rating among test subjects.

“What we’ve learned from other diseases is they can help you design clinical trials more effectively and efficiently,” says Schenk, the CEO of Prothena. But, honestly, the new trials on a vaccine for Parkinson’s are not going all that fast. To date, there is no easy way to measure if someone is sick or well, or how they’re progressing. If alpha synuclein is indeed the problem, they don’t have a good way of knowing if a drug is reducing it.

Without that ability, measuring success is laborious and even subjective, involving asking patients how they’re feeling over long periods of time or rating them on scales developed by movement disorder specialists. “We need an imaging mechanism so we can image alpha synuclein in the brain,” says Kuldip Dave, director of research programs for the Fox Foundation, which is leading a consortium to develop such a technique.

Researchers are hesitant to say how long it will take or even whether these vaccines will come to market. All three are still in phase I trials, testing primarily for safety and tolerability of human subjects.

The first trial run by drug maker AFFiRiS was small — just 32 people. Those not on the placebo showed a 60 percent response rate, which the chief medical officer described to me as “OK, not great.” The patients did tolerate the drug well. The company is running other trials to be completed by the end of next year with tweaked versions, before going to a broader phase II study devoted entirely to efficacy.

The Prothena trials are larger. “Getting there as quickly as possible is all we think about,” Schenk says. Biogen, meanwhile, has the advantage of its expertise in Alzheimer’s research. Outside experts say because of the difficulty of the science and the stringency of FDA requirements, any certified immunotherapy is at least six to seven years away.

In the meantime, the flurry of biotech investment in Parkinson’s research includes treatment designed to bring immediate relief rather than a cure, most focused around better delivery of levodopa to the system, such as an inhaler and an insulin-style pump that delivers the drug to the intestine for quick absorption.

That’s good news, but it’s far from the promise of a vaccine, which could stop the progress of the disease in millions worldwide; it may even roll it back. No one knows for sure.

And no one knows if it will come in time for my dad.

Bret Schulte is an associate professor of journalism at the University of Arkansas.
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