The latest in ALS research at Ohio State

Gail Hogan: Thank you for joining us for Health Talks. I'm Gail Hogan and physician scientist, Dr. Stephen Kolb, is here to tell us about the latest research for Lou Gehrig's disease or ALS. Dr. Kolb, thank you for being here.

Stephen Kolb, MD, PhD: Thank you for having me.

Gail Hogan: What is ALS?

Stephen Kolb, MD, PhD: Well, ALS is a neurodegenerative disease, so a disease where neurons are starting to die before they're supposed to, and in the case of ALS, they are motor neurons. So, motor neurons are the very specialized cells that connect your brain to muscle, so anything that you do, whether it's just moving around or whether it's speaking, breathing, or swallowing, that involves a connection of your brain to muscle. In ALS, motor neurons die and people become progressively weak. They become less and less able to be independent and move around. Ultimately, it affects speech, swallowing, and breathing.

Gail Hogan: What does ALS stand for?

Stephen Kolb, MD, PhD: It's an old term, so ALS stands for Amyotrophic Lateral Sclerosis.

Gail Hogan: Wow.

Stephen Kolb, MD, PhD: Yeah, it's a mouthful.

Gail Hogan: No wonder you say ALS.

Stephen Kolb, MD, PhD: That's why we say ALS. I think that it actually has an anatomical description. Amyotrophic means muscle loss, and lateral sclerosis, believe it or not, is because there was scarring in the spinal cord back in the late-1800s in people who had ALS, and when it was first described, they called it amyotrophic for muscle weakness, lateral sclerosis for this loss of neurons in the spinal cord. We call it ALS. I mean, it's known as Lou Gehrig's disease because he was a very prominent, famous person, who had the disease. It's actually known as Charcot's disease in Europe it's known, and there have been many more athletes who have had ALS over the years as well, but ALS is probably the most recognizable now.

Gail Hogan: What are symptoms of ALS, and how does it treat it?

Stephen Kolb, MD, PhD: Yeah. Well, I wish it was treated better. ALS is a disease of progressive weakness, so as opposed to a sudden onset, for example, a stroke where all of a sudden you become very disabled, in ALS, it's something that starts much more subtly, and often it takes about a year for people to finally receive the diagnosis, because you don't wake up one day with all of the signs and symptoms. So, the signs and symptoms are weakness primarily, but it is progressive, and it does not come and go. And it tends to start in one place in the body and then spread slowly to other parts of the body. Then, as I said, it does ultimately affect the swallowing and breathing muscles.

And so, people end up dying of respiratory insufficiency, or they can die of complications from problems with swallowing if those aren't tended to. I'm impotent, as a clinician, to stop the progression of ALS. It's been a difficult disease. Like Alzheimer's and Parkinson's, other neurodegenerative diseases, it's very hard to know why that's happening, but I'm very proud and passionate about the multidisciplinary care, which means a whole bunch of providers in one spot who see people who have ALS at Ohio State, who try and to help anticipate problems before they happen and support them through that journey, all the while fighting like heck to understand the why and how to stop it.

Gail Hogan: Are there risk factors with this?

Stephen Kolb, MD, PhD: The number one risk factor is age, so it affects people who are, in general, in their sort of mid-50s to 60s or so, a little bit earlier than the other big neurodegenerative diseases, but it's a very wide sort of distribution there, so age is the number one thing. People who serve in the US military are twice as likely to have ALS as other people. It is, of course, anecdotally known that people who are athletes, and people who tend to be otherwise healthy tend to develop ALS for whatever reason. And sometimes I wonder if being well-endowed in their motor neurons puts them at risk in some way, but to be honest, things like pesticides, environmental exposures, all these other things, it's very hard to nail down those exact things. I would say what we've learned lately that has really been helpful is that there's definitely also a genetic predisposition, and there's definitely more genes associated with ALS now than there ever were, so I guess I would say age is the number one, and then lots of other things that we don't understand.

Gail Hogan: You mentioned this gene as the newest discoverer, which is why you are in research, because you're excited about it.

Stephen Kolb, MD, PhD: Yeah.

Gail Hogan: I know you are. Can you explain what this study is about and how it can be helpful to patients?

