ALS Crowd Episode 3: Dr. Michael Weiss on ALS among neurological disorders

Michael Weiss, M.D.: University of Washington
Director of the Neuromuscular Diseases Division
Professor of Neurology
Adjunct Professor of Rehabilitation Medicine

Interview date: Friday, August 1, 2014


Dr. Michael Weiss, MD of the University of Washington discusses ALS’ relationship to other neurological disorders and his current ALS medical trials.


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Full Transcript

Seth: Welcome to Episode 3 of ALS Crowd Radio. I’m your host, Seth Christensen, here with my co-host, Amy Christensen. We are excited today to have Dr. Michael Weiss of the University of Washington with us. I’ll have Amy introduce him.

Amy: Thank you.

Dr. Weiss, Director of the Neuromuscular Disease Division, is a University of Washington Professor of Neurology and Adjunct Professor in the Department of Rehabilitation Medicine. He sees patients at the University of Washington Medical Center. His clinical interests include the diagnosis and treatment of neuromuscular diseases including ALS and a vast number of other neuromuscular diseases.

Welcome to the show today, Dr. Weiss.

Dr. Weiss: Well, thank you so much, Seth and Amy.

Seth: It’s great to have you here today. Our listeners are excited to discuss ALS among other neurological disorders. I thought we will start off, Dr. Weiss, by asking you our typical loaded question. What is ALS?

Dr. Weiss: So ALS is a disorder that affects the nerves that arise in the brain and in the spinal cord that send signals to muscles. There are two populations of so-called motor neurons that seem to undergo this degeneration. And as a consequence over a period of time, the muscles begin to twitch and they shrink and then they become weak and the muscles can be any muscles in the arms and the legs, the muscles of breathing, and the muscles of speech and swallowing. Any of those areas can be affected and it’s variable in how those areas are affected usually and over time.

What we don’t know exactly is what triggers this disease. We have some ideas about that and that’s led to some therapy like Riluzole which is a glutamate-blocker. So we think that there’s a normal chemical in the nervous system called Glutamate that if there’s too much of it, it’s not cleared from the environment or the neurons by the supporting cells, the glial cells, and as a consequence, there’s damage to the motor neurons and over time, they die.

That discovery a number of years ago led to the initiation and development of Riluzole which remains the only FDA-approved treatment for the disease but unfortunately, doesn’t do nearly as much as we would like and it only slows the disease down somewhat.

So there are a lot of other areas of interest that are being explored as potential causes of ALS. Like so-called oxidative stress: whereby the byproduct of energy metabolism by these little energy factories and neurons and the motor neurons’ mitochondria cause damage to the neurons and cells because the byproducts of these oxygen-free radicals are not removed and they damage the motor neurons.

There are other ideas that we’re exploring like inflammation: activation of inflammatory cells in the brain and the spinal cord called microglia that they lead to a cascade of events that damage motor neurons. And then finally, I think another really interesting focus is about these proteins that deposit in, not where the nuclear material of the cells are, that is where the RNA originates but further out in the so-called cytoplasm, we can see these proteins deposit and there are different proteins but they all seem to be very typical of ALS but also of other degenerative diseases and that’s why ALS shares similarities shares with other degenerative diseases where this happens as well.

My area of focus recently has been on another potential cause of ALS which is something called hyperexcitability: there’s evidence that in ALS in very early stages, and looking at the animal models of ALS and tissue-culture models, that the neurons are over-excited, that they’re over-stimulated and the thought is that that could potentially lead to premature death of neurons. And so one thought would be “Could we rescue viable neurons by suppressing this excitation with medicines that do that?” So I’m doing a study using the drug mexiletine which is a sodium channel-blocker, sodium being important for exciting neurons and having them send electricity or action potentials down to their processes down to muscle.

And so mexiletine, we think, is suppressing that; we’re hoping it’s going to suppress that and that’s in clinical trial right now. We sure hope to have results of that study probably by the end of the year.

Seth: We love to hear about news, if that would be okay, we’d like to talk about that a little more later on.

Dr. Weiss: Sure.

Seth: One brief question. You mentioned two populations of motor neurons that are affected in ALS. Could you clarify what those are?

Dr. Weiss: Yes.

The two populations of motor neurons are motor neurons that arise in the cortex of the brain, the higher part of the brain, and then they send their projections or axons down to the spinal cord and then eventually they interface with spinal motor neurons, that’s the second population or they’re sometimes called anterior horn cells. And then those neurons send processes to the muscle and the muscle start to shrink and become weak as those neurons die because they require nutrients from those neurons via those axons, those projections, and that’s what leads to the wasting of the muscles. And when they’re damaged, that’s what leads to the twitching of the muscles, as well, and weakness, of course.

Seth: Now we have our heard our other guests mention upper and lower motor neurons. Are those synonyms or are those different?

Dr. Weiss: That’s another way that they’re categorized, cortical motor neurons or upper motor neurons. And so when they’re damaged, the typical manifestations are jumpy reflexes and stiffness or increased muscle tone, incoordination, and weakness, to some extent. But when the spinal motor neurons or the lower motor neurons, are damaged, that’s what leads to the wasting of the muscle and twitching as I mentioned. So that is another way to look them, upper and lower motor neurons.

Seth: Great. Thank you for that clarification.

Dr. Weiss: Sure, sure.

Seth: Now, you began to mention that ALS has some commonality with other neurological disorders. I would like us to talk a bit about those other distant or near cousins of ALS. What other diseases are in the same family?

Dr. Weiss: Well, I think that diseases that are similar are ones that have similar defining pathology, and so one of those diseases which also can co-exist with ALS is Frontotemporal Dementia. We all hear about Alzheimer’s Dementia, Frontotemporal Dementia is not uncommon but a less-common form of dementia and that is characterized so much by memory changes early on but rather behavioral changes where patient’s behavior seem to change or sometimes they become paranoid or obsessive-compulsive or they lose the ability to project into the future. They might seem like they’re depressed but they’re really just apathetic, it causes apathy. And sometimes it affects language so they have difficulty, not necessarily just slurring the words, but finding the words.

Recent studies have suggested as many as 10% of patients with ALS actually have Frontotemporal Dementia as well if you do some rigorous testing for it. Those are usually questionnaires that psychologists often administer. We do a bedside test called the ALS Cognitive Behavioral Screen, which is a sort of quicker screen that usually has to be corroborated with further testing to see if that’s indeed the case.

And then up to about probably another 40% of patients, or all-told, 50% of all ALS patients can have some more modest impairment of executive function like being able to project in the future plan, make decisions or behavioral changes or language problems. Not to the degree that they would meet well-defined criteria for Frontotemporal Dementia.So what’s common to both Frontotemporal Dementia and ALS or sporadic ALS at least, patients without SOD1 gene mutations, that form of familial ALS, is that there is a particular protein that seems to accumulate or aggregate outside the nucleus of neurons, both in Frontotemporal Dementia not in motor neurons but other neurons in the cortex but also in ALS patients and this is a protein called TAR DNA-binding protein 43,. And so that’s important regulatory protein for the nuclear machinery basically translating RNA into proteins and so that should usually be in the nucleus of these neurons. And every neuron normally, we have TDP-43 but for some reason but it seems to leave the nucleus and go into the cytoplasm and then it sort of clumps together. And that’s true of both Frontotemporal Dementia, not motor neurons but other neurons and in ALS. That’s what makes those diseases linked as well as the fact that ALS patients often have some element of Frontotemporal dysfunction that’s not Frontotemporal Dementia.

Seth: Great…we’ve heard from other guests of the interest in the connection between these two. What other diseases or disorders or syndromes are in the relative neighborhood of ALS?

Dr. Weiss: So other diseases that are on the spectrum of ALS–I tend to lump this together with classic Lou Gehrig’s disease because I just think it’s part of the same disorder. Diseases with patients with just pure lower motor neuron findings those are patients that have but it’s not as progressive muscular atrophy. Those patients don’t have the jumpy reflexes or the stiffness because they don’t have the upper motor neuron findings of classic Lou Gehrig’s disease patients but they do have the weakness and they do get breathing issues because it affects the muscles that help them breath like the diaphragm. They don’t usually get swelling problems either and it’s a disease that tends to progress in a manner that’s similar to ALS but at a slower rate.

And then other variants of ALS that I, again, think of as likely being on the same spectrum, for some they call Progressive Bulbar Palsy where patients just have speech and swallowing difficulties but over time, they usually develop the other features of ALS. And then there’s a disease that just involves the upper motor neurons and this disease, I think, there’s some controversy as to whether or not it really is on the same spectrum of ALS and this is called Primary Lateral Sclerosis and those patients have a very, very long course, decades. And while they can get breathing issues, they can certainly get swallowing issues, the progression is extremely slow. So the variants of ALS tend to be much less common than ALS itself. Certainly less that 5% or 10% for most of these disorders I mentioned.

Now other diseases that could look like ALS that are forms of motor neuron disease include a condition called Spinal Muscular Atrophy. That’s a disease that’s typically inherited and presents in most patients, in early life or childhood or in infancy, and it can be quite lethal when it presents very early in life. But occasionally in adults, there are patients that present or juveniles, we see that they present in a way that’s somewhat analogous to ALS. They just have lower motor neuron findings and they usually have fairly similar symptoms on both sides and it infects the muscles that are closer to the trunk and not so much further down. Sometimes, while not always, they have a genetic mutation that helps confirm the diagnosis. And then there’s another inherited late onset form of motor disease that we tend to see really just in men called Kennedy’s disease or X-Linked Spinal and Bulbar Muscular Atrophy. And that’s, again, a lot less common than classic Lou Gehrig’s disease. I think some recent literature suggests it’s probably a magnitude of maybe, I would say, certainly no more than maybe 1 in 5… So ALS are probably 4 to 5 per 100,000 new cases a year and Kennedy’s disease is more like 1 in 500,000 patients a year so a lot less common. Kennedy’s disease, we always want to identify if we can because it’s not a lethal disease, it’s very rarely lethal. It can run in families but because it’s X-Linked recessive, that means that the mother would be a carrier and then only typically men get it although there are rare reports of women getting mild forms of it. And it progresses in a manner that’s much slower than ALS but it typically involves speech and swallowing and it can involve the arms and leg muscles and it can involve the breathing and it just involves the lower motor neurons. It doesn’t involve upper motor neurons. So that’s a disease I always want to be sure about because it changes prognosis even if I don’t have a specific treatment for it.

I do want to call attention to one other disease that we always look for, that we want to be sure about even though it’s technically not a motor neuron disease and that’s a disease called Multifocal Motor Neuropathy. And so that’s a disease that is often mistaken for ALS. It’s a disease that affects not the neurons but rather the nerves and the nerves that are just in the arms and the legs, not in the brain. The nerves are extending from the spinal motor neurons. What happens in this disorder is patients can get weak and then over time, they can get some wasting or thinning of the muscle. Usually beginning in the arms, it doesn’t typically involve swallowing or breathing but it’s hard to find, it’s hard to identify sometimes. What happens is it causes injury to the coating around the nerve, the myelin, but those findings can be very hard indeed to spot and the only way to detect them is nerve conduction testing. But that’s a disease that maybe almost as common, according to some recent literature, as Lou Gehrig’s disease itself. So it’s one that we absolutely do not want to miss and I always consider that when I’m seeing a patient with the question of Lou Gehrig’s disease to be very sure I’m not missing that because it is potentially treatable. There was something called intravenous immunoglobulin therapy which is full human antibody which can reverse the weakness to some extent.

Seth: Now are disorders like Guillain-Barré, CIDP, and MS are considered related as well?

Dr. Weiss: They’re not related but sometimes — I don’t know about Guillain-Barré syndrome mimicking Lou Gehrig’s disease. I think that probably doesn’t happen too often because that’s a disease that is very formaden…It occurs very quickly over the course of a few weeks or patients start with no symptoms and they become quite weak. That’s not something that typically happens in Lou Gehrig’s disease.

Sometimes patients with Lou Gehrig’s disease have sort of precipitous additional weakness but over time, they continue to incur deficits that really gradually accumulate. In Guillain-Barré syndrome, they reach their weakest point typically within 2 to 4 weeks, certainly no more than 4 weeks. And they often have a sensory component where they have some changes in sensation and then the nerve test helps define that disease.

There is a chronic form of that disease called Chronic Inflammatory Demyelinating Polyneuropathy or Polyradiculoneuropathy which is a mouthful. It’s also known as CIDP and there are pure motor forms of CIDP and so those are rare; very, very rare, and those patients are defined by the nerve conduction study. Again, because even though they have weakness that’s progressing slowly in the manner analogous to ALS, they don’t have upper motor neuron signs and the nerve conduction testing shows again entry to the coating around the nerve, the myelin. That’s why that test is so important in trying to be very sure about the question of Lou Gehrig’s disease. In my opinion, as uncomfortable as it is, it’s indispensible because I don’t want to miss a treatable disorder.

Seth: Of course. And lastly the MS question, are they the same family?

Dr. Weiss: No. MS is a disease that I guess, commonly mimic Lou Gehrig’s disease but the difference is it presents usually with transient worsening multiple occasions. Occasionally, it will present with more of a slowly-progressive course but the symptoms are often incompatible or atypical for Lou Gehrig’s disease such as numbness or changes in vision. So those would make me think of a different disorder. And then the disease is virtually always detected by imaging, by doing an MRI of the brain usually; or if not the brain, the spinal cord. And I virtually always again will use neuroimaging, typically an MRI, in my evaluation, patients with Lou Gehrig’s disease, just to be sure about that possibility or anything else. Though I have to say, I think clinically-inexperienced ALS doctors are probably not going to mistake MS for Lou Gehrig’s disease; probably not because the symptoms are so different for the most part.

