Slowing ALS: Medicine's Next Big Thing?

SAN FRANCISCO. (KFSN) -- This year, more than 5,600 people in the United States will be told they have ALS. Within five years, many of those people will be robbed of their ability to work, to walk, to even talk. Until one day, they won't even be able to breathe. Now there may be new hope to slow the effects of this devastating disease.

ALS patient Mary Pat Murray told Ivanhoe, "I can carry on a conversation. I can eat. I can drink. I can have a normal (life), as normal as my life is now."

But Mary Pat Murray knows what ALS will eventually do to her.

Also known as Lou Gehrig's disease, ALS destroys the nerve cells, eventually attacking every muscle in the body.

Neuroscientist and Neurologist at Washington University School of Medicine in St. Louis, Azad Bonni, MD, PhD, FRCPC, explained, "It hits people in the prime of their careers, the prime of their lives. So, it's quite devastating."

Right now, there is only one drug, Riluzole, approved to treat ALS, but Dr. Bonni says it's ineffective. His research suggests that a heart drug may slow the destruction of nerve cells in ALS patients.

"We have found one of the targets that may be important in the disease, is an enzyme that actually has been used as a target for drugs in heart disease," said Dr. Bonni.

In ALS, cells that support nerve cells are more active than they should be and actually cause nerve damage. Studies in Bonni's lab show the drug Digoxin targets the support cells, slowing them down. Mice in his lab lived 20 more healthy days, it doesn't seem like a lot, but in human time, it is!

Dr. Bonni said, "We're looking for ways to not only extend life, in these types of diseases but also improve the quality of life."

Murray knows it might be too late for her, but with each new drug, comes new hope for other people not yet diagnosed.

Drugs that target support cells may turn out not only to be beneficial for ALS patients but also those suffering from other neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases, but researchers stress more testing will need to be done before such drugs can be tried in patients.

Slowing ALS: Medicine's Next Big Thing? -- Research Summary

BACKGROUND: ALS, or amyotrophic lateral sclerosis, was first discovered by a French neurologist Jean-Martin Charcot in 1869. It is a neurological disease that rapidly progresses and kills motor neurons, causing muscle weakness and atrophy. Commonly referred to as Lou Gehrig's disease, there are over 12,000 people in the United States diagnosed with the disease and it is one of the most common neuromuscular diseases around the world. Many ALS patients die from respiratory failure due to their diaphragm collapsing within three to five years from the onset of symptoms. There are two types of ALS, sporadic and familial (or genetic). Only five to 10 percent of ALS cases are inherited, while 90 to 95 percent develop the disease with no known associated risk factors. (Source: http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_ALS.htm, http://www.alsa.org/about-als/what-is-als.html)

TREATMENTS: Currently, the only medication approved by the FDA for ALS is Riluzole, a medication that can alter the progression of the disease introduced in 1995. There are a few side effects associated with Riluzole, including dizziness and risk of liver damage, but doctors hope that future research will develop better medications or find a combination that reduces the effects. Physical therapy is also used to help with pain and mobility as well as improving a patient's quality of life by giving them the independence to move around. Additional support and care is a necessity for ALS patients. Speech therapists, nutritionists and caregivers work in tandem to help patients who have muscle atrophy preventing them from eating or speaking properly. ALS patients retain their cognitive abilities, despite the complications from the condition, and can become depressed or anxious about their disease, so a solid support system is essential in treating ALS. (Source: http://www.alsa.org/about-als/facts-you-should-know.html, http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_ALS.htm#287704842, http://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/basics/treatment/con-20024397)

NEW TECHNOLOGY: Researchers at Washington University School of Medicine in St. Louis have been testing a medication called Digoxin, a medication typically used in heart patients, in the treatment of ALS. Led by Azad Bonni, MD, PhD, a Neuroscientist and Neurologist at Washington University, the study used mice models with a mutated gene that caused symptoms resembling ALS, including paralysis. Doctors found that a protein located in nervous system cells called astrocytes, sodium-potassium ATPase, was in high quantities in the ALS mice. Dr. Bonni and his team treated the mice with Digoxin, which works by inhibiting the sodium-potassium ATPase. Mice treated with the drug lived on average 15 percent longer and were healthier. (Source: Azad Bonni, MD, PhD, http://www.dddmag.com/printpdf/news/2014/10/heart-drug-may-help-treat-als-mouse-study-shows)

For more information on this report, please contact:

Judy Martin

Director, Media Relations

314-286-0105

martinju@wustl.edu

Slowing ALS: Medicine's Next Big Thing? -- Doctor's In-depth Interview

Azad Bonni, M.D., Ph.D., Neuroscientist and Neurologist, Professor of Neurobiology and Chairman of Anatomy and Neurobiology at Washington University School of Medicine talks about a drug that could help slow the effects of ALS.

Interview conducted by Ivanhoe Broadcast News in April 2015.

What is ALS?

Dr. Bonni: ALS is amyotrophic laterals sclerosis. It's also known as Lou Gehrig's disease and it's a disease that leads to progressive paralysis of muscles. It's a neurodegenerative disease that affects a person's mobility and eventually their ability to breathe. It's nearly uniformly fatal, so in most cases patients die within five years.

Is there only one drug that's approved?

Dr. Bonni: There's one FDA approved drug and it may extend life by two months.

Is there a big emphasis on the quality of life rather than just life?

Dr. Bonni: Absolutely, I think that's really important. The goal is to not only extend life in these types of diseases but also improve their quality of life during that extension.

