An Answer to ALS?

For Michael Tsun, the first sign of trouble came late in 2012, when the Fairfax County, Virginia, resident began feeling pain in his shoulders and around his buttocks. Soon thereafter, Tsun and his physician took aim at polymyalgia rheumatica (pmr), a pain syndrome that often hits men over 50.

“This is going to be the most comprehensive project ever undertaken in ALS for certain,” Rothstein says. It might even rank as “the most comprehensive project ever undertaken in any type of neurological disease.”  -Jeff Rothstein

“This is going to be the most comprehensive project ever undertaken in ALS for certain,” Rothstein says. It might even rank as “the most comprehensive project ever undertaken in any type of neurological disease.”  -Jeff Rothstein

Tsun, then 62, started taking prednisone and methotrexate, two drugs that usually deliver PMR relief after a bit of dosage juggling and side-effect managing. But Tsun decided after six months to stop taking them. He feared that they were causing a new problem with slurred speech. Soon thereafter, his body began making too much saliva, leading to coughing fits and drooling.

Over time, his slurring problems grew worse, and he started breaking out now and again into boisterous laughter at inappropriate moments.

Tsun felt like he had seen this symptom mix before. A pulmonologist with a practice specializing in internal medicine, he had cared for perhaps half a dozen patients over the years with amyotrophic lateral sclerosis (ALS), the degenerative and deadly neurological disorder that many people know better as Lou Gehrig’s disease, after the famous baseball star who died from it in 1941.
Tsun’s ALS patients had also exhibited muscle stiffness, twitching and slurring. He now started wondering if his problems would turn out to be early steps in a frightening journey of physical decline, with leg and arm muscles growing weaker and weaker to the point of total failure, and the muscles he needed to speak, swallow and breathe following suit in short order.

“It was a very sad illness to see,” Tsun says. As a physician, all he could do was be supportive and offer palliative care.

After making this tentative self-diagnosis, Tsun retreated into a shell of denial. He did not share his worries with his primary care doctor, nor did he seek out a specialist who might confirm his suspicions once and for all.

“I was hesitant to seek help,” he says. “I knew that the prognosis was poor.”
It was Tsun’s wife, Betty, and the couple’s grown son, Matthew, an attorney, who coaxed him out of that shell. They argued that no physician could be objective when it came to a self-diagnosis like this one, and Tsun had to concede they had a point.

But when he did go see a neurologist in the spring of 2014, it turned out that his diagnosis was on the mark. Soon after that, the pulmonologist-turned-patient arrived in Baltimore to see Nicholas Maragakis, co-medical director of the ALS Clinic at Johns Hopkins.

“I was devastated,” Tsun says.

An Ambitious Project

At the moment, there is little that ALS clinicians can offer a new patient in the way of prognostic details. ALS tends to strike people in their late 50s and early 60s. Six in 10 victims are men. Nine in 10 are white. Most patients will succumb to the disease in three to four years. Others die much more quickly. A lucky few manage to hang in there—one in 10 survives for 10 years, and one in 20 makes it to 20.

Clinicians like Maragakis are unable to predict early on which new patients will land on which survival curve. Nor can they give patients reliable warnings about which mix of symptoms is likely for which cases, or how speedy and severe any individual’s decline will most likely turn out to be.
“When patients come in here, they are in a very difficult place,” Maragakis says. “They are full of questions about what’s going to happen and what they can do about it, but for the most part, they are asking things that at this point we are unable to answer in a definitive way.”

It has been like this for nearly two centuries now. Back in 1824, the Scottish surgeon and philosopher Sir Charles Bell was the first to describe a condition whose characteristics match those of ALS. It was 1874 when the French neurologist Jean-Martin Charcot gave the disease a name and pinpointed its cause in neurological problems of a mysterious nature.
It would be wildly inaccurate, however, to say that nothing has been learned about ALS over that long stretch. In fact, the important discoveries from the last few years alone are way too voluminous to catalog here.

Here is the big frustration in ALS circles: that knowledge has not yet turned into clinical breakthroughs that make a big difference for patients. Just one drug, riluzole, is approved for ALS care, and it is of modest value, helping patients live for five or six extra months.
Is there any hope on the horizon that this state of affairs might change at last?

The short answer is yes. There is a palpable sense of hope in ALS science circles these days. And that optimism very much includes a fingers-crossed suspicion that treatment advances are just up ahead on the research horizon.

The excitement is fueled in part by important new discoveries. In recent years, scientists have pinpointed a key genetic cause of the disease and begun sorting through, to an unprecedented degree, the way that mutation plays out inside the brain’s motor neuron cells.

Another source of real optimism is Answer ALS, a new undertaking headquartered at the Robert Packard Center for ALS Research at Johns Hopkins. Over the next three years, that venture will build a gigantic new information repository with highly detailed data and images from 1,000 patients at five top clinics around the country.

One indication of its prospects: More than $20 million in private financing to support the project has been raised in impressively short order.