Seth: Thank you.

Amy: All right. We just want to tell our listeners to prepare any questions. We wanted to share the phone number that you need to call in at. The number is 516-590-0362. And if you have a question, please press the number 1 so we can know that you’ve called in.

Seth: Great. Thank you, Amy. Dr. Weiss, thank you for your answers so far.

Dr. Weiss: Sure.

Seth: So we are told that roughly 35,000 people in the US are living with the diagnosis of ALS at any given time. The disorders you mentioned are, in the most part, a smaller population. Do we have any idea of a comparative numbers for these other disorders?

Dr. Weiss: Yes. So the only disorder I think that would be more common than ALS is Multiple Sclerosis and I’m not sure I know off the top of my head what the incidence or the number of new cases or prevalence of multiple sclerosis is but I think it’s more substantial than ALS for sure. I can say this about this other more likely mimics given all these things that I think about more carefully because, as I said, I think MS is very unlikely to be mistaken for ALS most of the time. Diseases like Spinal Bulbar Muscular Atrophy or Kennedy’s disease, the incidence is probably 1 in 500,000 new cases a year so it’s a lot less common. Multifocal Motor Neuropathy with conduction block, this other really common mimic of ALS is very common. In fact, some recent literature suggests that it’s almost as common as ALS; it’s about 1 in 100,000. Whereas based on this very recent CDC epidemiologic study, which isn’t all that different from previous studies, they looked at the number of existing cases of ALS and they found there are 4 per 100,000 in United States so they didn’t list the incidence that is the new cases a year. So Multifocal Motor Neuropathy with conduction block is the most common mimic of ALS and that is the one that I absolutely don’t want to miss because, as I said, that is treatable. Motor CIDP or CIDP in general probably has an incidence that is not terribly different than ALS either but because most patients have sensory symptoms, they’re not going to be generally mistaken for ALs. But there is a pure motor form of CIDP that is so uncommon that I’ve only seen a few cases of it and we don’t know the incidence of that or the prevalence. That is how many new cases or how many current cases there are. My guess it’s very, very uncommon.

Seth: Thank you. Now, in researching these various disorders, are we learning more about ALS through cross-disease research?

Dr. Weiss: Well, I think we are with Frontotemporal Dementia, there’s no question about that. We’re finding this common connection that we didn’t know existed until very recently so we used to think that Lou Gehrig’s disease was a standalone disease; that it was very distinct from other degenerative diseases in that there’s only targeting of motor neurons and clearly that is not true for some patients. So it has gotten us thinking, “Are there other populations of nerve cells that could potentially be involved?” And so there is even some preliminary information that sometimes there is some minor component of sensory nerves that are involved. That hasn’t been well-corroborated but there definitely have been a few studies that suggest that. I think it’s always been hard to understand why just motor neurons are implicated in ALS so I think this is suggesting that maybe that it isn’t; clearly, it is not just motor neurons.

I’m not sure in terms of treatment if these are understanding of these diseases is going to push therapies along necessarily but I think that it really is helping us to define the pathology better, the sort of principle pathologic features of the disease that you’re hopeful will lead to treatment.

So one thought that I’ve had which I think there’s been somewhat conflicted evidence is that these proteins themselves, like TDP-43 in particular but other proteins like Ubiquitin which deposit in the cytoplasm on the neurons, that they actually in and of themselves, damage the neurons and that the reason why they’re there in the first place is because there’s a pyramid of a process by which they’re cleared from the cells. So we all have a breakdown of proteins in our nerve cells and other cells. So what do we do with these breakdown products is basically it’s sort of like when we finish our meal we have food that we have to get rid of, the next food part, whatever the end result of that meal is, how do we get rid of these proteins? Well, we do that by a process that’s called autophagy. And autophagy is basically — I use the analogy it’s like the garbage disposal cells. We get rid of constitutive proteins that we don’t need anymore; they’re byproducts of other processes within the cells. And so the question has been whether there’s impairment of autophagy in ALS. And there is some evidence for that but it’s somewhat conflicted. So another question then would be if we can be very sure about autophagy being impaired and therefore, that means that we can’t get rid of these proteins that are damaging to the cells, is there a way to fix the problem? Can we promote autophagy? Basically, can we throw some drano down the pipe and unclog it? So there are medications that can do that and these are medicines that are often used to suppress inflammation but primarily they’re in the family of anti-organ transplant rejection agents and one of them is Sirolimus, the other name for it is Rapamycin, and there’s other ones as well that do very much the same thing. And so that’s a question that I wonder about. If we could promote autophagy, could that at least arrest further damage of neurons? And that’s something that I haven’t put together in a trial but something I’ve thought about that maybe we should think about doing a specific trial to address that. There’ve been other studies using medicines that also promote autophagy. I believe Arimoclomol does have to some extent and lithium. And if lithium didn’t help but maybe another agent would. So I think that is an area of interest that I have that I think needs to explore it in terms of its therapeutic potential.

Seth: Excellent segue into your research. You mentioned areas of interest. Maybe now would be a good time to return to your work on hyperexcitability.

Dr. Weiss: Right, so a little bit more background about hyperexcitability in ALS. So this has become an area of interest and an area of focus for my therapeutic trials, in particular mexiletine, which is a study that I designed with some ideas that were put forth by Bob Brown who is previously at Massachusetts General Hospital, now University of Massachusetts. So he had done some initial studies thinking to show that there is evidence for hyperexcitability of motor neurons, in particular, in the mouse model, the most common use of mouse model for ALS, SOD1-mice. And then he showed that in particular, mexiletine slowed the rate of decline in these animals and improved survival significantly. Other studies have shown that in these animals, either before they’re even born, embryonic animals, if you take out their motor neurons and you measure the electrical current in the motor neurons using something called patch clamping, that there’s evidence that they’re over-excited, and then the reason for that appears that there’s too much sodium that’s being driven into the cells. So what mexiletine does is it blocks sodium current, to prevent sodium from getting into the cells. And so the big question is does that cause the damage? We don’t know that, but we do know that in these animal models for ALS, that they don’t develop signs of the disease until well after they’re born; usually a number of weeks after. There is also even some information in patients using a technique that induces movement in the limbs by sending magnetic waves down the motor neurons in the cortex all the way to the spinal cord then down the spinal motor neurons and their projections to the muscle. That the neurons are over-excited in ALS patients so these studies have been done in ALS patients because it takes much lower level of magnetic stimulus to generate a response. So that means that they’re very susceptible to the stimulus, that they’re over-excited.

Unfortunately, we can’t really do the same kind of experiments in humans that we can do in this mouse model and then there’s always this question as the model how reliable is it to humans, especially sporadic ALS. But nonetheless, there is this information that the hyperexcitability occurs and it occurs not only in the spinal motor neurons but in the cortex based on these kinds of experiments.

So that was what led to mexiletine and then there is another study that I’m not the principal investigator for but would like to be involved in it. It’s another NEALS study. It’s using a drug called Retigabine which is anti-epileptic. What Retigabine does is it also blocks current going in and out of neurons and it’s blocking specifically, potassium current, not sodium. This study, the idea for it came about because of the other experiments I mentioned, the other studies that I mentioned, but also based on experiments that were done at Harvard Medical School by Kevin Eggan whose a very prominent ALS neuroscientist there and others. Kevin has an interest in what are known as induced pluripotent stem cells or iPS cells. These are cells that are derived from other kinds of cells like skin cells, typically, and then they are reprogrammed to form other cells and in the case of what Kevin’s doing, motor neurons. So he actually took skin cells from patients with familial ALS with SOD1 mutations and then he reprogrammed them to make them into motor neuron cells and culture. And then he did very similar kind of experiments, what I mentioned earlier in the SOD1 mice where he had somebody help him probably, micro patch clamping. And again, he showed evidence for hyperexcitability that he could block with Retigabine. I think he looked at other medications but that was the one that he found was most helpful and that is an FDA-approved drug so it easier to do studies and potentially get the drug to patients if we already have a drug that’s on the market.

So that’s what led to this study that’s about to start, I don’t know when it’s going to start and we hope to be a part of it. It’s a NEALS-sponsored study but it’s addressing the exact same potential, so-called pathogenic mechanism for ALS, that is hyper-excitability leading to damage to the neurons, both the upper and lower motor neurons, and then questions can we arrest or slow the disease down by preventing that from continuing to happen with this medication.

Seth: Wonderful. And I am sure we’ll hear more about that as it becomes up and we will forward that through our website. On the study you are leading with mexcilitine…in that study, you mentioned that as well on the way, are you finished recruiting or how can we help?

Dr. Weiss: So we’re finished recruiting and we should have our last patient through the study that is get to their last visit by the middle of September. We hope to have some preliminary results to report at the Northeast ALS Consortium meeting in, I think it’s in late October. And then if not, then one of the other meetings like the Packard Center meeting which is an ALS meeting sponsored by Johns Hopkins University, or the American Academy of Neurology meeting which is usually in April. And so it’s a Phase 2 study which means it’s not a huge study and I don’t think there are any other studies that are Phase 3 right now for ALS but it’s 60-subject study, 10 centers, all NEAL sites, Northeast ALS Consortium sites. And so it’s going well, we haven’t had any major safety issues at all so we’ve learned that much that the drug is fairly safe. Now the question is can we show benefit in slowing the disease.

The other parameter that we’re measuring is because, unfortunately, a lot of clinical trial in ALS have not been successful in slowing the disease down, one other goal is even if it doesn’t do that, and we’re still optimistic that it will and we will need to probably do a bigger study to very much approve that, but the other goal is to see if it has an effect on muscle cramping. So muscle cramping, as I’m sure a lot of listeners are aware, is a very big problem in many ALS patients and there isn’t great medication for it. And the reason why the cramping occurs or we believe this is the reason, is because when the spinal motor neurons die and the nerve processes degenerate, then other neurons and their nerve processes can temporarily take their place. And then when they do take their place and they send little newly-formed branches to the muscle that’s lost its nerve supply, what happens is those branches, I guess, they’re not mature; they take a while to mature and sometimes they never do; they are again, over excited and that’s what leads to cramping. And so, again, the thought that is if we suppress that hyperexcitability, that could potentially benefit patients of cramping, as well. So that’s another part of the study, to see if it improves muscle cramping in our patients and we’re hopeful that that will be the case, as well.

Seth: Thank you. We’ll prepare for our last question and then invite listeners to call in, Amy.

Amy: Yes. The phone number for that is 516-590-0362. Please press number 1 if you have a question so we know.

Seth: Great. While our listeners dial in, I want to ask Dr. Weiss, what is the greatest opportunity in your mind for our listeners to get involved in ALS research?

Dr. Weiss: Well, it depends on how you mean. So obviously this is ALS research, we’re always looking for sources of funding. So if there are contributions, there are some very useful organizations. There are some organizations that I think could really use that money, Muscular Dystrophy Association. They have unfortunately had some financial issues which just made it real challenging for them to fund any clinical trials or any research recently. So they’re in great need of any support. There’s also an organization called the ALS Therapy Development Institute which is run by a very prominent neuroscientist, Steve Perrin. And his goal is doing what’s called translational research which is looking at this problem, not necessarily looking at the cause of ALS but trying to establish a potential treatment and then taking it usually with the help of Northeast ALS Consortium to the patient, or at least, into a critical trial, thus becoming a conduit for potential therapeutics. So I’m sure that’s another organization that would benefit from any contributions. And then probably the ALS Association as well but it doesn’t have to be financial contributions. There are always events that are important for raising money that I think having a presence would be of help. Like there are walkathons, the ALS Association has a walkathon coming up, I believe, I don’t remember the date. And obviously, patients can’t do it, with ALS, may not be able to walk but just having being present really, I think, it can show to the public the seriousness of this disease so that they become involved and potentially we can find another way to help finance some of these research projects that are under-financed because this is really still considered to be an orphan disease and that means that there isn’t a lot of funding coming from the NIH directed towards ALS research, unfortunately. Hopefully that will change but I don’t know when at this point.

Seth: Thank you. We here at ALS Crowd are huge fans of the MDA, ALS TDI, and the ALS Association. I’m grateful you mentioned them.

With that, we will prepare to go to the phone lines. We will take our first caller. Caller 1, you’re on the air with Dr. Michael Weiss.

Dr. Weiss: Hello.

Caller: Hi! I have a couple of questions. I want to go back to the MMN diagnosis. I am wondering, what is the testing for MMN? And I know it’s a lot of tests, there’s false positive, false negative, there’s no sure thing. Also along that line… IVIG treatment, how long do you normally give the treatment before you decide if it’s working or not or what’s the criteria to know if it’s working?

And then another question is why isn’t IVIG treatment being used for Lou Gehrig’s? Let me preempt that by saying I’ve been given IVIG treatment. I noticed a difference in how I felt; less fatigue, less fasciculation, more dexterity but oddly, my doctor said “No, it’s all in your head. No more.”

Dr. Weiss: So those are great questions and they do come up a lot.

So there had actually have been some small studies in just ALS patients alone with IVIG that have not clearly shown benefit. But if there’s any consideration of the diagnosis of the Multifocal Motor Neuropathy, I always give patients a treatment trial if their insurance will allow. That’s always a struggle.

So Multifocal Motor Neuropathy with conduction block is defined by the electrophysiology, the nerve conduction testing showing conduction block which is an area along the course of the nerve where we’re stimulating the nerve to the muscle where there is a block in the signal; the cause of loss of the coating or the myelin. Now there are patients for whom that is a challenge to see or maybe they don’t meet all the formal criteria that have been put forth by different organizations. But the thing that I always think about is they cannot have upper motor neuron signs so Multifocal Motor Neuropathy patients well should not have jumpy reflexes or increased muscle tone. That’s the case. I know they don’t have it.