Are the numbers of ALS going up?

Dr. Bonni: I think that there may be more appreciation for the diagnosis. Unlike the case for autism where there's been clearly an increase over the last few decades, ALS is probably stable in terms of numbers. I think there's been more appreciation for the disease.

When you see someone with ALS, you know they're being robbed of their muscle function. Their brain is still there, and active, but they just can't get things out anymore.

Dr. Bonni: I think that's one of the problems; it hits people in the prime of their careers and the prime of their life. It's quite devastating. Although, the numbers are not as high as is the case for Alzheimer's disease, which is much more common, still ALS has a major effect on people and their families. The effect on society is even more than just the numbers. There are about 30,000 patients with ALS in the United States.

From diagnosis to death, it's five years and in that time you watch a rapid decline?

Dr. Bonni: Absolutely, and often it's less than five years but within five years almost all patients succumb to the disease.

You have found a new drug that can stop the progression?

Dr. Bonni: We have found a drug that has potential for treatment of ALS. It's still in the very early days but through an unexpected sort of discovery that we've made in the laboratory, we have found that one of the targets in the disease is an enzyme that has been used as a target for drugs in heart disease. It immediately told us to think about a drug that's been used in congestive heart failure. That drug turns out to work very well in cell culture models. That's just in cell culture. But we also know that if we take away the target of the drug through genetic engineering in mice that prolongs life in a mouse model of ALS.

When it prolongs life does it also stop the disease?

Dr. Bonni: It doesn't stop the disease. Instead, it seems to slow the progression of the disease. It wouldn't be a cure but it would significantly slow the progression.

At what rate would it slow it? Would it take it from 100 percent progression to 50 percent?

Dr. Bonni: The way that we are looking at it is that in the mouse it extends the life of the mouse by 20 days, which may not seem like a lot but a mouse doesn't live as long as a human. It actually would be quite significant, increasing lifespan by over 13%. We also find that the quality of the mouse's life improves, they're much more mobile. It's not just extending life but also the health span of the mice. This is not with a drug. This is with when we take out one copy of a gene that is the target of this drug. We still have to do experiments with the drug.

What's so nice about this is this is a drug?

Dr. Bonni: The drug works really well in cell culture. We've already tested it in cell culture where we take the motor nerve cells that are targeted in this disease, and we place them in culture. We add the drug together with other cells that are really important for this process. We find that the drug prevents the degeneration of motor nerve cells in culture and it's a very strong effect there. We're optimistic that from there we should go forward with testing in animal models and ultimately if it works there, to clinical trials.

How soon could that be?

Dr. Bonni: I think it will take some time. We're talking a few years.

In your study you're also talking about ATP? What is that?

Dr. Bonni: That's the target of this drug. It's an ATPase, a pump. It's a pump that's targeted by this drug. This drug is not in the nerve cells but in support cells, they're called astrocytes. It's in those cells and what that pump does is maintains the correct potential across the membrane. All cells in the body need that kind of potential for proper function. The pump ejects sodium from the cell in exchange for potassium. And it's an ATPase because it uses up ATP, which is the fuel of the cell.

What is the different function with an ALS patient with sodium and the potassium?

Dr. Bonni: We're finding that in the support cells, these astrocytes, the pump is more active than in normal cells. Because it's abnormally active, it's a higher level of activity and that drug inhibits the activity of the pump.

With this research that you're doing, could you get to the heart of what causes ALS and how it works in the body?

Dr. Bonni: It's getting to the question of how ALS works. There have been recent studies that show although the cells that degenerate are these motor nerve cells in the spinal cord, which innervate the muscles, a lot of the harmful effects are in the astrocytes, these other cells that are right next door to the motor nerve cells. These cells normally support the motor nerve cells by providing nutrients and making sure that the neighborhood of the nerve cells has the right mix of electrolytes. In ALS, the astrocytes are turning from being good guys into bad guys and they are producing harmful effects. We were looking for targets and players within the nerve cells that would be important. And we had some evidence from other studies so we started going in to it thinking that we would identify a mechanism, a target within the nerve cells. But unexpectedly we found the target in astrocytes, this pump in the astrocytes. We weren't looking for this pump. We were actually looking for a completely different protein but our antibody that we used that recognizes other protein recognized this pump. But it wasn't supposed to do that. Normally we don't pursue these kinds of things but it really jumped out at us in the experiments and we had to pursue it. We spent several years on this experiment and found that it is important.

When you were first starting out, would you recognize the wrong thing and try it again?

Dr. Bonni: It was interesting because we had seen that "wrong" protein come up in different situations. We were looking for a stress response in the nerve cells. We had tested it in culture and also in the spinal cord of mouse models of ALS. We kept seeing this "wrong" protein. Most of the time we don't pursue these types of things because it doesn't lead to anything, but this time it was so clear that you could see it. But it wasn't there in the mice that didn't have the disease. That protein that we identified isn't the pump itself; it's a different protein that interacts physically with this pump. That's how it started. It took us longer because the first protein we identified was just a protein that doesn't have enzymatic activity. We then went step by step and it led us to the pump. Then when we found the pump I was really excited because I'm also a neurologist and a physician. My brother is a cardiologist, a heart doctor, so I knew that this pump is a target for medications in cardiology and it's been used a lot. I was really excited about it because I thought immediately that this could be a really important clue for not just understanding the disease but potentially for treatment down the line.

If you would like more information, please contact:

Judy Martin

Director, Media Relations

Washington University School of Medicine

martinju@wustl.edu

314-286-0105