• ALS Crowd Radio Episodes
    • Oct 02, 2014

    ALS Crowd Episode 7: Dr. Jeffrey Rothstein on IPS cell research and therapy

Wednesday,  October 15, 2014

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Learn more about the deep work being done by Dr. Jeffrey Rothstein at the Brain Science Institute at Johns Hopkins in ALS research and how collaboration of many institutions can drive ALS research at a faster pace.


Seth: Hello and welcome to Episode 7 of ALS Crowd Radio. I’m your host, Seth Christensen here as always with Amy Christensen. We are thrilled today to have as our guest Dr. Jeffrey Rothstein of Johns Hopkins Medical Center. Amy?


Amy: Dr. Jeffrey Rothstein M.D., Ph.D. organized the Robert Packard Center for ALS Research at Johns Hopkins and serves as its Medical Director. This is the first multi-institutional, multi-national collaborative academic organization devoted to understanding the cause of ALS and translating the information into new drug and cell-based therapies. Dr. Rothstein’s clinical specialization is in neuromuscular disease with a particular focus on ALS. Other clinical areas relevant to his laboratory-based research include epilepsy, spinocerebellar ataxia, and brain tumors.


Dr. Rothstein has received numerous awards for his work on ALS, including the Sheila Essay award, recognizing his worldwide contribution to ALS research, as well as the Diamond Award for ALS Research, the Lois Pope Foundation Award for Medical Research, and The Landa Foundation Lectureship. He has received and/or submitted almost a dozen patents applications based on his laboratory research. He is the co-founder of Ruxton Pharmaceuticals and serves as its scientific advisor.


Dr. Rothstein has been the principal and/or local investigator in almost a dozen national or international trials in ALS. He is the author of over 150 articles on the basic and clinical neuroscience. Dr. Rothstein’s laboratory research is funded through the NIH, the MDA, the ALSA, and Project ALS.


Seth: Dr. Rothstein, thank you for being with us today.


Dr. Rothstein: It’s my pleasure to join all of you this afternoon.


Seth: Well, we are thrilled for today’s show. As always, we will take callers towards the end of this show. Amy, will you share that number?


Amy: Yes. Callers, please call in to 516-590-0362 and press 1 indicating that you have a question for Dr. Rothstein.


Seth: Excellent! Thank you. Dr. Rothstein, we always like to start off with a bit of a loaded question. What in your mind is the cause of ALS?


Dr. Rothstein: That’s a particularly loaded question to start with. The clinician-scientist in me will say that 10% of ALS we know exactly the cause, and it’s caused by a defective gene; hence, 90% plus of patients we don’t really know what causes it. We have a lot of clues not on complementary medicine. We can often refer to things that we pretty much don’t think cause it. There’s not a lot of good evidence that what you eat causes the disease. By the way, I’m going to tell you these things not that there aren’t always some potential for exceptions, but when we look for things, we look for very strong evidence in something, so diet, no; where you live, no; who’s your spouse, no. The vast majority of things are not really causal agents.


Now, what we’re beginning to understand is that even when you have the disease when it’s not in your family — and that we traditionally call sporadic ALS, meaning it happens out of the blue — we’re now learning that actually, a fair number of patients do carry a gene defect even when it’s not seen in mom or dad, aunts and uncles, or grandparents.


Why we call that sporadic, it must mean it’s in the family, and the best example of that — we may come back to this discussion — is this new gene which is quite important to all of ALS and actually other diseases. That’s the gene often referred to as C9orf72, which actually means chromosome 9 open reading frame 72. We often just shorten it to C9.


That gene is found in 8% to 10% of patients with sporadic ALS with no family history. In fact, in some countries in Europe, that gene mutation is found in up to 20% of patients with no family history. So what it really teaches us — and I know that this is a bit of a long answer — is that even though we can’t readily identify the cause in the large percentage of patients, we’re beginning to think that they actually may be a genetic-based disease even when there’s no family history.


Seth: Now, is there evidence that C9 is a cause of ALS or simply found in that population?


Dr. Rothstein: There’s very good evidence that it’s causing ALS in those patients. That comes from both standard genetic studies and now the fields — and I think we’re going to talk a little bit more about it, so we’ve now made what are called induced pluripotent cells or stem cells from the patient’s skin and blood.


When we make it from those patients who carry that mutation, we see dramatic defects, and the same defects that we’ve actually seen in patients who’ve been gracious enough to offer their bodies at death in autopsied brain, so we firmly believe this is a cause of ALS.


Seth: Great! Thank you for that answer. We are receiving a little feedback on the line. I hope that our listeners are not hearing that, but regardless, we will keep going and hopefully it will flatten out.


Thank you for that answer. So given the state of ALS research today, what is your focus of research?


Dr. Rothstein: There are many different ways in which we could try to understand the disease. Having been working at ALS for a number of years, any good research program or any reasonable program changed it over the years. In my early years, we study what is now considered and what we call a downstream pathway. Something happens well after the disease starts, but we often believe or we used to believe that that would be a good target for drug therapy because we see patients well into the disease clinically.