There’s an antibody test for Multifocal Motor Neuropathy that is helpful but it’s not nearly as sensitive as we would like. It only has a sensitivity of about 40% and that is the antibody that’s something called GM1 which is a complex sugar that’s present on nerves. We used to think it was very sensitive but recent studies suggest it’s not. And occasionally, can even be weakly positive in ALS patients. If that test were to come back more than just weakly positive for sure, I think that’s the rationale for using IVIg but it’s really other things that… There’s a clinical features of Multifocal Motor Neuropathy that cannot have upper motor neuron signs. They shouldn’t have any trouble swallowing or chewing, and they don’t typically have breathing issues. Otherwise, sometimes it is hard to know for sure and sometimes I’ll just treat and ask what would I treat with, what should be my protocol? So the protocol I use is similar to what I use for CIDP patients which was pretty well-defined based on IVIg study done in CIDP called the ICE study.

And basically I do induction course or I’m giving patients a double dose, 2 grams per kilogram body weight is the dose I give them. And then every three weeks I give them 1 gram per kilogram body weight for three times. There isn’t any consensus on this but I’m measuring is I’m assessing individual muscle groups through using something called manual muscle testing…testing their muscles using a scale called the Medical Research Council scale which is what many neurologists use, MRC scale. And what I use as my criteria is the patients have to have an improvement of at least two muscles by at least one grade. This is just me so there’s no consensus for this, and then I measure their grip strength with a device called the dynamometer. And there are probably some other neurologists actually use dynamometry to measure other individual muscles. And so what I’m looking for is at least a 20% increase because I’m not looking for improvement of fatigue. Unfortunately, there’s really no way to measure that and I’m not looking for improvement of muscle twitching because muscle twitching or fasciculations in ALS vary all the time. They come and go, they don’t correlate well with the disease, and unfortunately, it’s not going to help me too much. But that’s just the way I do it. Now I don’t know what other neurologists use as their criteria but that’s just what I’ve always used. But when in doubt though, I always give patients a treatment trial.

I hoped I answered your question.

Caller: No, you did. My other question is you said on the nerve conduction test that you do see depletion of the myelin, and that’s seen with MMN because of nerve conduction blockage. I’m wondering if that is also true in ALS patients.

Dr. Weiss: No. no, so that is a distinguishing feature. So the myelin is not being damaged in ALS. So ALS — I’m sorry, what were you going to ask?

Caller: I was going to ask and that is only found with the use of a nerve conduction test?

Dr. Weiss: Yes, regrettably. Other than the clinical presentation of course which is somewhat challenging in distinguishing from motor neuron disease, ALS, it’s really the nerve conduction testing. What distinguishes MMN from ALS is the conduction block. That is actually required for a definitive diagnosis of MMN.

Caller: Sorry. I have one more question. What do you tell patients that you know… no one wants this diagnosis and you want to keep researching and finding things that can help you? But sometimes it’s so hard for a patient to find a doctor who’s proactive or will help them because it seems that they think, you know I should use the time I have left to do something great with your life or whatever. What advice do you give to your patient that really does want to keep searching out a way that they can improve this disease? They are living with this disease and hopefully finding that it’s not this disease.

Dr. Weiss: Well, I certainly try my best to be open-minded to what patients ask me about but my goal is also not to expose them to something that’s going to potentially decrease their survival. I don’t have this disease but I’ve talked to enough patients that say, “what do I have to lose?” Well, I guess it depends also on how fast the disease is progressing and in some patients, it doesn’t progress that quickly. And so the idea of subjecting them to an unconventional therapy that could potentially kill them is really for me, still somewhat unpalatable, and then that happens sometimes. But then there are other therapies where I tell patients I don’t know if this is going to help. There’s just no alert, no evidence one way or the other. I like there to be some kind of a rationale for doing it. Like it’s an antioxidant for instance and therefore it’s getting rid of oxygen-free radicals and so there are protocols that are being used by patients and I’m not going to go into detail but were that is the case, then I tell them “I don’t know. I don’t know if it’s helping. I don’t think there’s any harm to doing this, I’m not going to have a problem with you doing this if you want, and I’m okay with that.”

So it really depends on what they find out on what they research and what they ask me about, whether I’m okay or not. There is a very useful resource which obviously, if you were to read it, you may agree or not agree with the information. But there’s something known as ALS Untangled. I don’t know if you know about this. So ALS Untangled, I guess it’s a collaborative editorial. I don’t know how else to describe it. Basically, it’s an investigation of an alternative therapy for which there hasn’t been a real true clinical trial, nothing published on the National Library of Medicine website, and it’s run by Richard Bedlack who is the Director of the ALS Center at Duke University.

So what he does is he gets the opinion of all these ALS neurologists or I don’t know if it has to be a neurologist but usually neurologist, at ALS Centers, usually academic centers throughout United States, about alternative therapies and their utility or lack of utility, should they be even studied or is there really no good scientific rationale and are they potentially harmful? And of course, this is the opinion of himself and all of us who participate. But nonetheless, you might find that useful.

I don’t know the exact website but if you put in ALS Untangled, it will take you right to them and then there are multiple numbers of publications addressing specific topics. I think that Rick would be open to the idea of having some topics be patient-driven like you wanted to know, would he give you some information about it, I think that makes sense. If patients really want to know, then why don’t we see if we think it’s reasonable or not having or getting this consensus from ALS neurologists. There have been a number of these publications, they’re all open access. Yet they’re also published in a journal called ALS and other motor neuron. ALS, Frontotemporal Dementia, and other motor disorders is the name of the journal, which is the primary ALS journal.

Caller: Thank you. Thanks for giving your time. This has been a really great interview.

Dr. Weiss: I’m glad to hear it.

Seth: And thank you, caller, for pushing us and Dr. Weiss for keeping us abreast of the tough issues. We have time for one more caller. We’ll go to that caller now. You are on the air with Dr. Michael Weiss.

Dr. Weiss: Hello.

Amy: Go ahead with your question, caller.

Caller: Hello?

Seth: Yes, you are on.

Caller: Oh, yes. Hi! I have a question. Can you give us some perspective and help us understand about how many ALS specialists are worldwide that are maybe principal investigators doing active research?

Dr. Weiss: Well, I think the place to start is that there are a number of ALS centers through the United States that are either sponsored by the ALS Association or the MDA and they have specific expertise in ALS.

So the University of Washington, we’re an MDA-ALS center, and I believe there are something like 35 centers throughout the United States. Probably every center has a few ALS neurologists so if that gives you some perspective. And then the ALS Association, I imagine, has similar numbers, maybe more.

What I find is that in most big cities where there’s an MDA-ALS center, there’s probably equal numbers of ALS Association clinics. And all those groups of neurologists, probably most of them are doing clinical trials but they may not be the principal investigator, they may not be creating their own trial but they might be helping to implement it as a site.

So all the number of trials that are going on in the United States right now, most of them are being conducted through the Northeast ALS Consortium which is basically a group of physicians that are centered primarily at the Massachusetts General Hospital under the auspices of Dr. Merit Cudkowicz, I think she was on the program earlier. And what I can say is they basically run, I would say 2/3 of the ALS studies in the United States right now. And I believe there are probably about 12 or 13 studies going on right now and at least, 2/3 of them are sponsored by the Northeast ALS Consortium. My mexiletine study is sponsored by the Northeast ALS Consortium.

Then Europe, I don’t know what the infrastructures for doing studies. There are also basic scientists at a number of institutions have a real focus on ALS and they aren’t necessarily doing clinical trials. And there are groups at Johns Hopkins Hospital and University of Massachusetts and Massachusetts General Hospital and their place is along the West Coast like Bob Bellows group down at Peter Sinai and Bob Bowser down at the Barrow in Arizona. So those are among the focal points for ALS Neuroscience research. I don’t know if I can give you a specific number about how many doctors are involved in research. But it’s a fair number of neurologists so they have taken a very strong interest to understanding the disease and then trying to do trials. Do we want it to be more? Sure, we do. We want more doctors to be involved in this disease in trying to treat it. And I think the largest group of doctors probably at the Massachusetts General Hospital right now and they’re probably eight neurologists there have been doing trials or have an interest in ALS research.

I’m not sure I answered your question but I think that’s the closest —

Caller: Oh, no. you did. I just wanted to get some perspective.

And I have another question for you. With the mortality rate of ALS, it seems like… I know a lot of times the scientific research is very incremental. And I think in ALS, instead of base hits youwant really big swings in the plate. So in your opinion, what elements need to be in place for more aggressive or bigger risk-taking, I guess you would say, to really make a leap forward?

Dr. Weiss: Well, that’s a great question. So I think that we have to just start thinking outside the box more than we ever have and take new approaches that we haven’t taken before, but it’s also a question of study designs. So unfortunately, there have been a number of studies that have not shown benefit ultimately; maybe in smaller studies, they have. And then there was this very big study that was done a couple of years ago sponsored by Biogen, dexpramipexole study. And I believe that was the largest study, clinical trial, ever done in ALS, a multi-national study. I forgot the exact number of patients but there are probably over 80 centers; we were part of that study.

Unfortunately, it turned out that even after the fairly robust and surprising benefit from the smaller Phase 2 study which showed the drug was slowing decline and it was decreasing the rate of decline in regard to breathing parameters for FVC and changes in the ALS functional rating scales which is a very important questionnaire of activities of daily living that ALS patients. We have them fill it out in our clinic, a pretty straightforward questionnaire but very important parameter that we can quantify. But even though it showed improvement or slowing of the rated decline of those functions in the Phase 2 smaller study, Phase 3 study was negative, and it cost the drug company 75 million dollars. And I don’t think that they’re turning their back on ALS but the idea of doing another big trial like that that’s going to cost that much money who will not lead to, quite frankly, any additional revenue for the drug company is going to be unpalatable for some of these drug companies.

So then the question in my mind is should we looking at others kind of study designs that would really answer this question at least quicker? And there was a study that was done recently that tried to do that. It was the Tamoxifen/ Creatine study where there were two drugs that shown benefit mostly in pre-clinical animal models. And the idea being compared this two potential drugs and then we’re going to take whichever drug does better, assuming one does, to a bigger study. That way we’re sort of hedging our bets. And I think that that is a very unique way to look at clinical trial design that that might be a way to move things forward more quickly without wasting time on drugs that are just not going to work even though they should benefit in the ALS mice.

And so I think that that might continue to be a good approach to this. Unfortunately because it’s so much cheaper, if we have a positive Phase 2 trial, in my opinion, we have to replicate the Phase 2 trial before we do a big Phase 3. That way, we won’t scare off drug companies that are willing to invest a lot of money and then we sort of hedged our bets again by showing that we’ve corroborated the results on two different occasions. I guess it could even be done in parallel if that were possible except then you wouldn’t know if either study was going to be positive. So if there are short studies and one shows benefit, makes sense to me, just repeat the study see if it shows benefit again and then do a Phase3 if the drug company is willing to pay for it. So that’s kind of my thoughts about drug trials.

Caller: Another follow up to that. Are there any indications that there is maybe low-hanging fruit with some existing drugs that are maybe used for other diseases that might be applicable that you could pass in ALS? I think that would be a less expensive, more rapid type option.

Dr. Weiss: Absolutely! That’s what we’re all hoping to do, that’s why I picked mexiletine as the drug because it’s already FDA-approved. I didn’t mention this earlier, it’s a cardiac antiarrhythmic agent. Cardiologists don’t use it very much because it’s not very effective but it’s an older drug, so that’s one.

And then Retigabine is already the drug in the other trial I mentioned, going to start relatively soon, that’s another one that’s already FDA-approved for treating epilepsy. And then Tamoxifen/ Creatine, both of those drugs. Tamoxifen is anti-hormonal therapy for breast cancer and then Creatine is this over-the-counter supplement but Creatine did not work though. It doesn’t seem to be beneficial

So we are trying to do that because I think as clinical trials in ALS, we recognize how hard it is to start with a novel drug. Unfortunately though, if we could get a smart pharmacologist help us, I don’t think we can ignore that possibility that we need to come up with a new drug that is not out there. We kind of have to do both because we haven’t found the drug that’s already existing that clearly slows the disease down significantly. But you’re right. That’s easier to do those studies for sure if the drug’s already out there.

Caller: Well, it seems like they’re working on all angles so thank you, Dr. Weiss, so much for taking my call and for the show.

Dr. Weiss: You’re very welcome.

Seth: And thank you, caller, for those questions. We are now at the end of our call. Dr. Weiss, anything else that you would like to mention before we wrap up?

Dr. Weiss: Well, I’d just like to say for those patients out there, there are definitely a lot of neurologists out there who would like nothing more to see an end to this disease or some viable treatment. We’re on your side; we’re going to continue to be on your side. And I have no doubt we’re going to find a better way to treat this disease sometime in the near future. And so I don’t want you to give up hope because that’s one thing that I’m convinced there is somewhere down the road. I don’t know when but I’m sure that….

Seth: All right. When you figure that one please come back on this show.

Dr. Weiss: Seth, you’re going to be the first to know. You’ll be one of the first to know.

Seth: All right. Thank you for that. Thank you for not only time but your dedication to this community.

Dr. Weiss: I am happy to continue to help any way I can.

Seth: Excellent. For our listeners, a full transcript of this interview will be available within the week and posted to our website. Thank you to Dr. Michael Weiss and we look forward to solving this disease. Thank you.

Dr. Weiss: Thanks, everybody.

