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ALS Q&A: What's On the Horizon?

neuron

By Brenda Goodman
WebMD Health News

The ice bucket challenge has become a fundraising juggernaut for a rare but devastating disease: amyotrophic lateral sclerosis, or ALS.

ALS strikes without warning, gradually destroying nerves. This robs people of their ability to move, speak, and eventually, breathe. The average survival time for patients given a diagnosis of ALS is just 3 to 5 years. At any given time, there are about 30,000 Americans living with the disease.

The ALS Association says the ice bucket challenge has raised nearly $ 95 million — and that’s just since late July. Over the same time period last year, the association had raised $ 2.7 million.

Along with all that money, questions are being raised about how the sudden windfall will be spent and whether it could finally bring some answers that might lead to new treatments.

Jonathan Glass, MD, is a professor of neurology and pathology at Emory University in Atlanta, where he directs the Emory ALS Center.  He’s involved in a first-of-its-kind study that is injecting neural stem cells into the spinal cords of patients with ALS to see if the cells can repair their damaged nerves.

We asked him about what all this new money for ALS means, and what’s on the horizon for patients.

Q: What do you think of the ice bucket challenge?

A: It’s crazy. It’s absolutely crazy. We’re hoping for some money from that. It means two things, really. It puts a huge infusion of cash into research projects that have already been designed but have never had enough money to fund. The other thing is the awareness. Somebody pointed out to me the number of hits on the Wikipedia page for ALS has just skyrocketed over the last several weeks. And I think that’s because people are saying, ‘What’s this all about? Why am I doing this?’ It may be fun, but I think a lot of people are asking questions.

In terms of funding for research, I think it is awareness that makes a big difference. All this public awareness raises money. Hopefully, the money will be put in the right hands and put in the right place, and it will come up with something.

Q: What is still unknown about ALS?

A: Everything is unknown.

We know what it does. We know what it can do. We know how to describe it. But I can tell you that we have no idea why it happens.

Even in the 10% of people who have a familial disease, meaning it runs in families — and now we can identify the gene mutations that cause that disease — we still don’t know how those familial mutations actually cause nerve degeneration.

So, I mean, the best example of this is back in 1993, the first gene for familial ALS was described and discovered for superoxide dismutase 1, or SOD1.

This is a protein that’s present in all cells. It has to do with detoxifying, or what are called the oxidative stress cells. You see a lot of it in the liver and all over the place. But for some reason, mutations in this gene cause ALS. So very quickly, there was a lot of research into this. There were animals made that carried the human mutation and developed a disease that looks like human ALS. They develop age-related weakness and death, but in fact, after 20 years of studying this gene and studying these animals and all the models that have been made, we still argue and debate about how mutations in this gene can cause this disease.  So there’s your example right there. We have a target. We know what it is, but we have no idea how it works.

The latest one is c9orf72. It’s probably the most common mutation that causes genetically based ALS, but we don’t know how it works.

And that leaves us with the 90% of people who have non-genetically based ALS, meaning you don’t inherit it from one of your parents. You can go through the literature and you can find all kinds of claims about what causes ALS, from oxidative stress, to abnormalities in the inflammatory system or the autoimmune system. Some people think trauma may lead to the disease.  There are people that think pesticides may have something to do with it. The reality is we just don’t know.

We don’t even know if this is one disease. It may be multiple diseases that kind of coalesce into a similar clinical picture.

If you came to my clinic and looked at 20 patients with ALS, you might argue that the patient in room 1 has a very different disease than the patient in room 3. How can you call it the same disease? These are young people or old people, slowly progressing or rapidly progressing. Some people have difficulty around the mouth and tongue area and they can’t speak or swallow, or other people who are absolutely perfect there, but they can’t walk. But we call it all the same disease.

So there are enormous numbers of questions.

Q: What’s coming down the pike with treatments?

A: There’s one drug on the market called Riluzole. It’s been around since 1995. It slows the disease down a little bit, probably by about 10%. So if you look at large groups of patients on the drug and compare them to patients off the drug, the groups on the drug live about 10% longer, in general.

Many patients will go and try experimental treatments or even unproven alternative therapies because they’ll say, ‘Well, Riluzole doesn’t work.’ But, in fact, it does work. It’s the only one that works. It just doesn’t work very well.

