Hunt for ALS cure may offer insight on other diseases

The long trail of research into amyotrophic lateral sclerosis is littered with disappointment.

Decades of research have resulted in only one drug treatment for the terrible disease, and that drug only offers a few months of extra life, at best. Meanwhile, study after study has ended in failure — recently a drug that just a year ago seemed promising showed no benefits in a late-stage clinical trial.

And yet, scientists say, every failure has added to the complex fabric of understanding of not just ALS — a neurodegenerative disease that usually kills its victims within five years — but a whole host of similar conditions that also have long eluded treatment. ALS research may just one day open the door to treating Parkinson’s disease and Huntington’s disease, and the Holy Grail of neurological disorders: Alzheimer’s disease.

“The hope is we’ll wake up one morning and find out that all this knowledge has expanded to a point that the diseases make sense,” said Dr. Jonathan Katz, director of neuromuscular research at the Forbes Norris MDA/ALS Research Center at California Pacific Medical Center in San Francisco. “The problem is you feel like you’re digging for buried treasure, only you don’t know how deep it’s buried. It looks like we’ve gone a long way in understanding ALS, but you have no idea how far you have to go.

“It can feel depressing a lot of times,” Katz said, “but at other times, very hopeful.”

Amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease for the baseball legend who died of it in 1941, is a profoundly devastating condition that causes the brain cells that control movement to die, leaving patients increasingly paralyzed, often over a very short period of time.

The disease is always fatal, and most people die of respiratory failure as they lose the ability to breathe on their own. There are some known genetic causes of ALS, but most cases are spontaneous, meaning they occur in people seemingly at random. Some scientists have noticed an apparent increased risk of ALS in certain athletes, but it’s unclear how big of a risk that is, or why.

There is only one drug, called riluzole, approved by the Food and Drug Administration specifically to treat ALS. Riluzole can slow progression of the disease and may delay the need for breathing assistance, but the drug only gives patients an extra few months of life, at best.

In the past decade, doctors have found a half-dozen treatments that, while not specifically targeted to ALS, can alleviate some symptoms of the disease and make patients more comfortable.

Perhaps most notably, scientists have developed two breathing mechanisms that can prolong the lives of ALS patients. One is a mask that can be worn part time and forces air into the lungs without the need for a ventilator, and the other is a type of pacemaker for the diaphragm that strengthens the muscles used in breathing.

But these treatments don’t treat the disease itself, and they can’t stop or even slow the death march of neurons. And that’s the game-changer scientists are doggedly hunting.

“Even if it’s not going to cure the disease, if we can find something that adds 10 years of life and delays things, that’d be great,” said Dr. Steve Finkbeiner, a senior investigator at the Gladstone Institutes in San Francisco.

Promising threads of research include stem cells, which scientists believe may be able to replace some of the insulating cells, known as glial cells, that protect neurons and are damaged in ALS and other neurodegenerative disorders. Ideally, doctors would like to find a way to replace the neurons affected by ALS, but regrowing brain cells is complicated.

As things stand now, the state of ALS therapy is similar to cancer 50 or more years ago, said Dr. John Day, a neurologist who is in the process of building a neuromuscular program at Stanford University.

“It used to be when you got diagnosed with cancer, it was curtains — hang the black crepe. Now there’s this expectation that you can treat cancer. But we’re still back in the old days when it comes to ALS,” Day said.

ALS is, technically, a rare disease in the United States, afflicting about 30,000 Americans at any given time. But it shares many characteristics with more common diseases like Parkinson’s and Alzheimer’s.

In all of these diseases, neurons are under attack, and scientists have found unnatural buildups of mutated proteins. It’s believed that all of the conditions are caused to some degree by inflammation, although the exact process is not clear.

What sets them apart is often the types of neurons that are killed — in ALS, it’s motor neurons that control muscles; in Alzheimer’s, it’s neurons responsible for memory and cognitive function, for example.

There are also different types of proteins involved in the toxic buildup in different diseases.

But there are enough similarities that many scientists believe it’s possible to find a drug that could provide some benefit to multiple diseases. And ALS, for a variety of reasons, is a natural target to study.

Because ALS is so deadly, the FDA has relaxed rules for conducting clinical trials into new drugs, which means it may be faster and cheaper to study ALS therapies than something like Alzheimer’s.

The connection to Alzheimer’s — which is expected to have a strangling effect on the national health care system in the next couple of decades as the baby boomer generation gets hit with it — has meant more research is going into ALS than would otherwise, given how relatively few people it affects.

At Gladstone, scientists are developing a line of ALS-affected neurons, which will help them better study the disease process in the lab. Those neurons are being manufactured from stem cells taken from patients with ALS that are induced to become brain cells.

Gladstone researchers also have created a tool they call a “robotic microscope” that allows them to track living neurons — for example, the ALS-affected neurons — over long periods of time. “It’s been a real eye-opener for us to have this form of imaging,” said Finkbeiner. “We can see all the interactions occurring while the cell is alive, and it’s quite complex.”

But even as scientists develop better tools and a deeper understanding of how diseases like ALS work, Finkbeiner wonders if that’s even a necessary goal.

In recent years, he said, he’s spent more time with ALS patients and their families and has come to understand just how desperate they are for any kind of treatment — even a few more years or months of quality life would be a dream.

“If we have to scale Mount Everest to solve this disease, how long is that going to take?” he said. In other words, it may be that seeking all of the answers to the neurodegenerative mysteries is a luxury scientists can’t afford.

“We’re just looking for something that seems to work, and we can figure out why later on,” said Jim Barber, a 68-year-old Walnut Creek, Calif., man who was diagnosed with ALS in 2006 and is a member of the California ALS Research Network.