ALS Crowd Episode 2: Dr. John Ravits on ALS causes and new research targets

Dr. John Ravits, MD
UC San Diego School of Medicine
Interview Date: July 11, 2014



What causes ALS? Dr, John Ravits addresses the question of what we know and don’t know about its cause. He notes that ALS is not a genetic disease in the majority of cases. He describes how the disease might spread when it begins in a localized area. He shares some popular research theories and targets: that it may be connected to RNA messaging errors, may be affected by how cells discard or recycle proteins, may be connected to abnormalities of the axon-transport, or that proteins may be folding incorrectly. He tells the story of the 2011 discovery of a mutated gene called C9orf92 (also found in frontaltemporal dementia) by the Mayo Clinic Jacksonville and the NIH simultaneously in 2011. He shares that this gene creates a very big repeating mutation. He describes the promise and challenge of new stem cell therapies and notes the increase in ALS attention from pharmaceutical companies and researchers, but encourages patients to keep the heat on to help push the field forward.  


The live ALS Crowd Radio podcast with Dr. Ravits

Online Health Radio at Blog Talk Radio with ALS Crowd Radio on BlogTalkRadio

Full Transcript

Seth: Hello and welcome to Episode 2 of ALS Crowd Radio. I’m your host Seth Christensen. We are thrilled today that we have Dr. John Ravits with us in the studio, and I will have my co-host Amy introduce him.

Amy: Thank you. A graduate of Yale University, Dr. Ravits earned his MD from the Mayo Clinic School of Medicine and completed his internship and residency in neurology at UC San Diego. He then did fellowships in neurophysiology and neuromuscular disease: one year at the Brigham and Women’s Hospital, Harvard Medical School, and two years at the National Institute of Neurological Diseases and Stroke, National Institutes of Health.

In 1986 he joined the medical staff of Virginia Mason Medical Center in Seattle, specializing in neuromuscular disorders and neurophysiology. He served as the Director of their Clinical Neurophysiology Laboratory and, for several years, as head of the Section of Neurology. In 2004, he started a translational research program at the Benaroya Research Institute at Virginia Mason to focus on research of ALS.

Dr. Ravits has been a co-investigator for several ALS clinical trials. He is an ad hoc journal reviewer of Muscle & Nerve, Journal of Clinical Neurophysiology, Journal of Neurological Sciences and Acta Neurological Scandinavia.

Seth: Dr. Ravits, thank you for being here with us today. One second. Dr. Ravits, can you hear me?

Dr. Ravits: I can hear you very well.

Seth: We have you now. Thank you for being here with us today.

Dr. Ravits: And thank you for including me. Glad to be here.

Seth: We have a number of issues to talk about today, but I wanted to give our listeners a main thrust of the biology or mechanisms of ALS. So we will start off by asking a very loaded question: What is the cause of ALS?

Dr. Ravits: Well, it is a great way to start and challenges me and all of us. I think the first answer, of course, we don’t really know what’s the cause of ALS. We know what it is in about 10% of cases and it’s genetic so it’s a genetic mutation. We’ve identified about 65% of this 10% with genetic mutations. The reason that’s so exciting is because It gives us a clue as to really what is the cause, what’s the molecular mechanism, what’s the actual switch that happens in the disease. But of course it doesn’t apply to the other 90+% of patients where we don’t really know the cause. We can say it’s sporadic which means it’s out of the blue, so it just hits and we don’t understand that group which is the main group.

Seth: Of those 10%, could you explain a little further what the 65-35 split is comprised of?

Dr. Ravits:  Sure. Let me make a couple of points. Just interrupt me if you want to — I may pause longer on some things. I think one of the first things that patients always are concerned about is, “Did I get this?” or “Am I going to pass this on to my kids?” And so I just want to reassure that as we currently think about ALS, it’s not primarily a genetic disease. It’s only in the small 10%–it is actually probably growing maybe to as big as 15% or 18%–but the rest really does not seem to be genetic and does not seem to be transmitted to the children.

So for those of you who are worried about that, most of the time we define it on the basis that there’s been a sibling, brother or sister, or a parent or an aunt or an uncle or somebody else operationally approach it is just by the genetic history or the family history. And as I say most of the time, it’s not genetic.

So what a genetic disease is that you inherit it from one parent or the other and it’s a specific mutation or a change in the genetic code that gets transmitted. And then that single mutation somehow throws the switch into the disease. And so that’s where most of the research is now because we can understand that switch or what it is that that switch is doing, then we have a chance of understanding the biology of the disease and obviously ultimately trying to treat it intelligently so that we can really undermine more root causes of the disease.

Of the genetics, there are many different mutations. So there are some that are much more common than others, but there are many mutations that have been identified. So the research now is moving in many lines of direction because every time a mutation’s identified then that’s a research opportunity and people jump on it. And it’s showing us lots of different aspects of the cell or of the neuron that are vulnerable or that are pathways that it may set off. So it’s now looking like ALS is obviously very complicated, but multiple directions or multiple triggers can set up problems in the cell to create the disease.

Does that answer your question, you think?

Seth: Yes, very much. One question further on that. Do we know how these mutations take place?

Dr. Ravits: Originally, way back that’s more of an evolutionary question. Yes, mutations occur spontaneously, but it goes back thousands of years as to when the mutation started. I mean one of the discussions that’s being had at the science level is that as people live longer, mutations that have been there all along wouldn’t have had time to express themselves just because of life longevity of people. So as longevity improves, then people live longer and then it uncovers more mutations. So it’s been through evolution, through hundreds and thousands of years.

Seth: So for those families who do have a documented case of familial ALS, the mutation didn’t happen in the 1980s, for example.

Dr. Ravits: Correct. That’s correct. I think part of the change is that medicine’s improving, diagnosis is improving, communications are improving. So a lot of times people didn’t know what they had or they didn’t live long enough to show the disease, but it’s been there and we think it’s probably just the problem of early diagnosis or communication with the family as to what really happened.

Seth: With these families, are we able most often do identify the first family member and where the gene was manifest or activated?

Dr. Ravits: I’m not sure I understand your question.

Seth: In the family with ALS, is it hard to identify the first person who had the ALS symptoms?

Dr. Ravits: Yes. Well, some of that I think is the difference of a genealogy…how well is the history known. But I think if you’re asking how do we identify the genes… that’s going through a huge revolution right now in terms of our ability to identify and define genetic mutations. That’s been probably, I would say, about a ten-year revolution that’s been going on in terms of our abilities to find genes and to find mutations. And it continues to transform the research in terms of our abilities to identify this.

The genetic code is essentially like a book of letters. It carries all the information. It’s got 3.5 billion codes in it. We’re able to sequence that now, so you can essentially sequence the DNA, the entire DNA which at one point took years to do. Now it takes days to do. And then with advances in computers, their challenge becomes a computer challenge as to trying to identify the uniqueness and mine through all that data.

What’s happened over these last ten years has been this enormous technological and computer revolution in trying to identify genetic abnormalities.

Seth: Thank you for that. I know you could go on into areas that and others, like me, would probably be lost in. For our listeners, you can read a list of Dr. Ravits’ publications on the UC San Diego website.

Moving on to our next category, talking about the biology of ALS, I wonder what major systems that are involved in the biology of ALS? For example, is there a GI tract onset or a manifestation or a hepatic or lymphatic influence of ALS?

Dr. Ravits: I’m going to say that there’s a short answer and a long answer, a simple answer and more complex answer. First, let’s keep the simple answer and that is, fundamentally, ALS hits the motor system. So it’s a neurological only disease. It hits a specific part of the nervous system and neurologic system, and that’s the motor system. The nervous system is comprised of sensory and motor and cognitive and visual and auditory. You think about all the complexity of what we do.

ALS fundamentally hits the mobility or the motor system, the strength of the muscles and the rapidity and coordination and strength of muscles. That’s the essence of ALS. That’s the short and simple answer.

And just to now make it a little bit more complex, the muscles really control everything. So we talk about muscles of speech, muscles of our trunk and abdomen, muscles of breathing, muscles of the legs and for ambulation, muscles of the arms for coordination and dexterity and so on. Any of those can be affected. So it would seem like if it affects, say, your abdominal muscles, that it’s the GI but it’s really not; it’s the muscles of your abdomen and of your trunk that are affected. Same for breathing; it’s not really the respiratory system, it’s the muscles of breathing or the muscles of chewing and swallowing that get affected. So I think that to me, that’s the essence of ALS

Now, to make it even more complex though to bring it out a little bit, I think we are seeing as times goes on that it really is a complex disease. And we now see or understand that it can affect cognitive function or language function sometimes. It may affect metabolic functions, as a lot of patients that seem to have a problem with maintaining their weight, they lose weight. It doesn’t seem to be their swallowing or their ability to deliver nutrition in, but something else as if their metabolism has been reset. Metabolism may somehow be affected.

It gets more complicated as we study it. But still, fundamentally, the essence is motor effect.

Seth: Thank you. What do we know about why different patients are affected differently? One with bulbar onset, one with peripheral onset, what do we know about that today?

Dr. Ravits: It’s become I think a very significant topic of discussion as to why it has such a range of the way that it presents itself. We think it’s all the same, it’s all one disease or it’s all ALS, but it looks so different from one patient to the next. Some will have everything normal except the foot drop, and some will have everything normal except their speech and then they have trouble with communications, and some affects the arms. So it hits different parts of the body, but we think it’s the same disease and it’s just breaking out at some place in the motor system.

The motor system for the brain at the brain level and at the spinal cord level is very complicated. They’re very ordered and it’s very well organized. Somehow it breaks out in some region. And then I think one of the things we’re appreciating more and more is that once it starts and it seems to spread to neighboring areas, so there’s a spread effect. That’s been a big motivator for me in my research, not just that neurons are degenerating and strength is being lost but that there seems to be a spreading phenomenon. And why does it spread and how does it spread and what is spreading?

So things like that would be very important aspects of the biology to try to understand. But I think that’s one of the essential aspects of the disease. It breaks out somewhere and then it progresses outward.

Seth: Do we ever see a patient with a breakout in one area and then a breakout in a different area?

Dr. Ravits: Yes.

Seth: Or is that all patients?

Dr. Ravits: No. What I presented is a breakout in one area and a spread is a simplification and it’s being discussed. Certainly, there are patients who have two or three areas, or it breaks at one and then it pops up somewhere else. So it is complicated and I’m not sure we understand it. I’m not sure we understand all the phenomenology of what’s going on. I represent it as a more simplified, just for the sake of trying to visualize it and trying to understand it. But I think you’re right, it can break out in other areas and it can skip areas and it can jump and do other things. But that becomes pretty interesting and important to try to understand. What is it that’s skipping or jumping and what is that phenomenon?

At one point, going way back to the — well, back to Lou Gehrig actually, when Lou Gehrig was diagnosed, they said he had a chronic form of polio. So there has been in the history of the disease this idea that it’s a virus. I think part of the reason that was a popular theory at one point was because viruses spread. It can start somewhere like an infection and then it can spread. So as an explanation, viruses seems to explain some of the observations that we make.

Seth: Thank you. I will give you a little break here and remind those who are listening that at the end of the call we will be opening the lines for Q&A with Dr. Ravits. The number to dial in to is 516-590-0362. For those listening online, you will have to dial in via phone. And then once you have dialed in, press 1 and you will be put in the queue to ask your question.

Dr. Ravits: Say the number one more time.

Seth: Sure. Amy can say it for me.

Amy: The number is 516-590-0362 and then if you have a question, you press the number 1.

Seth: Thank you, Amy. All right. Moving on, we have talked about sort of the wide end of the funnel. But at a cellular level or molecular level, could you talk about what we know about the ALS process?

Dr. Ravits: I can tell you what some of the popular theories are, some of the theories that are emerging. I think this goes back to our discussion about the genetics because the genetics — let’s take ten different mutations across ALS. It’s important to say that it all looks above the same. So when we diagnose a patient we can’t say “Oh, this is the pattern that we would see with mutation X and this would be pattern with mutation Y.” We can’t say that. We can say we diagnose — for the most part, we can say this looks like it’s this pattern and then we have to check all the different genes if it’s a genetic case.

So the point is that sporadic ALS and familial ALS and the different types of genetic ALS, all would appear to be the same. It can be the same things — start with the legs, start with the arms, start with the speech.

So then we can say that with the different mutations that they all cause different kinds of changes. So now we’re appreciating that some of the problems have to do with the way — it seems that it has to do with the way that the DNA that’s in the nucleus of the cell, as the center part of the — the heart of the cell, the way that it’s able to make RNA, which is sort of the working part of the genetic code.

So DNA goes to RNA and then RNA goes to protein, and it all gets shuttled back and forth to  different compartments in the cell. And so some of the biology is telling us it has to do with the way that the RNA is made or processed. So that’s one line of direction that probably started about 2006 when we started appreciating just how important that was.

Another line of thought about this, it has to do with the way the cell takes care of itself, the way it discards proteins or recycles proteins. It shuttles them out when they’re done with their business, how it’s basically housekeeping or house clearing of the cell. So that has to do with what’s called protein degradation pathways. So there’s a bunch of genetic mutations that seem to line up with something being wrong in that direction or that function of the cell.

So those are a couple of the theories. Another one has to do, you know, the neuron has this huge long axon which is reaching from one region to another, so from the brain down to the spinal cord, at the spinal cord out to the muscle. Those are huge pathways or huge reach for the cell. And so things have to go up and down the axon. So that’s called axon transport, so the way things are moved up and down. There’s things pointing to there being abnormalities in axon transmission. And there’s a bunch of others.

So more and more people with each new identification of a gene and a team of researchers come in and try to understand that, it’s pointing out at all these different aspects of the cell’s function.

Seth: And which area of research are you focused on right now?

