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Melanie Cole (Host):  Welcome. This is Better Edge, a Northwestern Medicine podcast for physicians. I’m Melanie Cole and today we’re discussing ALS and the latest research. Joining me is Dr. Robert Kalb. He’s the Director of Les Turner ALS Center, Chief of Neuromuscular Disease in the Department of Neurology and a Les Turner Professor of Neurology at Northwestern Medicine. Dr. Kalb it’s a pleasure to have you join us today. speak a little bit about ALS. What are some of the current treatments available to patients now as compared to 20 years ago.

Robert Kalb, MD (Guest):  ALS, amyotrophic lateral sclerosis was recognized about 150 years ago by a famous French Neurologist named Charcot and the disease presents with weakness and it’s slowly progressive and it’s typically in a middle aged individual. Men and women are equally affected. The most prominent feature is the slowly progressive weakness. And when a neurologist examines a patient and comes to the conclusion that a person has ALS, that diagnosis is often made by excluding a series of other diseases that might look the same and also there’s a very characteristic pattern of physical findings in ALS.

Over the past 40 years, we have discovered that a significant percentage of ALS is due to a mutation in a single gene. And we understand the genetic basis of familial ALS reasonably well. I’d say we know most of the genes that are involved. These are single genes that carry a mutation that causes familial ALS. And then base don those genetic insights, we have ideas about what might be going wrong in the disease and this helps us to devise new therapies and to test therapies. Currently, there are two different medications that have been approved by the Food and Drug Administration, the FDA.

One is a tablet called riluzole. It’s taken once in the morning and once at the end of the day. It’s definitely proven to have a beneficial effect in slowing the disease. And more recently, a new medication called Radicava has become available. It is an infusion. It’s given for – daily for two weeks and then there’s a two week rest period and then two weeks back on. It too has been shown to slow the progression of the disease.

That said, both riluzole and Radicava have a relatively modest effect on the disease. They are disease modifying, they slow the disease, but the prolongation of life is typically in the range of a few more months. So, we still have a very large task ahead of us to discover new and more powerful medicines that can really bend the arch of disease.

Host:  Well thank you for that explanation. Dr. Kalb, you have nearly 30 years of NIH funding and 100 peer-reviewed publications under your belt. Speak briefly for us about your research using genetically engineered mice and other disease models. How are these findings helping us to understand ALS and develop new therapies to treat it?

Dr. Kalb:  When there’s familial disease, when it runs in a family; we know a far amount of the genes when mutated, can cause familial ALS. Based on that information, we’ve been able to build models that permit us to study the underlying disease process. So, models have been made in mice that express the mutant gene or they have been expressed in fruit flies. They’ve been expressed in Baker’s yeast. They’ve been expressed in a little worm called C. elegans. And these platforms allow us to find out what’s going wrong in those worms or flies or mice and then test ideas.

One of the things that we see at autopsy in individuals who have succumbed to ALS is a build up of misfolded proteins. Normally cells are very efficient at identifying proteins that are damaged, basically destroying them using a specialized machinery. And in ALS, we find that cells have accumulated garbage essentially. Misfolded proteins that have not been properly degraded. And that dovetails with some of the genetic causes of disease because the mutations in genes that are involved in protein degradation have been found to cause ALS.

So, much of my lab has been studying how cells identify misfolded proteins, how they target them for destruction, why that system goes awry as individuals age and are there new therapies or new ways to intervene to stimulate the destruction of those misfolded aggregated proteins. And we think, and we’re not the only lab, there are many labs across the country and the world that are interested in a similar problem. We think that if we could stimulate the process of recognition and degradation of misfolded proteins; that this would have a general beneficial effect, that any person ALS whether they had familial disease or sporadic disease would benefit from such an intervention.

And let me also mention, that this accumulation of misfolded proteins problem is actually common to all neurodegenerative diseases that’s prominently seen in Alzheimer’s disease, in Parkinson’s disease, in Huntington’s disease. So, this is a recurrent theme that we see in neurodegeneration and there is a lot of interest in the field in many, many labs including mine on the general problem of recognition and degradation of misfolded proteins.

Host:  That’s absolutely fascinating Dr. Kalb, and I was reading some of that research. So interesting and promising as well. Northwester Medicine recently hosted the annual Les Turner Symposium on ALS and neurorepair where you gave a presentation on the importance of membrane trafficking and hot that process is disrupted in ALS. Tell us a little bit about that and the symposium.

Dr. Kalb:  This was a symposium that was put together by Dr. Hande Ozdinler, she’s done this for many years. She’s a member of the Les Turner Center and her lab has been quite successful and has been a recipient of support from the Les Turner Foundation for many years. In this symposium that Dr. Ozdinler organized, we had a few labs from Northwestern that included Evangelos Kiskinis as well as my own and also some individuals from sister institutions that have strong neurodegenerative disease programs. Chris Donnelly was here and Udai Pandey and unfortunately, we wanted Eva Feldman from the University of Michigan to come but the weather was not accommodating. These are all different labs that use different approaches to get at the underlying pathological process.