Stephen Kolb, MD, PhD: Well, our recent study has created a model for one of the genes that was more recently discovered to be associated with ALS. That gene name is KIF5A, which is just a silly kind of name, but what that gene encodes, genes make proteins, and proteins are the little machines. This is a very cool gene, because it makes a protein that shuttles things along motor neurons, so if you imagine my motor neuron is in my spinal cord, but it goes all the way out here. LeBron James has these really long motor neurons. How do you get things down that axon, that long tube? And that's what this KIF5A does. So when we saw that that gene had been associated with ALS, and by the way, our clinic was one of the clinics that provided the DNA for the discovery of that gene, but once we saw that that gene came out of it, we wanted to make a model system. And so, we were very proud that we have developed the first model system that people are now able to look at and ask this question, "Why? Why does that gene mutation result in ALS?"

Gail Hogan: So, now that you've discovered the gene, you have to figure out how it can be helpful to patients.

Stephen Kolb, MD, PhD: That's exactly right, and I think that there's really two ways of having, once a gene is discovered to be associated with ALS or any neurodegenerative disease, for example, it has two real important meanings. One is for the lab to help us understand the why. As I said earlier, we don't know why people get ALS. We are getting smarter to know that there are these genes that are associated with it, but we don't know why those gene mutations lead to it, and so those are questions that really can only be answered in the lab with different model systems that we've now contributed to. So, we have a plan, and we have collaborators that we are working with, of course, to try to understand the why. Why is it? What is it that it carries, for example? Since it's a little cool protein that carries things, what does it carry and what's different when you have this ALS mutation?

That is the kind of research that will help in this specific type of gene mutation, but I think it's very important to understand that these are basic principles too. So, we will probably learn things that generalize to just understanding how these motor neurons that don't divide that we've had. Mine are getting older all the time. They have to live for 100 years, and so how does that even happen normally? And so, this kind of research, while it may seem kind of nerdy and restricted to a very rare population, it has the potential to give us insights into how these cells work, which is what we really need to do. The second way that understanding a gene, what is going on, is that we can then attack it with gene therapy and other types of therapies, and that is really one of the things that I really couldn't say 10 years ago, because the progress in gene therapy was really not as advanced as it is today.

Gail Hogan: Are there certain people who are at risk? You mentioned sometimes athletes especially, people who are very physically fit, seem to fall into this category.

Stephen Kolb, MD, PhD: Yeah.

Gail Hogan: Anything else?

Stephen Kolb, MD, PhD: Yeah, no. I think that, certainly, as I mentioned, there's a genetic risk. So, definitely, once we understand that someone has ALS, everyone in clinic nowadays gets gene testing and helps us with that, so that if you are someone related to that person, who does not have ALS, and you have your genes tested and you have one of those associated variants, it's not a certainty that you'll get ALS, but your risk is definitely now very much increased. So, other than that, I feel that it's probably a wear and tear kind of thing. There's not maybe one thing that causes ALS. ALS is definitely a syndrome.

In other words, just like breast cancer is a syndrome, and then a physician and a researcher would do a biopsy, they do genetics, and so forth, and then ten women with breast cancer, two might receive this therapy, three might receive that, and so forth, we're getting to that point in ALS now where we are able to model the disease better than we could. We're able to understand that people who develop ALS are probably not at least initially starting ALS all in the same way. And so, the future is really that we're going to be treating these people with this, those people with that, and so forth. So I'm very much looking forward to contributing, and Ohio State is already contributing to that mindset so that we are not really treating everyone all the same.

Gail Hogan: What do nerve damage and aging have to do with this?

Stephen Kolb, MD, PhD: That is an awesome question. I mean, I think, as I said, aging is the number one risk factor. I like to sort of think that the task biologically of having this motor neuron survive for 100 years is a pretty big ask, that evolution has figured out and we're able to do. And so, any subtle change in that might end up causing a problem, so during aging, we all are subjected to wear and tear. There's sort of the use factor of things, and so I think that, for whatever reason, there's a threshold at which, at some point for some people, that then the disease begins, so what I like to think about is a row of dominoes that are kind of all set up and everything's fine, and then something is going to hit that first domino when it comes to that first motor neuron that is not well, and then ends up dying.