Dr. Ravits: Well, I think in my laboratory there’s two main directions. One has to do with the spread phenomenon. So I’m hugely interested in how that may occur and trying to characterize it and understand it and, to some extent, exploit it. Pathologically, we’re trying to understand it. So that’s a big part of my research.

The second has to do with a new mutation that was identified three years ago now, 2011, which turns out to be single most common genetic cause which is called C9orf72, and that’s become a real exciting story in ALS especially for about the last three years. So maybe we can spend a minute and I’ll tell you a little bit about that story if you want.

Seth: Yes, please. We like to hear anything that’s considered exciting.

Dr. Ravits: Okay. This gets into this overlap of ALS and dementia so that’s probably — maybe this is a time to talk a little bit about how we used to say that ALS doesn’t affect the mind; that it really just affects the strength and never affects the mind. I think we’re realizing over time that it can affect the mind. It can affect what’s called frontal temporal function–so language, sometimes behavior, sometimes executive functions, judgments, things like that can be affected and it’s more common than we realized. Oftentimes when it does happen it’s not severe; it’s a mild problem but for some occasional patients, it’s actually a very severe part of their disease.

Now you’re asking about other functions like kidneys and liver and things like that but we now see that ALS can affect other functions within the nervous system and that’s called frontotemporal dementia. It turns out that there are families where if you look at the family and you say — we used to not pay attention to the dementia part of it but all of a sudden if you start overlapping them and say it’s either dementia or ALS, it turns out that there’s families that have both and it turns out it’s a significant part of ALS. It’s probably about 6% of sporadic patients and maybe about 40% of the genetic patients — up to 40% of the genetic patients. So it’s really the single most common gene that we’ve identified.

That was identified in 2011 when two different teams; one, a team at the Mayo Clinic in Jacksonville, Florida and the other is a research team at the National Institutes of Health simultaneously identified this gene. It was called C9orf72. Just to tell you how exciting this is, the C9orf72, what that means is that it’s on chromosome 9, C9 is chromosome 9, orf is O-R-F, is open reading frame, so it means that the computer showed that there was a stretch in the DNA, a long stretch of the DNA that predicted that a gene was there but nobody really knew if a gene was there or not. And then 72 means there was number 72. So there are thousands of these all over the genome areas that the computer would say this might be a gene. An open reading frame means that you can read along and it looks like there’s sensible code in that region.

It’s only thought to be a gene, nobody knew for sure. And then in 2011 two teams simultaneously identified that, in fact, there were mutations in there that were the cause of ALS. And it was also the cause of frontotemporal dementia. So all of a sudden it brought at the genetic level ALS and the frontotemporal dementia field together because one gene could do either. It was common in both of these diseases together at a genetic level.

And the third thing that was so striking about it is that it was a totally different kind of a mutation. Usually, a mutation is you just have a single letter that’s changed, a single letter in the code has changed and then that just skews the whole meaning of what that stretch does. But in this case, there wasn’t a single letter that was changed. It was a whole group of letters that were repeating and this repeat which is not abnormal; that there’s a repeat, but it was huge, it was a huge repeat. So rather than just being a small little stretch where there was repetition. That repetition became extremely large. So it was a totally different kind of a mutation that had never been thought about in ALS.

But the fourth thing is that this particular kind of a mutation had already been recognized going back to the 1990s for other diseases. So there’s a bunch of other diseases like muscular dystrophy, myotonic muscular dystrophy. There’s a disease called Huntington’s disease. There’s about 20 or 30 of these disease, all characterized by these large repetitions, these large expansions, they’re called.

And so all of a sudden now, ALS was in – and that had been an area of very productive, very active research for, say, 20 years. And so all of a sudden, it brought ALS now right into the ground zero of that area of research or that part of the scientific research. So that was a huge explosion for the field.

I guess the fifth thing is that, separate from this, there had been people — drug companies and biotech companies — that were able to think of strategies in which you could actually target that gene and try to actually alter and silence or quiet the gene so that it wouldn’t do its badness, so to speak. And so all of a sudden now, the C9orf72 has the potential of being a treatable aspect.

So it’s a huge activity right now, trying to see if we can target it with these new gene therapies and then, of course, trying to figure out what’s the right way to target it and then quickly trying to get that into patients. So that’s what’s happened in that particular area over the last three years, a huge transformation of us now trying to think about some very fundamental treatments for the disease.

Seth: Now, perhaps a question that will show my lack of a scientific background, but how confident are we of ALS symptoms in those patients with the C9orf72 mutation? How confident are we that those are a one-for-one match? Do all C9orf72 cells end up manifesting in ALS?

Dr. Ravits: Yes, okay. Actually, I want to say two things about that. But first, to answer your question directly, the answer is it’s not known. You can carry the mutation and not get the disease. So that’s true for all the genetic mutations. In the phenomena, we call that penetrance, if you carry the mutation what’s the likelihood that it’s going to penetrate through and actually cause a disease or just stay silent. We know that all of the genes have the potential of not penetrating, and so you can carry the gene and not necessarily get the disease. That’s certainly true for C9orf72. You can be a carrier and not get the disease or it may be waiting to happen or maybe it doesn’t ever trigger. So those are big questions we’re trying to understand.

One thing I just want to back up and add to that too which is we’re saying before is that a lot of times, the scientists and research communities are all excited about these genes but they’re actually a rare part of the disease. So if 90% of ALS is sporadic, why are we spending so much time and resources on this small little niche group?

I think the answer is twofold. One is that’s where we have possibility. The sporadic patients are so complicated. We don’t really know how to treat it. So anything we learn in these genetic patients will apply to the sporadic patients as we gather knowledge and momentum. That’s one aspect. The other is that if we can engineer these genetic therapies for these genetic patients and we can find some sort of genetic switch for the sporadic patients, then again we’ve done a lot already to get us into the sort of Holy Land of real gene treatment.

So we’re all learning. We’re all growing. We’re all in this journey but the reason that the genetics is getting its share of attention has to do with the possibilities are nobody’s forgotten the greater group which is the sporadic patients. That’s what we’re really – that’s the Holy Grail.

Seth: Thank you for that. For those of our listeners new to genetics, is a gene like the C9orf72 something that will show up in an over-the-counter or a popular genetic mapping service?

Dr. Ravits: I don’t think so. It’s tricky to do the testing. So if you mean where people mail in and get their genome sequenced for a fee? No, I don’t think this will show up then because it’s too – the routine test wouldn’t pick it up. It has to be specifically sought after.

Seth: Great. Thank you. Back to my question earlier about what you were focused on today. Are there trials coming out of UC San Diego on your research?

Dr. Ravits: There are discussions for that, yes. I think, I would say, in the background for all of these, ALS has really attracted the attention of lots of big pharmaceutical companies. So that’s been a pretty exciting switch over the last couple of years as well where it used to be – we felt as a community, the ALS community, that we’re not being paid attention to by the pharmaceutical companies. And because there were bigger markets and more common diseases and things like blood pressure and back pain and diabetes, heart disease, we’re getting, you know — because it’s affected so many more, hundreds and millions of patients.

But now, I think there’s been kind of a sea change. I think the different diseases — there’s been lots of breakthroughs in cancers and heart and diabetes and so on, and I think some of the drug companies anyway are really trying to make a difference. ALS has really emerged as a disease, as a challenge for drug development. So it’s exciting that so much attention it’s drawing and how the pharmaceutical industry is really increasingly motivated and interested in trying to do something meaningful for ALS.

So there’s lots of discussions, lots of things being tried, lots of trials that I think are being thought about and we’ll see develop over the next couple of years and we’ll see more and more. Certainly, you see, we’re part of that discussion as much as we can be.

Seth: Thank you.

Dr. Ravits: I think stem cells is another one. I guess it is going to be a complicated one. But of course, it’s got lots of attention. Maybe this is a good time to just spend a minute talking about what’s happening in the development of stem cell therapies.

Seth: Yes, please.

Dr. Ravits: So the stem cell therapies are looking at a lot of different diseases – again, heart, musculoskeletal, arthritis, diabetes, for pancreas replacement and things like that – but clearly the neurodegenerative diseases is a big part of what’s thought to be potential for stem cells . Of the degenerative diseases, ALS is certainly one of the top ones that the stem cell enterprise or the stem cell research groups are looking at.

So there’s lots of things that I think everybody’s heard on the news, different companies, different products, different approaches, different trials. And there’s a bunch more that are waiting to happen or trying to get funding or trying to get their cell lines better developed or more predictable and things like that. So I think we’ll see a lot of that developing also over the next five to ten years. We’ll see a lot of different approaches to stem cells.

I think stem cells is going to be a hard application in part because of what we’re talking about earlier is the local properties. If it begins in the leg, then where are you going to put the stem cells? Would you want to put it in, say, the lumbar spinal cord? But if it begins in the arm, then you have to go to a different region. So some of the issues that have to do with how far will these stem cells reach in terms of what they’re going to rescue, and so some of the strategies are going to be pretty complex. You combine that by the fact that to get them in, they have to usually — most of them are being delivered surgically so there’s a surgical implantation or transplantation to get them delivered in the first place.

So it’s got a lot of challenges as a field to try to get this, particularly for a disease like ALS. But we’ll see that happening and more and more people are coming up with new approaches.

Seth: Thank you. We started off with a very loaded question. Maybe we’ll move to the end of the interview with a really tough question. What is the greatest factor hindering your research today?

Dr. Ravits: Well, probably the single biggest challenge has to do with just the complexity of the disease, trying to really understand and model it and test it. So the disease itself is really the biggest challenge. We could talk about funding and things like that, but I think the bottom line is even if we had unlimited resources, it’s still a hugely complicated disease and we need to understand it.

To me, we need to be smarter than ALS if we’re going to beat it. So just trying to do things, we really have to understand it, be smarter than it, and then get there first with our treatments or with really fundamental root therapy. So I think that’s I see as the biggest challenge.

Obviously, funding, getting people in the field, trying to get young investigators, trying to get people with the clinical training to come into the field, get young scientists, get the old scientists, get everybody involved, and trying to get a share of the research funding. So that’s obviously another constraint.

Seth: So the mystery of ALS itself is the biggest hurdle… we understand the complexity of that issue. Thank you for your answer.

We will prepare to go to callers now. Again, the phone number to dial in to, Amy, if you could read that one more time.

Amy: The number is 516-590-0362 and press number 1 for your question.

Seth: So while we allow people to dial in, I’ll ask a wrap-up question of you, Dr. Ravits. What, in your view, is the greatest opportunity for our listeners to get involved or help?

Dr. Ravits: Great question. I think it’s different for everybody so I think probably the best advice or the most important thing you can do is to, first of all, take care of yourselves; the patients take care of themselves and their family members and so on and just fasten your seatbelt and make the best of it and the most of things and to realize how hard everybody’s trying and so to get your house in order in terms of just taking good care of yourselves.

But beyond that, obviously, I think the second thing probably would be to keep the heat on. Patients and families need to speak out, need to speak their minds, need to speak freely and openly. It’s an open community. The ALS community is very open and we have lots of different voices and to keep speaking out and keep putting the pressure on and keep asking good, hard questions. It’s a very easy community to be engaged in. I mean, everybody wants the same thing.

So in terms of as a community, it’s really not very complex as to what we want and need. It’s just how to get there that’s the challenge. It’s a great community to be a part of. It’s an open group and everybody needs to hear ideas. Our ideas change and it changes because people speak out and they’re part of it. I guess that would be an important opportunity and an important thing that everybody can do.

And then I think a third thing is people need to be assertive with their care providers to make sure that they’re being heard, that they’re understood, that they’re assertive in what they need. And if people aren’t paying attention or aren’t hearing, then to not be shy about it and speak out. This is important. It’s important for the providers to hear, and it’s important for you to be heard. So I think that’s the third thing.

And the healthcare system does care but it’s complicated and it’s not going to care if people don’t speak out and don’t assert themselves because in part, ALS is a niche disease and ALS is a complicated disease. It’s a different model then we have with some of the other diseases.

Then, of course, the last thing is fundraising and research. For both, actually, a lot of the resources not only are needed in research but are needed in the clinics too that are providing bed care. So that’s a huge part of it. A lot of the patients will want to give to research but realize that the clinics that are providing the care are oftentimes badly in need of support – financial support. Most of the care is not reimbursed and so clinics do have to justify themselves in their medical centers and need a lot support. So it’s everybody – the doctors and the scientists that need the financial support.

Seth: Thank you for those answers. We’ll now go to our first caller. Caller number 1, you are live with Dr. Ravits.

Caller: Yes. Hi, Dr. Ravits. Thanks so much for taking time today.

Dr. Ravits: Sure.

Caller: I have a question for you about what you talked about earlier when you said you were specializing on how it could potentially spread. And I wonder how’s that involved with or what factors might be that cause this spread. Could you elaborate more about what you have learned about the spread? And are there other triggering events or things that ALS patients could control like diet or things to minimize the spread when that occurs?

Dr. Ravits: Sure. That’s a great question. So I think this concept of spreading disease is also a theme that’s emerging in other diseases like in Parkinson’s disease and Alzheimer’s disease and in frontotemporal dementia. Some of the other degenerative diseases, more and more we’re hearing about this concept of spread. Probably, the area that’s the most popular right now scientifically has to do with this phenomenon called protein folding. I don’t want to get too complicated here, but basically a protein is just a sequence of chemicals and then it folds into a shape and then the shape does different functions. It can do structural, it can be part of a membrane, it can be part of signaling, it can be a part of housekeeping inside a cell — lots of different aspects of proteins. But it’s folded into a shape and the shape seems to be an important part of how it functions.

