What Causes ALS? With Robert Kalb, MD

Erin Spain: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, editor of the Breakthroughs newsletter. Amyotrophic lateral sclerosis, ALS, or Lou Gehrig's disease, is one of the most serious of motor neuron diseases. Can progress quickly with life expectancy of only three to five years after diagnosis. There's a sense of urgency here at Northwestern to study, better understand and treat this disease with a new faculty member leading the way.

Robert Kalb: I'm Robert Kalb. I'm a professor of neurology at Northwestern University Feinberg School of Medicine. I'm the division chief for neuromuscular medicine and the director of the Les Turner ALS Center.

Erin Spain: Let's talk a little bit about ALS. Can you describe a person with ALS and how do you diagnose them?

Robert Kalb: ALS or amyotrophic lateral sclerosis is a degenerative disorder, neuromuscular disorder where patients become progressively weak, and it's due to the selective loss of motor neurons and the neurons that instruct the motor neurons what to do. So there's an upper motor neuron, that's the instructor, and the lower motor neuron, that is connected to muscle cells, in both of those nerve cells are vulnerable in this disease and progressively die, leading to progressive weakness. Typically the cause of death is due to inability to get enough oxygen in, because breathing is impaired too. It's part of a family of neurodegenerative diseases, which includes Alzheimer's disease or Parkinson's disease or Huntington's disease. Those are all adult onset nerve cell disorders. What distinguishes them is that the population of nerve cells that die is specific for each of these disorders. Although we are learning that there's a lot of overlap between them. So there are patients that have ALS that will sometimes have parkinsonian features or people that have a type of dementia called frontotemporal dementia, which looks like Alzheimer's disease, but it's actually not exactly the same. And some of those individuals with frontaltemporal dementia will also have ALS. So that I think that as we've gotten better at keeping people alive over longer periods of time because of better and better interventions that we're seeing, that these diseases, the borders between these diseases, are often blurred.

Erin Spain: When somebody comes to Northwestern and they come to the ALS, the Les Turner ALS Center, what happens next?

Robert Kalb: So ALS is a clinical diagnosis. There is no test, there's no blood test. There is no imaging tests. There's no electrophysiologic test that makes the diagnosis. It's a constellation of signs and symptoms. The constellation of issues that a patient will describe, you know, I don't feel right or this isn't right, I can't do x, y, and z. It's a combination of those symptoms and signs, these sort of things that a neurologist when examining a patient will say, oh, well this isn't right, or there are there are no sensory symptoms and so the diagnosis of ALS is made by excluding other causes and assembling all the facts together in one unit. Typically patients will first see their general practitioner and saying, you know, maybe my, my hand isn't functioning well or I can't walk correctly, or I'm having difficulty articulating my speech or swallowing. Often what happens is a person is referred to, a neurologist, decides that these symptoms belong in a neurological sphere. Virtually all neurologists will be able to make the diagnosis of ALS, but because it's a relatively rare disease, you, clinically a practitioner may only see one patient once every 10 years. And so they, they, they want to be sure before assigning this horrid diagnosis that the diagnosis is correct. And then at that point they often get referred to a more specialized place like Northwestern. And you know, we have a clinic that has hundreds of patients with ALS at any one time. Many, many physicians who are quite experienced in diagnosis, diagnosing and managing ALS. You know, once a person gets to our clinic and we assemble all of the pieces of information and include the positive and the negative results, we're pretty confident that, that a person will, you know, if a person has ALS that we can give them that diagnosis. And then once they are enrolled in the ALS clinic, they can get a variety of services and support through the Les Turner Center. So this is the charity which supports patient's care as well as a basic science research. And the model is what's known as a multidisciplinary clinic, so a patient will see an ALS, a neurologist, and also maybe a pulmonary doctor and then a physical therapist and an occupational therapist and a speech therapist and in nutrition at an individual with a specialty in nutrition, because this is important in disease. Devices, communication, social work, psych assistance, you know, these are, we integrate all of these services to make the quality of life the best that we possibly can. And, and I think that, it's a long day, but it's a very fruitful day for the patients because they get a lot out of it. And then there are home services that are also provided through the Les Turner Center. Visits, you know, does a person need a ramp? I'm getting up and down the stairs. These are all part of this comprehensive multidisciplinary service that we provide.

Erin Spain: How do you treat someone? What are the current treatments out there that can either prolong life or increase the quality of life?