That doesn’t mean we haven’t tried. There have been more than 80 to 100 clinical trials of other types of drugs in ALS. These are really well-done clinical trials by very well-meaning investigators, and unfortunately, none of them have worked.

Having said that, it doesn’t slow us down very much. And we’re looking toward new types of therapies.

What’s most exciting on the horizon is our new understanding that there may be other genetic factors, other than just the single genes, that might cause the disease in families. There may be genetic burden or genetic risk factors that are more subtle that need to be addressed.

And that’s going to be addressed probably on a multinational, worldwide scale when we launch the whole genome project. We’re going to do whole genome sequences in 15,000 patients and 7,500 controls and again look for the subtleties and the differences in the patients and the controls.

(In) clinical trials typically, we say, “This group of patients [has] this disease.” But what if this was not one disease? What if this was 10 diseases? And so we’re trying a drug that might work on one of those 10 diseases, but we’re trying it on nine diseases that it won’t work on.  This has been addressed in cancer. We now test patients with breast cancer to find out if they’re estrogen receptor positive or negative. And we do that because we know they will respond to different types of treatments in very different ways. We haven’t reached that point in ALS yet. We’re looking for things called biomarkers to see if we can separate patients who have different markers. We need to group these patients better to see if we can kind of approach them differently with different types of therapeutics.

There are some gene-based therapies going on.

When it comes to other kinds of drugs, unfortunately, the well right now is dry, and we need to refill it with new ideas and new approaches.

Q: How’s your stem cell trial going?

A: We’re moving forward. We’ve finished our phase 2 trial. We’re moving towards a phase 3 trial to see if it really works. We’ll start that earlier next year.

We’ve operated on a total of 30 patients so far. Six of those patients have had two surgeries, one in the lumbar [lower back] region and one in the cervical [neck] region.

The most those patients have gotten is 16 million neural stem cells: 8 million cells in the cervical region, 8 million in the lumbar region of the spine. They tolerated it well. And it added up to a total of 40 injections, which we didn’t think we could do when we first started, but now we know the spinal cord can tolerate it. Now we want to expand it to other centers and see if we can do it in a larger population to see if it actually works. So that’s pretty exciting.

Q: Do you have any sense of whether the stem cells are helping? Two of the stem cell patients we’ve spoken with have reported that their symptoms got better for a time, but then seemed to return. They also say their disease progression is slower than it was before the trial. Have you been able to measure those improvements?

A: First let me say that’s not an unusual response in any clinical trial. You have a devastating disease that is going to kill you, and you’re going through a major surgery. You think, “I’m going through all these risks.” You feel like it’s got to help.

But I’m not sure that’s the answer. There may be something to what they’re experiencing. But we haven’t been able to measure the improvement that patients are describing. But it’s not unique to this trial that patients are describing this.

Q: You did have one patient, Ted Harada, who has shown marked improvement after getting the stem cells injected in his spine.  He told us there was a moment with you in your office when you had retested him, rechecked all his progress, and you sat down and said, “You know, all my patients die. And I’ve always thought my whole career that if I could help just one patient get better, then all the work would be worth it. Now [that] I’ve helped one patient, instead of having answers, I just have more questions.” How do you explain what happened to him?

A: Yes, it’s true. But I’m not ready to retire yet, even though I’ve helped one patient.

I don’t know why he’s better. Based on his response to the trial, we’ve started a new trial which is going on now called the immunosuppression trial. The question with Ted was: Did the stem cells do it, or did the immunosuppression do it?

All these patients who get stem cells have to be immunosuppressed so their stem cells aren’t rejected by the immune system. They get standard anti-rejection medications that are given to kidney transplant patients and liver transplants patients. We did that because we thought that was the right thing to do. We never expected it would be something that was going to make them better. So when Ted got better, so spectacularly, one of the questions that came up was, “Is it possible that the drugs we gave him actually made him better?” So we designed this trial, it’s in full swing, of 30 patients. We’re seeing whether we can reproduce Ted in one of those 30 patients.

We’re measuring all kinds of immune functions at the same time. Taking samples of spinal fluids, blood. So if we make a patient better, we’ll know what we did to make that patient better, which would be fantastic.

 

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