So there’s a whole theory that somehow the protein gets misfolded so it changes shape and so it gets a kink in it and all of a sudden then it’s not functioning. But not only that, that that kink in the protein is able to take it’s like proteins, the same proteins and then induce them to similar misfolding so that the kink that started in one protein then rolls out to another protein, same protein, not just any protein but it’s the same specific protein. They start misfolding and then one misfold leads to another and then that is an idea of what’s called propagation, so that it can then propagate.

So that’s become a very exciting area of does this occur? How does it occur? What functions are lost when the protein misfolds? And then how can we stop it from misfolding? So I think that’s probably one of the most popular. There’s a lot of other ways in which you could explain the spread, but that’s I think the one that’s got most of our attentions right now, most of our imagination.

In terms of what triggers it in the first place, nobody knows. So the short answer is we don’t know. When you think about like a computer and when your computer gets a lock on it, somehow it crashes. And I think it’s because of all this electricity that’s going on. Some random thing gets thrown in and then it gets thrown off. So it’s possible that in all the maintenance of a protein. It’s just a statistical phenomenon and then once it starts, then it starts cascading.

So the trigger is not known. Maybe it’s just a random event. People have looked at diet, looked at trauma. Trauma is becoming a big area of research right now, like the brain injuries and does that somehow set things up for problems. Exercise has been looked at as there’s something in like high athletes or in excess physical activity that might do it. These are all the areas that — environmental exposures, toxins, agricultural products. So all of these things have been looked at but nobody’s really been able to get the goods on any of it to identify what it is. So the answer is we don’t know what triggers it.

Caller: Well, thank you. That’s great information. And can I ask a follow-up question?

Dr. Ravits: Sure.

Caller: Now that genome sequencing is kind of opening up this whole new world and the C9orf72 is a fairly recent discovery, is there a way of taking the genetic markers from multiple patients that don’t have the sporadic ALS and kind of overlaying them to see if there are any other genetic mutations that pop up?

Dr. Ravits: Yes and that’s being done. Big time it’s being done. So it started actually probably maybe ten years ago. They’re called the Whole Genome Association Studies. So you take, basically, all the sporadic patients — thousands of them — sequence the genome then basically line it up and then try to look at every space or every column and see if they’re a mutation. And that’s going through different iterations.

So it started with what was called in early generation of these high throughput technologies and it showed a few things, but not as much — we all thought it would show some really powerful insights and it didn’t really. It was kind of disappointing. Now it’s being redone and it will continue to be redone as the technologies improve, as we try to comb through it and see what’s possible in the genome of sporadic patients that’s maybe different than other patients. And it’s a huge computer challenge. So a lot of the work is being done not only by geneticists, but by the computational biologists.

But I can assure you that it’s a highly active area of research, very competitive, which is good for everybody because we have big groups in different parts of the world kind of competing trying to break the code on ALS to see if there’s something there. So that’s a very active area of research right now.

And the groups are getting together. I guess the other good news is that as competitive as research is, science in ALS kind of works both ways. It works to everybody’s good because groups are competing to try to have breakthroughs, but they’re also working together, and so sharing information and sharing approaches and sharing materials and things like that so that people are working together as well.

Caller: And then is t all information kept in one system? That seems to be a database challenge.

Dr. Ravits: It’s a huge database challenge and a lot of it’s just done through the cloud exchange. But then also some of the challenges what you call wet labs. So you actually have the DNA and then as a technology improves your way of sort of sequencing the data, then it has to be redone because then it’s not — you have to generate the data all over again. So the DNA is being shared and stored and sequenced by different groups.

Caller: Okay. Well, thank you so much. Thank you very much for taking my call.

Dr. Ravits: Sure. Good questions.

Seth: Thank you, caller 1. We’ll now open that line for caller 2.

Caller: Hi, Doctor. You spoke about the way ALS affects the different systems specifically the metabolism. How does nutrition play a part in treating ALS?

Dr. Ravits: Oh, great question. Probably, if there’s one single — I don’t know if you call it a breakthrough but one single factor we’ve recognized in terms of quality of life and duration of life is trying to deal with the nutritional challenges from ALS. And I’d say the challenges are twofold. Some patients have a lot of trouble chewing or swallowing food so it’s primarily an intake problem. And that’s where feeding tubes and things like that help compensate for the ingestion and the intake of nutrition.

But then we talked about this other group who, independent of that, seemed to have trouble maintaining their weight. And to me that’s a bigger challenge with the patients because putting in a feeding tube is not going to solve it because the problem is not the intake in the first place. And then I guess there’s a third group who just have loss of appetite. They just lose interest in food and it’s trying to stimulate the appetite. There’s actually a couple of drugs that will help with that.

But I think the short answer to your question is we don’t know of any one specific nutritional factor that’s important. It’s just nutrition in general is important. So just trying to maintain nutrition, maintain weight seems to be an important part of taking care of patients or patients taking care of themselves.

Caller: Okay, great. Thank you.

Seth: All right, thank you, caller. Moving on to our final caller, caller 3, you are now on the air with Dr. Ravits. Please go ahead, caller 3.

Caller: Am I hearable?

Seth: Yes, you are. Thank you.

Caller: Okay. Dr. Ravits, first of all, I would like to thank you. It’s a delight to hear you. Your reputation precedes you in this area and we are very grateful that you would take time to share here.

My question kind of overlaps one of the previous callers who asked about the coordination, the database and the coordination of information. And what you shared is that it was quite exciting that people are hoping to go forward and consequently almost competing to find the key, the code that would unlock this disease.

May I ask, are you adequately pleased with the level right now of the sharing of research and of findings? Do you think it could be improved? Do you think that it’s about as best it could be? And just as an uninformed person I think, okay, are we talking about nationwide researches happening in ten centers? Is it happening in every medical school? What are we talking about? What’s the coordination challenge?

Dr. Ravits: Okay. So let me break that into different levels if I could. One level would be the genetic testing that we were talking about earlier, and I’m not a geneticist so I’m not involved in those DNA studies. My studies are more at the RNA level so it’s a little bit different.

So if the DNA where you have big — trying to sequence the genome and then search through it, I would think there’s I think probably two big groups in the United States and a bunch of European groups as a confederation, a couple of different European groups. I think one, mainland Europe. I think there’s an active group in England and an active group in Ireland. I think those are the major and Italy has got great research and the Japanese have great research. So I think these groups are — I’m not in the know on that. I just know the people who are doing it, and they always seem to be trying to pull their data or to share the data and then try different computational approaches.

I’m not aware — I mean there’s always competition, but I think it’s pretty good the way they’re sharing and trying to pool it because the idea being the more numbers you have, the more likely you will find something. I think the problem has just been it’s not showing us as much as we thought was there or that we would find.

Caller: I see.

Dr. Ravits: So I think to me that’s the biggest problem is just what we thought before we got there would be a greater area of exploration isn’t just revealing it. And a lot of it is not done by people necessarily in the ALS field as well. I mean it’s people with the genetic tools and their computational power. So I don’t think collaboration is impeding anything that I can see. It’s always slower than we wish and it’s not as rewarding as were hoping. I think that’s the major thing.

At the more science level in the stuff that I’m doing, I would say I’m kind of new to science. I was mostly in clinical work for most of my career. About ten years ago, I started converting and I’m more and more converting. I’m kind of reinventing myself and rediscovering. I’m coming into a new world where I thought it would be wickedly cutthroat and competitive. And it is very competitive, but I’ve never yet had an encounter where I thought somebody was unpleasant or not sharing or wasn’t smart or careful or diligent, I think.

So we compete with each other but at the same time we know each other and we work with each other. I’m actually hugely impressed at the level that this is conducted. I think one of the things — people start holding — there’s too much data. It’s not that people aren’t sharing. There’s just too much to do and too much to share. I’m hugely impressed.

Caller: I greatly appreciate that and I’m encouraged by it. Again, thank you so much.

Dr. Ravits: Sure.

Seth: Thank you, caller 3, for that question. That brings us to the end of our call. Dr. Ravits, is there anything you would like to share in the closing?

Dr. Ravits: Well, I think as I’ve been trying to highlight, I guess the thing I’ve been trying to communicate is how exciting things are. I think the flipside of that is how slowly it’s moving. It’s not ever moving fast enough for any one patient. That’s always the balance is to try to keep people’s hopes up and convey how truthful things are now but to also realize how complicated the problem is. And it’s not going to be easy to beat this.

So I think we’re all on the same side. That’s a hugely important thing. We are working as fast as we can. But at the same time, we got a big challenge ahead of us.

Seth: Thank you for being on our show, and thank you for your research and dedication. We sincerely appreciate you. For those who were not able to cast the phone call today, please go to The audio from this call will be archived there, and the transcript for the call will be posted there one week from today. Again, we thank Dr. John Ravits of UC San Diego for your time. Please tune in for our next show. Thank you.

ALS Crowd Episode 1: Dr. Merit Cudkowicz on the state of ALS research today

Dr. Merit Cudkowicz, MD
Massachusetts General Hospital
Interview Date: June 26, 2014



Dr. Cudkowicz, MD of Massachusetts General Hospital and top ALS researcher, gives an overarching view of the state of ALS discoveries. She describes what ALS is and how its biggest challenge is its variation in each patient (heterogeneity).  She describes very exciting new approaches. One approach is a surgical approach using fetal stem cells by Neuralstem to grow new stem cells, which is being studied at the safety/dosage stage. She describes an approach using a patient’s own stem cells by a company called Brainstorm where the stem cells are removed, treated and returned to the patient. This approach is now in clinical trials in Israel and the US. She shares a Phase III trial by GSK that uses an antibody to affect a protein that stops neurons from growing. She explains another approach that uses skin cells to make motor neurons used in combination with an existing drug now used for seizures called Retigabire. She also explains a drug by Cytokentics that helps affect muscle strength. She notes that there is now greater interest in the scientific community to study ALS and is very hopeful about new discoveries. She shares how patients can learn about ALS clinical trials. She notes that the two most important hurdles to overcome in ALS research are to gather and study a large enough patient population’s biomarkers and then to acquire necessary funding to continue research projects that can move the field forward. 

The live ALS Crowd Radio podcast with Dr. Cudkowicz

Online Health Radio at Blog Talk Radio with ALS Crowd Radio on BlogTalkRadio

Full Transcript

Seth: Welcome to the inaugural show for ALS Crowd Radio. I’m your host, Seth Christensen, and we are thrilled to be here with you today.

A little first about the ALS Crowd mission: ALS Crowd is a brand new, not-for-profit organization, a division of the Crowd Care Foundation dedicated to connecting ALS patients and researchers to eventually develop a cure.

I as an ALS patient, was diagnosed four years ago. At the time of my diagnosis it was explained to me that ALS is a diagnosis that only comes through a process of elimination. There is no definitive biomarker or bloodtest to diagnose one with this syndrome and we today will explore this topic further.

You can follow us on as well as our Facebook and Twitter page. At the end of today’s show, we will have time for Q&A with a number of callers. The call in for this online is 516-590-0362.

This time I would like introduce my wife and co-host.

Amy: Hi. My name is Amy Christensen. I am here to welcome our guest today. Her name is Dr. Dr. Merit Cudkowicz. She is the Chief of Neurology Service, Director of the Amyotrophic Lateral Sclerosis Clinic and Co-Director of the Neuromuscular Division at Massachusetts General Hospital. She is the Julianne Dorn Professor of Neurology at Massachusetts General at Harvard Medical School. Dr. Cudkowicz completed medical training at Harvard Medical School and was a resident in Neurology at MGH. She obtained her master’s degree in Clinical Epidemiology from the Harvard School of Public Health.

Dr. Cudkowicz’s research and clinical activities are dedicated to the study and treatment of patients with neurodegenerative disorders, in particular, amyotrophic lateral sclerosis (ALS). She directs the MGH ALS clinic and the Neurology Clinical Trials Unit. She is one of the founders and co-directors of NEALS, Northeast ALS Consortium, a group of 92 clinical sites in the United States and Canada dedicated to performing collaborative academic led clinical trials in ALS. In conjunction with the NEALS consortium, she planned and completed 7 multi-center clinical trials in ALS and is currently leading three new trials in ALS.

Dr. Cudkowicz received the American Academy of Neurology 2009 Sheila Essay ALS award. Dr. Cudkowicz is on the Research Council of the American Academy of Neurology and the medical advisory boards for the Muscular Dystrophy Association.

Seth: Now with that, we would like to welcome Dr. Merit Cudkowicz to the call. Dr. Cudkowicz, are you there?

Dr. Cudkowicz: Yes. Thank you, Seth and Amy, for having me for this inaugural radio show. I’m very excited to be here.

Seth: Well, you are an incredible part of the ALS community and a good friend of ours. So we’re thrilled to have you. Dr. Cudkowicz, I thought we would start off this inaugural show by somewhat defining ALS in as far as we can. If you could have a sort of a lay level, describe ALS to us and including what we know about its biology in relation to other disease categories.

Dr. Cudkowicz: Absolutely. ALS stands for amyotrophic lateral sclerosis. It’s also called here in the US, Lou Gehrig’s disease, and one might also hear it called in other countries a motor neuron disease. What it is is a disease that happens to people as they age, so something we call a neurodegenerative disorder. It affects these nerve cells called motor neurons. When those are affected, people develop symptoms such as muscle weakness or muscle twitching and cramps. It’s a serious disorder and it’s one that we really absolutely need to find cures and treatments for.