Robert Kalb: The good news is that we've learned much more about the disease over the past decades. We're very good at anticipating what patients' needs are, for devices to help people move around and to move safely and to make sure that food goes down the right pipe. There are breathing assist devices. I think that they've done great things and improving quality of life, but I don't think that we have really made a fundamental change in the arc of disease. I think that basically for the majority of individuals who have ALS, it means they have three to five years from the onset of diagnosis until death.

Erin Spain: And that's why research is so important.

Robert Kalb: Right, the key here is to understand the underlying basic biology that's going wrong in motor neurons and cells that are supporting them and intervene. I think that we're in a better place now than we've ever been. I mean it's an incredibly exciting time for basic science research and also for translating those basic science observations into new therapies.

Erin Spain: You are very confident that there will be a cure or a very effective treatment for ALS. Maybe there'll be something new as soon as in five years. You've said. What makes you so optimistic?

Robert Kalb: I'm quite sure that at some point there will be a pill, you take the pill in the morning, once a day in the disease never progresses. I'm confident in that, but whether that's six years from now or 15 years from now, I can't see that into the crystal ball and make that prediction. However, there are other technologies, specifically something called antisense oligonucleotides or ASOs that I think are going to be fabulously powerful for the treatment of ALS patients. So in the beginning, what will happen is, I'm going to predict, that antisense oligos will be used to treat patients with familial forms of disease. We know the mutant gene, we design an antisense oligos to target that gene, to reduce the abundance of that gene. And by reducing the abundance of the toxic gene, there should be less toxicity. And the reason I'm very high on this technology is that there already is an example of this working. There's a childhood disease called spinal muscular atrophy. It's a childhood motor neuron disease. Over the past 20 years we've identified with a genetic abnormality is in spinal muscular atrophy. We have devised animal models of spinal muscular atrophy. We have devised antisense oligonucleotides, which corrected in animal models. We have given it to human beings and it has had a fundamental change in the course of SMA in children. We are basically curing or having a huge impact on children and infants with spinal muscular atrophy. So this is a template. This is a pathway I know works. Identify the mutant gene, devise therapies that are used antisense oligos, give them to patients. The patients will get better. So with that pathway ahead of me, I think that it's overwhelmingly likely that antisense oligos technologies will turn out to be useful for patients with ALS in the beginning, the low hanging fruit will be individuals with familial forms of disease, but I think as we learn more and more about the basic biology and we're looking for targets in my lab that are not familial, that we will be able to target them with antisense oligos. So I'm very high on that technology.

Erin Spain: That story can gave me goosebumps. Where are they doing that? I'm just curious now, where are they doing that research with the children?

Robert Kalb: Nancy Kuntz and Vamshi Rao have been major players in the SMA world. This has been happening, so this is an. This is a great story. This is really an incredible success story and I think that neurologists, pediatric neurologists, are jumping up and down in excitement with this, you know, going from the gene to an effective therapy.

Erin Spain: This is happening at Lurie Children's?

Robert Kalb: It's actually happening in many centers, but we. So Luire has been a major player in this field and let me also say that we now have teenagers and young adults with spinal muscular atrophy, which we are treating in our clinic with these antisense oligonucleotides. We have more than 25 teenagers and young adults who have the milder form of spinal muscular atrophy and we are administering antisense oligonucleotides to them and they tell us that they're feeling stronger.  I mean, it's incredible. It's absolutely incredible. So, I see this as a very reasonable path are there going to be bumps along the road? Of course there are. Will other technologies supplement antisense oligos? Probably. Maybe who knows? CRISPR/Cas9, who knows? But but there's a clear pathway here and that's why I think that we're going to have effective therapies in the relatively near future.

Erin Spain: Just tell me a little bit about where your research, how far it's come in the past several decades and where you're at right now.

Robert Kalb: Let's just start by saying that most of most individuals who have ALS sporadic form of disease, which means that there's no clear genetic cause and about 10 or 15 percent, there's a clear single gene which is mutated that causes the disease and you can track it through a family, so all of our models of disease, so you need to, if you're going to study the disease in a mouse or a rat or in tissue culture or any of a variety of other tools, genetically manipulate organisms, you have to create that model by manipulating the gene which was defective in the patients with familial disease. So all of our models are based on familial disease. We use basically three different platforms. We use this model organism called C.elegans, caenorhabditis elegans. It's a teeny weeny little worm that lives in the soil. By the way, six Nobel prizes have been awarded for work using C.elegans. 

Erin Spain: That's very special worm.