Neurologist Jeffrey Rothstein, founder and director of both the ALS Clinic and the Packard Center at Johns Hopkins, is also the architect of this initiative. To hear him describe it, Answer ALS is aiming to spark a revolution in the way scientists look at this and other neurodegenerative diseases—by bringing every scrap of new, 21st-century medical technology and scientific knowledge to bear on solving the remaining mysteries of the disease and developing treatments that really work for patients.

Not So Rare

Like many other ALS patients, Curtis Brand, 71, did not hear any alarm bells three years ago in the early days of his encounter with the disease. At first, the weakness in his knees and lower back seemed a minor annoyance. He tried a round of physical therapy. Then came surgery to straighten out a hammertoe.

Brand and his wife, Judy, started to feel genuine alarm when Curtis’ recovery from that foot surgery progressed at a snail’s pace. Soon thereafter, Brand exhibited a kind of twitching under the skin known as fasciculations.

“I’m much more confident now that ... we will be able to make a dent in ALS in the coming years, and perhaps even cure it.” - Nicholas Maragarkis

“I’m much more confident now that ... we will be able to make a dent in ALS in the coming years, and perhaps even cure it.”
- Nicholas Maragarkis

They went to see a neurologist and then traveled to Baltimore in June 2014 to see Maragakis at the ALS Clinic. He is the one who confirmed that Brand has ALS.

Judy recalls the situation at the time of diagnosis as one of “total uncertainty” for her and Curtis. “You go online, and you try to find anything you can use,” she says. “But nothing we have done has slowed this down.”

Nonetheless, Curtis credits Maragakis with doing a remarkable job of helping him and Judy deal with their journey. Every time they leave his office, Curtis says, they do so feeling better about their situation, thanks to his warm smile and his first-rate bedside manner. They also trust that he will never serve up “false hope.”

At any given time, 30,000 people in the United States are living with ALS. About 6,000 new cases are diagnosed every year, roughly one every 90 minutes. Epidemiologically speaking, the prevalence of ALS is measured at two in 1,000, or 0.2 percent of the population. That number makes it tempting to toss around the word “rare—but that’s not a word Rothstein likes to hear.
“Is one in 500 really that uncommon?” he asks. “Don’t we all get to know at least 500 people in life? At some point, almost everyone will know a family member, a friend or, at the very least, a friend of a friend who is touched directly by this disease.”

A “Multi-omics” Approach

Answer ALS aims to take the science of the disease and move it, quite quickly, into the vanguard of 21st-century medicine. There, familiar and futuristic-sounding buzzwords will come into play—personalized brain medicine, for one, along with big data and machine learning. Rothstein, the co-director of Answer ALS, ticks off a string of –omics that will be in the picture too—genomics, proteomics, metabolomics and more.

“I call it the multi-omics approach,” he says.

But the big idea behind Answer ALS isn’t all that complicated. The best clinics and labs in the land are going to gather up every single image and scrap of information those 1,000 patients have to offer. The result will be a database so chock full of detail that there are multiple hard drives of data on every individual patient.

With help from big-data experts in the private sector, Answer ALS scientists will sort through all that information in search of patterns that reveal newly discernable disease phenotypes, suggest productive lines of scientific inquiry and lead the way, at long last, to breakthroughs at the bedside.

This mix of “big data, comprehensive biological analytics, technology and science would not have been possible a decade ago,” says Clive Svendsen, director of the Regenerative Medicine Institute at Cedars-Sinai Medical Center and co-director with Rothstein of Answer ALS.

At this point, a few words of caution seem advisable. Many senior scientists in ALS circles might well experience a touch of déjà vu when it comes to all the excitement surrounding recent discoveries. Back in the heady days of the 1990s, too, it seemed like important breakthroughs were just up ahead on the research horizon.

The first time ALS was linked to a genetic mutation was in 1993. The guilty party was a gene called SOD1, which, when normal, produces an enzyme that helps the brain stay healthy over time. That enzyme is missing when the mutation is present.

This discovery sparked a flurry of research activity, including the development at Johns Hopkins of a mouse model for the SOD1 mutation. That model soon became the testing ground for lots of promising new medications, including the aforementioned riluzole, which was derived from research done in Rothstein’s lab and became, in 1995, the first ALS drug to win FDA approval.

No one would have predicted two decades would go by without a major treatment advance.

Thomas Lloyd was earning his M.D. and Ph.D. at Baylor College of Medicine in those years. He is now a Johns Hopkins neurologist who studies ALS in Drosophila melanogaster, the fruit fly.

“I can remember being in seminars where people at the front of the room were saying things like, ‘Now that we have this gene, it’s just a matter of time before we have a treatment,’” Lloyd recalls.

In the years that followed, however, scientists learned that the SOD1 mutation comes into play in just a tiny number of inherited, or familial, ALS cases. (The bulk of ALS cases are actually “sporadic,” not inherited.) In the two decades that followed the approval of riluzole in 1995, more than 100 other drugs have been tested in the SOD1 mouse model.

“Maybe two dozen of those drugs did well enough to make it into human trials,” Rothstein says. “And in the end, not one of them worked in patients. One thing I can say for sure today is that I don’t want to spend another 20 years getting results like that.”

© Johns Hopkins Medicine