It’s rare. For example, in the United States at any one time, there might be about 35, 000 people who have ALS. Each year, about 5,000 to 6,000 new people are diagnosed with ALS in the United States. This is a worldwide illness. It affects all countries, all races, and ethnicities. It can affect all ages really. It tends to occur in the mid-50s on average but can hit people as young as 20, as old as 90. We really think it’s a syndrome, meaning that there are probably many different causes of ALS, though in the end, the illness is similar in that it’s really an illness of these nerve cells called the motor neurons and that we have in our brain and our spinal cord.

Seth: Excellent. Yeah, very much and that is a perfect introduction. I’m curious about what we do see globally. Are there any dissimilarities between the cases in the US and other countries? Do we have that information?

Dr. Cudkowicz: We do have information now on what ALS is like in many, many countries and particularly Europe and Canada. We’re really just starting to learn what it’s like in Asia and in some other places. In the big picture, it’s pretty similar in all these countries. There are a few spots in the world that are kind of hot spots where ALS is extremely common and a little different, for example, in the Key Islands in Japan and in also in Guam because sometimes it’s associated with other neuIrodegenerative diseases such as Parkinson’s disease or Alzheimer’s disease. Aside from those two palaces, it really does look clinically and biologically the same in all these countries.

Seth: Great. What are the variations in illness progress in different patients? Are young patients, for example, better off than their more advanced counterparts? Does age matter?

Dr. Cudkowicz: There’s huge variability between people with ALS. Some people who have very, very slow courses, fortunately, meaning that they might have the illness for 10, 20, 30 years, that’s about 10% of people with ALS. Then there’s the other extreme, another perhaps, 10%. They have a super rapid form–less than a year. Then there are really people who are everywhere in between. So that huge variation is really important for the field to try to understand, to try to figure out what causes that difference and how we can maybe make everybody a long, long super survivor of this illness.

It does vary with age. That was your question. So we know in general the younger someone is when they almost start so slower the illness and the converse, the older you are when it starts, the faster the course goes. But age is not really the primary driver of the huge variability that we see. We don’t actually yet know why again some people have this for 10, 20, 30 years and other people don’t, but there’s a lot of research going on right now to try to understand that.

Seth: Interesting. In addition to speed of illness progress, is there a difference in biologic onset? Are different people symptomatic in different ways?

Dr. Cudkowicz: Yes. So that’s a really good question. Yes, it does present differently between people. In about 80% of people, the illness will start in one of their limbs. It might start in the hand weakness, or the foot. But the other 20%, it starts in what we call the bulbar muscles. These are the muscles of speech, swallowing, breathing. The field is trying to also understand that variations of why it presents differently in different people with ALS.

Seth: Well, we are behind the field and there’s study of this. For our listeners’ sake, is there a leader in the collection of statistics? Is there a global body that attracts and disseminates information about ALS?

Dr. Cudkowicz: There are a couple of groups that are trying to really collect data from all patients with ALS. I want to say that I think this is really critical and a really important way to advance the field. These groups are working collaboratively. So I’ll just name a few of them. For example, there’s an ALS registry that is funded by the Department of Defense and run by the Center for Disease Control in Atlanta. Patients go to their website and enter data about themselves and there are questionnaires about risk factors, family history–really important sources of information. They also retrieve information from insurance companies, and all this pool of data is available for research. That’s one source.

The consortium that I direct called the Northeast ALS Consortium also has the policy that every research study we do whether it’s a trial or a biomarker study, that all that data from participants is shared with the research community. So we partnered with a couple of other foundations, the ALS Association, the Muscular Dystrophy Association, Prize4Life to gather all this large data set and make them openly available to researchers and there’s a project called POR-ACT.

Seth: Excellent. They’ll give sneak peak, maybe a spoiler at the end of the program, we do want to ask you how our listeners can get involved and how with these organizations and the others that we discussed between now and then. I thank you for that.

Changing gears, we would like now to talk about the state of ALS research today, where have we come from and what are we headed towards including the current trials and other hurdles that we still need to overcome. Perhaps, we could start off with theories that have been explored and proven wrong in the past. Could you speak to that point?

Dr. Cudkowicz: Globally, for ALS research, we’re way, way ahead of where the field was five or ten years ago. There’s an enormous number of people and companies and academics working on ALS, really globally. I think we’re in the time of a great hope. I’d also say that much of the work on ALS research really started in the ’90s. It hasn’t been that long that there have been the tools and the clues to really be able to study ALS. It’s still really in its infancy of trying to kind of figure it out.

For a time, there was a concern that maybe this was infectious and maybe a virus could cause it. I’d say that’s been largely proven wrong though it’s always hard to be 100%. The reason people thought it may be a virus is because polio is a motor neuron disease caused by a virus. So the thought was maybe there’s some other virus like that that’s causing this, and people looked hard for that and not been able to find at least any known virus.

I’d say that the other theories of ALS are still on the table. There have been a lot of them and they’re still active. I think that it’s important to keep them on the table because most likely ALS is not one disease. As I mentioned before that we really think that there’s many different ways that ALS can start whether it’s your immune system or something wrong with a gene in your body, or a protein problem, that it’s not one cause, one disease. For that reason, most of the theories are still kind of active in ALS.

Seth: I imagine that would be very complicated to deal with in a medical trial if you were trying to test a group of people and they may only have a different disease.

Dr. Cudkowicz: Absolutely. I think that’s one of our biggest challenges but not insurmountable. I think that it’s good to know what you’re up against and then try to figure it out so that you can do smarter trials and identify people who have maybe one particular biology, maybe that’s inflammation, and target drugs that target that biology, and use different drugs for different patients. Again, this is not unique to ALS. I mean I think most diseases come from many causes if you can think of just common diseases like high blood pressure. There are many different reasons people have high blood pressure and you’re treated differently depending on what the cause is. I think it’s the same for ALS. We’re going to get to the point where it’s different treatment for different patients.

Seth: Excellent. I am curious hearing you say that. What portion of the field is focusing on identifying a cause compared to the portion of the field that is attempting to treat. Is that a clear distinction?

Dr. Cudkowicz: I think it is a distinction. I’m not sure I know the proportions so I’d say that there’s a lot of effort on both ends. There’s a real belief that there’s a need to develop treatments for patients today that we know enough about the biology and not about the targets that we should be doing trials and therapeutic approaches now in people with ALS today. But while you do that, we really need to be supporting the basic science to understand the cause and the biology. Because the more we understand there, the better our treatments can be. So you really need both. I guess I’d say it’s probably about 50-50 at the moment.

Seth: Sure. How do you work on that plane while it’s in the air? I guess that’s the metaphor. Great. We would now like to move to probably the most exciting part of today’s show, which is discussing theories that are under consideration today and the trials designed to test those theories. Can you tell us about what keeps you up at night out of excitement?

Dr. Cudkowicz: Sure. I divide these theories into the genetic forms of the illness and the non-genetic forms. It can just take a minute to explain that.

So 90% of people with ALS do not have a family history or at least that we know of. So it’s what we call sporadic ALS. Then there are 10% people where the illness does run in their family. In those 10%, we know the genes in out 60% or 70% of those families. There have been huge advances in understanding the genetic causes of ALS. That is so important is because we think what we’ve learned from the genetic causes is going to be directly applicable to even the people without the family history. They can still help us understand the biology.

One of the most exciting things therapeutically is that with the whole gene revolution, we now have the tools to fix genetic mutations in people. There’s starting to be some trials just in the genetic forms of the illness and to fix the genetic mutation, and that excites everybody because it’s right at the cause of the illness and ideally really should work. We know it works in the lab and now it’s already starting to go into people.

Just for example, the two most common genetic causes of ALS are in the gene called SOD1 and another one, C9ORF72. There are companies and academics investigators working on ways to turn off those genes. One of them has already gone to patients in SOD1 families. I’d say that ALS is the pioneer there. This was the first time that type of approach was used for any neurological illness. Now, that approach is being used in many neurological illnesses. So that’s one area that really excites me and excites other people.

However, there are 90% of the other people with ALS who don’t have the genetic form and there’s still a lot of excitement there. One area that patients are surely excited about and I’m excited about is the use of stem cells in ALS and we’re early days here, and again the patients are really the pioneers here because its early days were stem cells in any neurological illness. There are two clinical trials going on now in the United States for people with ALS using stem cells.

Shall I talk about those now? Would that be helpful?

Seth: Yes, please. Go ahead.

Dr. Cudkowicz: One of them is with a company called Neuralstem. The idea here is to take stem cells that are from the spinal cord of a fetus and they’re grown to be nerve-like cells. They’re put in people right next to their motor neurons. So it’s a surgical approach. The idea is if you put healthy neurons or nerve-like cells right next to the entered motor neurons, can they create a healthy environment, secrete things that will make the motor neurons of the patient healthier? This has already been now done in two studies and about 30 patients have gone through this procedure. Again, this has never been done to anyone before, so the participants are really, really pioneers, and that’s moving forward into a bigger study now.

When we do these studies, the first thing you really have to figure out is safety and what’s the right dose. Dose in the stem cell trials is how any cells you’re putting in. These studies have really shown that so far that it looks like you can do this. This is safe and trying to figure out the right dose for people.

The other stem cell trial is with a company called Brainstorm. This uses people’s own stem cells. We all have stem cells in our body, in our bone marrow which is in our hips. They take those stem cells out and then they treat them so they have those secrete proteins that are good for your motor neurons that can help your motor neurons become healthier. They give those cells back to people in the fluid around the spinal cord and in the muscles. This is been done now in 24 people with ALS in Israel. They’re now bringing that study in the United States. It has officially started the three centers, Mass General, UMass, both in the Massachusetts and then Mayo Clinic in Minnesota.

I’m excited about both those. We don’t know if they’ll work. I mean we’re hopeful. There’s good science for them but I think it’s just the beginning of using stem cells as a way to help or kind of repair people’s motor neurons independent of what’s causing them to be injured in the first place.

Seth: To clarify what I think I just heard, we’re not looking at replacing damaged cells but we’re looking instead at causing an environment where they can follow the body’s natural tendency to heal.

Dr. Cudkowicz: Exactly. I think the idea of replacing a motor neuron is certainly something that people would like to do but the knowledge and the science isn’t quite there yet to do that. Certainly, there’s research in the lab to try to figure out how to do that but it’s still not ready for patient trials at this time.

Seth: Those are some of the most provocative or exciting studies. I assume there’s also more traditional pharmaceutical research going on?

Dr. Cudkowicz: Yes. Those are also really exciting. Even though started with the gene therapy approach and the stem cells because they’re really kind of the most novel in approach, it really could be that a small molecule or drug will be much more effective. We don’t know and it’s really important to keep developing those. There are, I’d say at the moment, probably about 14 clinical trials going on the in the world in ALS, in people with ALS. There’s a lot of promising therapies being developed. I’m happy to talk about a few of them if that would be of interest to the listeners.

Seth: Or maybe a one intermediate question. Do you know of those 14 trials, are they having any trouble recruiting patients, or is the subscription level higher than they can take?

Dr. Cudkowicz: I think there’s not one answer on that. There are some clinical trials that enroll very fast so that there are more people who want to be in it than can possibly be enrolled. But there are also other ones that are the opposite that even though the science is exciting, the drug is exciting that the enrollment takes longer than they hoped for. I think it has gotten much better in the last couple of years because I think the information is better that’s getting out to patients. I think patients and families know now much more about what’s going on. The trials are made known to people through webinars, through websites, or through their doctors in a much more proactive way, so that people have choices of whether they want to be part of it or not, and they have the information. That’s helped with enrollment.

Seth: Great. Thank you for that answer. Maybe we could go back and now talk about a few of those drug trials.

 Dr. Cudkowicz: Sure. When you develop drugs there’s what we call three phases of the development. The first one is when you’re first giving a new drug to people. It’s Phase I. They’re usually small, and you’re looking at safety in dosing. Then there’s a Phase II, which is maybe 100 people where you’re trying to look at longer-term safety and also is there a hint that it works, if things go in the right way. Is the drug doing what you hoped it should do? Then the last phase is Phase III. Those are larger studies maybe 500, 600 people. You’re really looking if it doesn’t work. If it works, then you go ask to get it on the market.

I want to talk about the one trial that’s in Phase III right now. That’s with a company called GSK, GlaxoSmithKline and the drug is what I call a NOGO-A body. The idea in this trial — the reason why I’m talking about this is we’ll have the results hopefully at the end of the year. It’s one that we’re going to have the results soonest from. The idea of this drug is to help repair motor neurons. So we all have in our bodies these proteins that inhibit the motor neurons from growing. One of them is called NOGO-A. This drug gets rid of the inhibitor. It allows your motor neurons to kind of sprout and regrow and repair themselves. That’s one approach that’s been taken to augment the body’s own ability to repair. It’s a study that’s going on internationally. We’re waiting for the results by the end of the year hopefully.

Seth: Okay, very exciting. Please continue.

Dr. Cudkowicz: Another one that we’re excited about, we’re going to be starting the next couple of months using the drug called Retigabine. This is also actually from the same company. Why I wanted to talk about it is because we’re always looking at ways that we can efficiently pick drugs that are going to be successful and how do we do that. So a new approach has been to take people’s skin cells. From their skin cells grow — you can actually make from people’s own skin cells; you can make motor neurons that kind of represent what their own motor neurons look like. It’s a very new technology, the persons figured it out got a Nobel Prize a couple of years ago. But it’s very important as a way to do an individual screening of whether the drug might work. We’re really hoping that this will be a way to screen drugs much faster for people with ALS.

When they did this they took skin cells from lots of people with ALS. They turned them into motor neurons and they studied them. What they found is, in people with ALS, these motor neurons were firing abnormally. It’s like something had turned them on. They were hyper excited. Then they went down to try to figure out why and they found that there’s a problem in something called a potassium channel. Then they looked, are there drugs out there in the market already that might be able to fix that problem. When they did that, they found one called Retigabine. This is a drug already on the market meaning that you can write a prescription for it for people with seizures.