Robert Kalb: We also use a primary neuron tissue culture models, which nerve cells that are derived from the spinal cords of mice or rats. And we also do some studies with mice too. As you could imagine, what we can do in the genetically manipulatable system happens much, much quicker than what happens with the mice. I think that looking at the genes that when mutated cause familial ALS, points to a several different cell biological processes that are likely to have gone awry in the patient cells, we think a major problem is the handling of misfolded proteins. My perspective on this is that proteins or are the workhorse of the cell. They are the things that they are the molecules that do all the work in a cell or many aspects of cell biology and they're constantly being synthesized and constantly being degraded. And at any one time there's an amount of a protein in a cell, but that amount is regulated by how many new copies of the proteins are being made and how fast that protein is being degraded. And just like a car wears out over time, a protein or a part of a car will wear out over time, due to use, a protein, will accumulate damage or will not function as well over time. And so the reason to get rid of proteins, to degrade then is to keep them fresh, to keep, you know, the battery's completely powered and the cylinders nice and clean.  We think that a major problem in ALS is the recognition of damaged proteins and disposal of them. And because this disposal process or the recognition and the disposal process is impaired, what ends up happening is an accumulation of damaged proteins and cells don't like that. Cells are very unhappy when misfolded damaged proteins accumulate. And this is actually a common theme for all neurodegenerative diseases and actually many diseases that even don't involve the nervous system. It's the accumulation of misfolded damaged proteins. And so a part of the research in my lab focuses on how these proteins are recognized,  how they are brought to the disposal unit cells have a trash disposal units and if any of those genes that we have found could become drug targets. If you could facilitate the recognition and degradation of a protein and that recognition process could be drugged, if we could make a drug that would accelerate that process, we think that that's gonna be an opportunity for treating patients. And so we're very actively involved in those aspects.

Erin Spain: We have several labs here that are part of the center. They're all sort of working on different aspects of ALS. Tell me a little bit about the folks that you have right now in the center of these investigators and what they're working on. Some exciting things they're working on.

Robert Kalb: I'll start with the most junior and go to the most senior. So Evangelos Kiskinis Kiskinis is an assistant professor in the Department of Neurology. He is very interested in using models of ALS that are based on human cells. So there's the technology for taking human skin cells and turning them into human motor neurons and growing them in a dish and then interrogating what they're doing correctly from a cell biological perspective and what's going awry. And so Evangelos is really a leader in the field of this, what's known as induced pluripotent stem cell derived motor neurons. And uh, he's been supported by the Les Turner Foundation and he just got a major NIH grant. So you know, he's a budding superstar if he's not a superstar already. Hande Ozdinler is a little bit more senior. She studies upper motor neuron. So as I said, the disease is a disease of the command neurons or the upper motor neurons as well as the lower motor neurons. And she has devised some incredibly clever a mouse models for looking at upper motor neuron disease. And what are the determinants of survival of those selves. There's another investigator Han-Xiang Deng who is sort of partially independent of another lab. He's done some really incredibly fabulous work identifying new genes that cause ALS and making mouse models of them. And part of that, as part of a partnership with a more senior investigator, Dr Teepu Siddique, Siddique is been at Northwestern for decades. He was part of the team that found the original gene, the first gene that when mutated causes familial ALS mutations in a gene called SOD, sod. Dr. Siddique is actively involved in both the animal level and more molecular biological aspects of motor neuron disease.

Erin Spain: You said before that you like hard problems to solve. You're a bit of a, actually saw you doing the New York Times crossword puzzle when I was walking in here. Has that always been a personality trait for you, sort of a puzzle solver trying to solve hard problems?

Robert Kalb: I like being Sherlock Holmes. I like a hard puzzle. I like to get the positive, the positive feedback when I put the last word in the crossword puzzle too, and we're not done there with ALS. But also I think you need to, I look at as a marathon, you need to go long here. If it was easy, we would already have the answer. If there was an obvious thing, we would already have the answer and we don't, and that just speaks of the incredibly complex, the incredible complexity of cells and in this bizarre way, they're really beautiful in there. I mean they do all sorts of really incredible things, but you've got to recognize that there they've had billions of years of evolution to become very good at what they do and we've just now having all the incredibly powerful tools to dig inside and find out what's going on. And I am committed, I think, I think everybody in the clinic or the physicians, Senda Driss and Mike Li and Teepu Siddique and myself and Robert Sufit, I think we're all very committed to taking care of the patients and going long hanging in there and willingness to see it through to the end and that's my goal is to get to the end, to put myself out of business.

Erin Spain: To find out more about Dr. Kalb's research, check out the latest issue of Northwestern Medicine magazine and Breakthroughs. I'm Erin Spain. Thanks for listening.