That research actually led to the first drug in ALS, riluzole. Unfortunately, it’s the only drug we have yet, so we work hard to move beyond both that drug in that kind of research. If I think about what we’re doing today, we’ve changed probably the research program almost 180 degrees. I’ll take a moment just to explain some of that.


When we think of ALS many years ago, we base our research on studying our patients. Of course, it’s limited. You can’t really get much from the patient’s blood. It’s not really telling us much about what’s going on wrong in the brain or in the spinal cord. The 1990s brought changes to all of medical research, not just ALS, and that includes the discovery of genes.


Even if genes were rare causes of disease, we could use those genes to build models, and building models both then and today is fundamentally important in trying to ascertain why a disease occurs and how you find a drug because again, I can’t sample my patient’s brain and spinal cord. It’s just not possible to really know what’s going on in their body while they’re sick, so a model becomes important.


What I’m getting to is those models actually led the mid-’90s to the first generation of mouse models for ALS, and those were revolutionary. Even today, the original mouse model based on mutation called SOD1, it beautifully — not perfectly, but beautifully recapitulates the clinical elements of the disease. These mice are just like our patients, albeit small and furry.


We use them for now quite frankly 25 years to try to first understand the disease hoping — and this is very clear — hoping that this mouse — which is obviously not a human — carries a mutation not common in the vast majority of our patients, but hoping that this would be a better tool to understand the disease, and then secondarily to find drugs. Although I’m going to be a little superficial here, I think 25 years later, that’s not panned out the way we had hoped.


All those researches are done with an enormous amount of research labs by many people. And just to be clear about one other element of research, I may do research. I’m a clinician-scientist. I see patients and I run a lab, but all of us need help when we do research. The advantage of a tool — say, a mouse model — is that now my lab could make a mouse, and I could distribute it to a thousand researchers, so it becomes an important multiplication factor to get more people engaged in the disease. That happened over the last 25 years and that was great.


Of course, now we can look back and say — well, better drugs, we actually have a better understanding of the disease, but not better drugs. Now, we have thousands of researchers helping us, but what evolved over those years is now, you didn’t have to be a clinician. You didn’t have to see a patient. You could study a mouse and fully understand the disease, you think, by studying a mouse.


I think one of the problems in all that, good idea, but you know what, if you don’t bring it back to a patient, is it really relevant? Some of us — not all, and I could argue that I’m being a little more vocal than others, and not on purpose because I’m just representing my own scientific bias, is that we really need to bring the science back to patients because maybe — this is a gamble — maybe the failings of the mouse just are in fact not very representative of what goes on in many of my patients.


By the way, I’m not saying these are not good tools. You asked me where are we today. About five years ago, I was fortunate because of government funding to be able to set up a consortium with colleagues from Harvard and Columbia to build the first library of a different model for ALS. That’s a model based on what are called induced pluripotent cells, cells derived from our patient’s skin or today from their blood, and cells are converted into what we commonly refer to as stem cells. These cells can be then turned into patient’s brain cells, so I can essentially take a very small biopsy of my patient’s skin and convert it into their brain cells.


Now, I don’t have a mouse. I’ve got the real cells of their brain without going into their skulls and I can better study that disease because it’s truly representative of the patient. So my research and a number of other researchers today have now moved away from the mouse again for a number of reasons and hoping — this is a gamble — hoping that this tool is far more representative of patients partly because it represents their natural genetic composition, their natural metabolism, and the same protein in the cells or the same proteins in my patients, which means if I can discover a pathway and a drug in those cells, I can also find the tools for when I give the drug to a patient. I’ll know if the drug worked properly. Those are known as biomarkers or pharmacodynamic markers.


In a big way, our laboratory has moved in this direction and now we have generated a large library of these cells in the world. We’ve already got 50 or 60 cell lines from ALS patients and behind that, another 200 fibroblast lines, lines based from cells, from tissue. Now, that’s the foundation of our new research, and then the bulk of our research is to specifically try to understand the C9 mutation and how it causes disease and how we can find drugs targeting it.


Seth: Incredible. I will pause to restate what you’re saying as best I understand, but we continue to have our little disruption on the line. Would you mind calling in — hanging up and calling into the following number?


Amy: Here it is, Dr. Rothstein, 516-590-0362.


Dr. Rothstein: I’ll call right back.


Seth: To our listeners, we apologize and hopefully we will be back on momentarily. Dr. Rothstein, welcome back.


Dr. Rothstein: Thanks very much. Hopefully it’s a better connection.


Seth: I hope so as well. So if I understood right in my non-scientific terms, you have built a model for testing a potential therapy and other research not on an animal model, but on an actual living cell model, is that correct?


Dr. Rothstein: Yes. To slightly amplify, these are actual human brain cells derived from our patients, so it’s the equivalent to their brain and spinal cord. The very cells become diseased.