But now, we want to use it for different reason–for ALS. A trial of this is going to start in people probably in the fall of this year to see what the right dose is and to look for safety and preliminary efficacy. The hope is that this should work. That’s the best thing if it works. Then the second thing that would come out of this is finding out if this is a good way to quickly screen for drugs. Again, getting back to this idea of more personalized medicine, if you can use people’s own skin and make the motor neurons and see if you can pick out what drugs might be helpful for them.

Seth: Extremely exciting. Are there other trials you care to mention at this time?

Dr. Cudkowicz: Sure. The other one I’d mention is with a company called Cytokinetics. This was a large study — what we call the Phase III — that was finished last April. This drug worked on your muscles directly. So one of the main symptoms in ALS is muscle weakness. This drug helped your muscles contract more efficiently to try to give them more strength. I would call it more of a symptomatic treatment. Can you give people more strength today so that they can do more things? The study was reported in April and it had somewhat mixed results but I think there’s some positive result in there.

When they looked at muscle strength, people on the drug actually did have higher strength as expected both in terms of their limb muscles as well as their breathing. But when they looked at overall function, they didn’t see a benefit. The study is now — it’s not yet going to market but the question is, should the field keep developing it given that that’s the only thing we’ve ever seen affects muscle strength in a positive way? The hope is that will continue so that we can figure out how to give it to people and get that benefit. I think we’re going to see another study of that coming up in the near future.

Seth: I’m curious whether these studies are primarily done by neurologists or if you have cross specialty interest as well?

Dr. Cudkowicz: The studies are primarily done by neurologists but there’s physiatrists who see people with ALS and do research. Physiatrists are rehabilitation doctors. The other healthcare professions that are very involved in the studies are, for example, like respiratory doctors or physical therapists, but most patients see neurologists and so most studies are run by neurologists.

Seth: Great. Where can our listeners find a list of these medical trials, their inclusion criteria, and progress?

Dr. Cudkowicz: There are a couple of options. I’ll tell you the easiest ones. Thanks to a donation from the ALS Association, we have a website that whose sole goal is to keep current information about clinical trials. That’s That’s one place. Then also besides having the information of the trial, we have an email address that people can ask questions and also have a 1-800 number that people can call if they have questions about a particular study.

The other place is a government-run website called Before any company or any investigator does a clinical trial, they’re required to post it on that government website. So it will always have any trial that’s about to start. Again, that’s When someone’s on that website, you put in search terms so you’ll put in ALS, and it would list every study that’s going on in the world really. Mainly Europe, Canada, and the US use this website.

So those are the two that I tend to tell people that I see in the clinic. The other places one can go to are the ALS Association website,the Muscular Dystrophy Association, and the ALS Therapy Development Institute website. They also keep a list of ALS trials.

Seth: Excellent. Outside the governmental and institutional bodies, are there any private companies that are leading the way in the ALS community?

Dr. Cudkowicz: There are a lot of pharmaceutical companies interested in ALS which is great news because we need to work with them. They have knowledge in the drugs and we really try hard to get them interested and excited about doing something in ALS. Right now, there are very many of them and I won’t leave any of them out but I’d say Biogen Idec is leading and really committed to ALS, GSK, Pfizer, Roche. Many drug companies have ALS as a potential area where they want to develop treatment.

Seth: Excellent. Jumping to the funding question, do you have any idea or does anyone have an idea of money spent annually on research or dedicated to ALS research?

Dr. Cudkowicz: I’d say it’s not enough but I think that any disease group would say that. There’s data on this from NIH. I don’t know the latest numbers but I know at some point the government was funding in the order of $40 million a year. That sounds like a lot but it really, really isn’t. If you really want to tackle an illness you need a lot more resources than that.

Seth: I agree. Thank you for that. The last question in this category: is there a way to summarize the gravest challenges impeding research today?

Dr. Cudkowicz: I think the biggest biologic challenge is the disease heterogeneity; this difference between people. I think until we really understand the biology behind that, it will be hard to develop really effective treatments. Just as you mentioned before, if you have 1,000 people and who have ten different kind of biology going on in a trial and you’re only attacking one of them, you might miss a signal. I think the field has really recognized that now and is focused on trying to understand that biology. That’s the biggest, I think, biologic challenge.

I think the other big challenges what we’re talking about before is the funding. We need to be attracting the smartest, most innovative scientist into the field. You do that in two ways: One is they’re very excited about science. I think that’s there already. People are really hopeful and excited about ALS and feel it’s tractable and can be figured out. They need the resources. It’s very hard to get money from the government now. There have been huge cuts so people really depend much more on philanthropy or other type of sources of funding to get the work done.

Seth: On your first point about the complexity of heterogeneity, what is the research on biomarkers or ALS today? Are we making a progress on finding common characteristics?

Dr. Cudkowicz: I think we’re making progress on biomarkers but it could be much faster if done in a much bigger way. Right now, there are a lot of people looking at maybe 50 patients with ALS looking at their MRIs or spinal fluids or blood cells and lots of different groups kind of looking. In order to really figure this out, we need data from thousands of people. Everyone calls it the “big data” idea but it’s really true. If for us to really figure out ALS, we need to be engaged with the patients that when they come to our clinic, we’re collecting meaningful data and sharing it, and doing biomarkers in really thousands of people. There’s a lot of initiative to try to do this and it really is down to a matter of raising the funds for it.

Seth: All right. Please go ahead.

Dr. Cudkowicz: I could say that this is being done in Alzheimer’s and Parkinson’s disease and has led to huge, huge new insights into those two illnesses. In Alzheimer’s, the government paid for a big biomarker study, and Parkinson’s, the Michael J. Fox Foundation is funding a huge biomarker initiative. We need the same thing in ALS. I think it would really speed up our understanding of the illness tremendously.

Seth: Excellent. I really appreciate you focusing on what we can do. Before we go to get call ins, I’ll ask on more question. But do you want to invite anyone to call in? There is no wrong question and we would love to hear from you. The number to dial in is again, 516-590-0362. We will now ask the final, formal questions from Dr. Cudkowicz, and maybe you already covered part of this. What, in your view, is the greatest opportunity for our listeners who get involve and help?

Dr. Cudkowicz: I think the greatest opportunity would be if — for the people with ALS if you would participate in some of these biomarker studies, often it’s really donating a tube of blood. Sometimes it’s a little bit more. Spinal fluid or MRI study but being proactive about in a way letting us learn from you. I think that is the only way we’re going to really crack this illness. I know it’s a lot to ask from people but it’s really incredibly important.

Seth: Excellent. Thank you. With that, we will open the call line. If callers dial in and then press 1 on your keypad, you will be invited into the call. I believe we have a few people dialed in. We will start with Caller 1.

Amy: Hi, Caller 1, what’s your question today?

Caller:  Thanks for taking my call. If you look at the disease ALS and the downside associated with it, I wonder why the treatments –? Only one known drug out there in the marketplace and no known cures, why aren’t –? I don’t know maybe this is not a fair question, why aren’t people being more aggressive with the disease in terms of experimenting? I was talking with the head of Oncology at a local hospital today and he just said, “You know what’s the outcome is going to be, why not be more aggressive with it. It’s worth the downside of doing somebody’s more aggressive things in trying them out and sharing the results with others.” I understand there’s a safety protocol that needs to be invoked, but are there things out there that were not tried right now? Is there a way to just push the envelope a little more?

Seth: Great question.

Dr. Cudkowicz: That’s a great question. I do think that, certainly, in the last couple of years, the level of risk and aggression has gone up a lot. Just for example that stem cell trial where patients are going under a neurosurgical procedure to have stem cells put in their spinal cord as aggressive as you’re going to get, plus some of the gene therapy trials. So there’s been a huge shift in the last couple of years to really go out there and try to do things that has scientific rationale. Even if they would have a higher risk of maybe some of the drugs.

You’re absolutely right that the mindset in ALS is not the same as in cancer. Part of that is actually from the FDA. We do not have the same approach. The patients and doctors have gone and lobbied for some change there. I think that patients were heard and the hope is that there’ll be some change so that we can get therapists to patients quicker.

Caller: You’re saying that the lobbying has happened. I mean that’s something that we could do as caregivers and patients. Is there something else we can do in pushing that area or the lobbying already happened and just waiting for the outcomes of that lobby?

Dr. Cudkowicz: I think there’s always room for more lobbying but doing it in a cohesive manner or I think it’s really important. I’d say that the champions there has really been the ALS Association and the MDA with lots of patients in and their caregivers going together with a single voice of “this is what we need and that we’d like.” I think they’re still — we have to keep lobbying all the time but I think having a kind of clear message in that and a kind of a group approach would be great.

I would recommend people if they haven’t already that they reach out to their local ALS Association and MDA. They all have these advocacy teams and enough to join them so that we have more people behind it. If people do it all on their own, then there are different messages going through and it’s much less effective I think.

Caller: Thank you for doing the show today and taking the time. This is kind of groundbreaking and I’m excited to see this happen. Thank You.

Dr. Cudkowicz: You’re welcome. Thank you.

Seth: With that we will go to our next caller.

Caller: Yes. Hi, doctor. Thank you so much for taking the time to do this show today. You mentioned next generation sequencing. I have a question for ALS patients. I have several questions I guess. First, what is the cost to do that? Should patients request that diagnosis and then where is that available for ALS patients right now?

Dr. Cudkowicz: Those are great questions. I don’t think that today doing like a whole genome sequence is going to be that useful. Those costs have come down a lot depending on where one does it. They range from $2,000 to $5,000, but I think more important is to consider getting people’s DNA tests for the known genes that cause ALS. The reason I think that’s important now as opposed to maybe a couple of years ago is because there’s treatment being developed just for the genetic forms. It’s important I think for someone else, they carry any of the known genes because of these new therapies. I’ll be a little more specific.

One of the most common genetic causes of ALS is in the mutation with Chromosome 9. It’s called C9orf72. This causes 40% of ALS in the families but it also is found in between 5% and 10% of people without any family history. If you don’t have a family history and you don’t get tested, you have no idea if you’re carrying that particular genetic mutation. There are several companies working on ways to fix such genetic mutation. I think getting tested is more important.

Now, the challenge is that can be a very expensive test that ranges again from a couple of hundred dollars to a couple of thousand depending on where you live your insurance and which company is used. Hopefully, that cost will come down. As technology improves, the cost should come down.

Caller: Is this whole exome sequencing cheaper that whole genome sequencing?

Dr. Cudkowicz: I believe it is. I just don’t think at the moment like people would know what to do with the data. I think it’s useful on the research side for sure but clinically if — unless it’s one of the known genes, it would be hard to know what to do clinically with the whole exome or whole genome sequence results.

Caller: You said there were targets — people targeting that C9. Are there other neuron diseases like Parkinson’s that have that same genetic mutation?

Dr. Cudkowicz: Not Parkinson’s disease but the C9 mutation is also found in people with something they call Frontotemporal dementia as well as another illness called Spinocerebellar atrophy or ataxia. It does look like that one gene can cause different disorders, one of them being ALS. The gene was only discovered three years ago and now a lot of people working on it and very complex but I think the key is that we’re not that far from studies and people of a way to turn off a mutation. So I think it’s getting more important for people to know if they carry that gene or not.

Caller: Okay. Well, thank you so much for taking time to answer my question.

Dr. Cudkowicz: You’re welcome. Thank you.

Seth: All right. We will take another caller. Caller 3, please go ahead.

Caller: Hi. It seems to me that there are lots of studies and things going on– it seems like you have to be in the right location. Is there any way — it makes it harder for a person to be treated or to be studied if they can’t live, say, in Boston or in Massachusetts. What is the reason for this? Are there ways around it? Are there ways to make this one accessible?

Dr. Cudkowicz: One of the goals of our ALS Consortium, the NEALS Consortium is to have a center everywhere in the United States. We do have a hundred centers so there are many centers that are close to patients. But in some of the trials, they’re small trials so they can’t be at a hundred centers. I think the one you’re referring to is the Brainstorm study that’s just had three centers. It does make it — it makes it impossible for people who live afar from those areas to be part of that particular study. The hope is that with a hundred centers out there in the US who know how to do clinical trials, there should be able to be at least one if not more studies at each of these centers.

Caller: Okay. Thank you.

Seth: Thank you, Caller 3. We have time for one more question. We will go to Caller 4. It looks like we have lost them. Being a little cognizant to Dr. Cudkowicz’s time, we will wrap up here. I would like to ask Dr. Cudkowicz, is there anything else key that you think we have not covered here that our listeners should be aware of?

Dr. Cudkowicz: I want to make sure we kind of ended with what I think is the truth which is this is an incredible time of hope in ALS. There are thousands of people study now as opposed to a hundred or so a couple of years ago. It doesn’t go a week where there isn’t a meeting in ALS, it’s really a hot field and one where there’s a lot of hope. One of the challenges is keeping up with the information. I think your website and this type of groups are really critical for sharing that exciting science with patients and their families. So I’m very upbeat and hopeful that there are some big changes and big events are around the corner for people with ALS and their families.

Seth: Well, thank you very much for you time. We will have the transcript from this our inaugural show available one week from now. We will archive this show for those who were not able to listen today.

Please do follow us on We will announce our next speaker as soon as we have verified that. Again, sincere thanks to Dr. Merit Cudkowicz. Thank you for your time.

Dr. Cudkowicz: Thank you for having me. It’s great to talk to everybody.

ALS Crowd on KSL News

Hear about Seth Christensen, his fight with ALS and his decision to make a difference in ALS research.