So, Dr. Pandey from the University of Pittsburgh uses the fruit flies. He’s interested in misfolded proteins and also how trauma can seem to accelerate the disease process. Chris Donnelly, who is also at the University of Pittsburgh studies why proteins stick together. Sometimes proteins will line up like spoons in a drawer and this may be a precursor to aggregation. He has a very powerful system for studying that. Dr. Kiskinis uses human cells that have been reprogramed to become motor neurons in a dish. It’s a very powerful technology. He studies cells form patients that have been through the magic of molecular biology turned into human motor neurons. It’s an incredibly powerful platform.

Dr. Ozdinler is interested in upper motor neurons so there’s a motor neuron that’s connected to muscle and that one degenerates in neurodegenerative disease but there’s also a command neuron on the brain that instructs the lower motor neuron what to do. Dr. Ozdinler’s work focuses on the upper motor neurons. And so I think that we each have our own particular perspective on what the key elements are and it’s not unlike having the elephant in the room and a bunch of blind men. Everybody seems to have an idea of one particular part but getting the whole picture together is really the difficulty that we’ve been struggling with over the decades of research that we’ve engaged in. And I think we’re getting a better idea of the bigger picture but, it’s not from a lack of trying. It’s just a tricky and difficult problem but I’m always an optimist that we can find a solution.

Host:  Well I’m certainly sure you can as well. The Northwestern Medicine Les Turner ALS Center offers multidisciplinary care to patients with ALS. Tell us a little bit more about the center Dr. Kalb and how this care model helps to improve the quality of life for patients and how do you see while you’re telling us that, how do you see some of your research translating to patient care?

Dr. Kalb:  The Les Turner Foundation is a charity that raises money in the Chicagoland area to support the Les Turner Foundation as well as to provide home services for patients. So, the Les Turner Center is the clinic and support for basic science research at Northwestern. We have a very long experience here at Northwestern in the diagnosis and management of individuals who have ALS. This Les Turner supported clinic has been in existence for almost 40 years. It’s called the Lois Insolia ALS Clinic and the lead physician is a doctor named Senda Driss. She and I see a very large number of ALS newly diagnosed ALS patients as well as follow up patients. In addition, Dr. Robert Sufit and Teepu Siddique, Dr. Siddique has also been important components of the clinic for many years.

It's a multidisciplinary clinic which means that after the neurologists see a patient and make a diagnosis and discuss what the disease is about; we encourage our patients to also be seen by pulmonary doctors and occupational therapists and speech therapists and nutritionists and we feel that by coordinating the care of our patients with many, many disciplines, we provide a better quality of life and we think that our patients actually live longer. And there are no clinics in the Chicagoland area that have this multidisciplinary approach but there are a few across the country and we are part of a consortium with them that allows us to enter into large clinical trials. So, along with the program at Harvard and Johns Hopkins, we are in a position to offer our patients not only multidisciplinary care but also to enable them to participate in large clinical trials that hopefully will lead to new advances in the therapy.

In addition to the clinic, the Les Turner Center also supports basic science research lab. It has supported the labs of Dr. Siddique and Dr. Kiskinis and Dr. Ozdinler, Dr. Deng, myself for many, many years and together the basic science research that’s been done here is the platform from which we are trying to develop new therapies to bring into the clinic. We are very interested in a number of different technologies and we’ve partnered with several different pharmaceutical companies to identify compounds that can be administered to patients with the hope that they will slow down disease.

And so, what we hope is that by supporting both basic science research and a robust clinic; that we can put together various types of knowledge, the clinical knowledge and the basic science knowledge for new and more effective therapies.

Host:  What a fascinating topic and your work is so interesting. Dr. Kalb as we wrap up, and you are telling us a little bit about what’s next in ALS research; let other providers know whether we all have a reason to be optimistic about the future of ALS treatment. It’s been in the media lately. We saw it all around in the news for a little while. Kind of give us a summary as we conclude and let other providers know what you would like them to know about referral to the Les Turner Center at Northwestern Medicine.

Dr. Kalb:  I think that the familial forms of the disease, I think that form of ALS will be the first that will be successfully treated. There are a number of pharmaceutical companies that have focused on very specific types of interventions, one of which is called antisense technology, antisense oligonucleotide technology. These are drugs that are administered by a spinal tap intrathecally. But they directly target the mutant protein. And I think that these will definitely be the first types of ALS that will be successfully treated, and I think that going forward, we will learn more and more targets to go for, not just the mutant gene that causes familial ALS but the more difficult problem of sporadic ALS. What are we going to attack? And I think that antisense oligo technology maybe the way to go or it may just be a stepping stone to other types of intervention.

I think that we really have a unique set of physicians and scientists here at Northwestern with enormous amounts of expertise and we are very comfortable in the diagnosis and management of ALS. We provide a lot of different services. And I think that our patients appreciate the accumulated knowledge that has been amassed in our clinic and if there is a patient in the community that has ALS and they are interested and willing to come to our clinic, I would definitely encourage them to do so. I understand that this can be a chore to get into downtown Chicago, but I think that the pay off is that we bring special expertise and knowledge that we hope will translate into more powerful and effective therapies right now and also in the future.

Host:  And passion too, Dr. Kalb, I can hear that when you speak. So, thank you so much for joining us. And that concludes this episode of Better Edge a Northwestern Medicine podcast for physicians. To refer your patient or for more information on the latest advances in medicine, please visit our website at www.nm.org to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. I’m Melanie Cole.