Then, things seem to spread, so once something hits that first domino, and then something else perhaps leads to that progression of disease. That would explain what we see in the clinic. People will come and explain that, "Well, it was just I got clumsy with my hand. It was no big deal. I went to physical therapy," or "I just sort of started tripping stuff with my feet," or "I started to slur my speech. It was very subtle. It was insidious and it's onset," but then it started to continue and go from there. We know that that is because it starts somewhere along the spinal cord, those motor neurons, and then it spreads from there. And so, I think that the progression of disease and the onset of disease are things that we're very interested in understanding.

Gail Hogan: And speaking of understanding, with this new gene and other things in research lab, you are finding more hope for people who have ALS?

Stephen Kolb, MD, PhD: Absolutely. I mean, obviously, the diagnosis of ALS is a diagnosis no one wants to hear, and we are very cognizant of that. But at the same time, my team at the Ohio State Clinic, we have a multidisciplinary clinic, which means we have, I think, eight or nine different providers who are all in one place, and we sit at a conference room, and in real time we talk about the people who are there. It's a pretty special place to support people who have ALS, even though we can't stop the disease. So, that is something that we're very passionate about, but I think that on the research side, what has given us real optimism is the fact that we understand more about the fact, more about the genetics of ALS, as I had mentioned before. In fact, we are one of the few clinics in the country that has a genetic counselor who is a faculty research person who sees every single patient in our clinic and collaborates with us on projects, who has helped with that.

We also have more optimism because of another disease, actually, and this disease is called spinal muscular atrophy. As the name denotes, it's also a disease of progressive muscle weakness. Only this one is a genetic disease that affects babies primarily, with work that has actually, much of it has occurred here at Ohio State. We now have gene therapies that are available for these kids, and so there's newborn screening, you get that screen and you find that your infant has this gene mutation, and you get gene therapy. Those, not only have we learned from spinal muscular atrophy, and much of that, as I said, is stuff that I've had the pleasure of being a part of on the research side, that has taught us that, not only can we change gene expression in a human being safely with gene therapy, something that we didn't really know before all of this, but we can also prevent them from getting weak.

So, it not only is changing gene expression because we know what the target is, but we can also help them in a major way. That is huge when it comes to ALS, because that takes off the table, "Well, is it safe to changing expression in the motor neuron with this gene therapy?" Yes, and so that is big news for being able to say, "All right. Well, maybe we're going to start having some wins here, and we're going to be able to have some successful gene therapies." In that regard, we are one of the few places who are doing gene therapy clinical trials in the country, and right now we have a clinical trial for one of those gene mutations, where we are one of the few in the country that are enrolling patients. Then, just recently, there was the first FDA-approved gene therapy for ALS for a specific, another gene that's there, because there's a list of genes now. That sort of speaks to the testament of our work here and my team's ability to do these things.

Gail Hogan: Can you explain the culture of the clinic when patients come to Ohio State?

Stephen Kolb, MD, PhD: I'd love to. That's something that we're very proud of. It's very clear that people who have ALS do better, both in lifespan and also, most importantly, quality of life if they're being served in a so-called multidisciplinary clinic. It is a team effort. When a person comes into the clinic, they are seen by everyone that they need to during that visit. They are offered any service that all of those providers have in the clinic or also outside the clinic, if needed. It's incredibly productive, because we, in real time, can say, "This person needs that. Let's try to get this going." My team and I really get very close to people who are going through this journey, and to have them help us with this is really a gift.

Gail Hogan: People watching this are going to want to know how they can be your patient or how they can be a patient at Ohio State.

Stephen Kolb, MD, PhD: Absolutely. There's a physician referral to our department for the clinic, and just simply say that motor neuron disease or consider motor neuron disease or ALS, and I think that that would get into either me or one of my awesome colleagues who see the patients with me side by side. People who are out there, who may not be able to come to Ohio State, they live farther out, they're still welcome to come and participate in our research program, because really, there's no other place that has the type of opportunities, and particularly the connection to laboratories that are committed to this disease, as Ohio State is in this region.

Gail Hogan: Dr. Kolb, thank you. You've done some impressive work.

Stephen Kolb, MD, PhD: Thank you.

Gail Hogan: And it is ongoing, I understand.

Stephen Kolb, MD, PhD: Yeah. That's correct. Yeah, thank you so much. It was a pleasure.

Gail Hogan: And thank you for watching Health Talks.

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