Seth: Now, how are we able to test and research using these cells? Are we able to, for example, test a new drug on these cells?


Dr. Rothstein: Yes. Let me elaborate on your question. I’ll take advantage of that at this moment.


The advantage of these cells is just enormous. At one level — and I should point out, and maybe we’ll get to this — the kind of program I’m about to tell you about is being spearheaded by Team Gleason in what’s now referred to as an Answer ALS initiative. It’s a plan to really build this as a platform.


By the way, what I’m about to describe is by no means my lab. This is a consortium of at least 40 different investigators who’ve come together to try to build this program. The simple idea is that we can build cells from every single patient we see in clinics. We’re talking about thousands, assuming the funds are there and the resources are there to really do this, but each patient could contribute blood or skin, and those cells can be over time — and the time has gotten shorter, but it can take at least four months to build those cells into new brain cells.


Those cells then in a dish — you can build all the different brain cells from a patient and rebuild a little mini brain in theory, and that was recently done in the news for Alzheimer’s disease. Essentially, each batch of cells will represent each patient and they can be used both to understand that patient’s biological defect, their genetic defects, their metabolism defects, but also can be used to screen for drugs that might fix that obvious defect.


Now, on one hand, I’m describing it quite simply, but on the other hand, it’s actually a quite challenging theory. These cells are actually expensive to study as our old mouse studies. They’re difficult, they’re slow, not at all surprising because we as humans grow pretty slow as well, but their great advantage is they really represent our patients and they can be used as a platform to discover drugs. In fact, numerous drug companies now are beginning to build platforms. The term “platform” really represents tools by which we can use these IPS cells, induced pluripotent or IPS cells, to find drugs.


Companies or big pharma become quite interested in this. Interestingly enough, they’re heavily reliant on us because this is not something that can be done yet without the knowledge base of what’s really being discovered in academics, so it’s an area of drug discovery and mechanism that’s really firmly rooted first and foremost in academic labs. A few labs and pharma have the experience that we have.


For this initiative that I’ve mentioned, this Answer ALS initiative with Team Gleason — and I should point out also the ALS Association — we’ve put together essentially just about all of the major experts in IPS cells in ALS, and in fact, in other areas to help us approach this for all of our patients.


Seth: Now, a little on that collaboration — and we are huge fans of Team Gleason and Answer ALS — can you talk about some of the organizations you have used to collaborate?


Dr. Rothstein: Yes, so two points. If I’m completely honest, we’re just starting, so we’ve had multiple meetings with the principal investigators. Part of this is very science-driven, but part of this is in fact heavily because of Team Gleason’s approach to ALS, and an important approach is it can’t just be scientists. So there are plans to include very much patient community guidance components to this program.


The other side, of course, has to be science. It’s the scientists and clinicians and basic scientists who know how to use these cells, but the overall guidance of the program is envisioned because — the term “envision” is very important — this is not yet operational. We’ve had multiple meetings to make this operational, but like all things, this won’t happen without funding, so someone is going to have to provide the funds, so we turn to Team Gleason to help raise the moneys to make this happen.


This is really a novel, collaborative approach, but it’s actually built on what we’ve done at Packard Center, and the Packard Center that I’ve built 15 years ago or so was actually based on strong mandatory academic collaboration. Today, we have well over a hundred investigators who are a part of this team that work littlie as teams. Not everyone works together, but small network teams.


When I talked earlier about building models, which is the foundation of discovery in ALS, almost every model in ALS today was built by Packard Center researchers, which by the way are not Johns Hopkins. Packard Center was designed to really involve researchers from around the world to a degree — and this is fundamentally important — who would agree to collaborate and share what’s referred to as unpublished data.


When you read something in the newspaper whether it’s ALS or Alzheimer’s, you’re actually reading about old research. We’ve been doing this typically for years before it ever makes it to the press, and we don’t want to wait that time. So when Packard was built, it was built on the foundations and the agreements by investigators that we’d only bring investigators who are willing to collaborate and openly discuss their research.


Seth: How do you fund such collaboration? Do these researchers go back to their inspectors and then seek funding for the team?


Dr. Rothstein: No. Packard, we’re not a big operation. We’re certainly smaller than MDA and ALSA. Actually, before I explain how we do it, I’ll point out right away. Since this was based on a scientific collaboration, it also has to make sure we include organizational collaborations. So for many years, and even now, we would often fund the grant. And then ALSA, the ALS Association, might also agree to fund it and we would share the costs.


The difference was — and I didn’t mention this before — there are certain set of rules if you’re a Packard investigator. This is different in most organizations. Packard has two components. One, we will fund the researcher and the grants are short. Most grants that I apply to when I go to the National Institute of Health are 50 to 90 pages that can take a month or two to write. Our grants are two pages.


The idea is that you can apply for a grant — actually, you can’t apply for a grant. You have to be asked to apply, so we cherry-pick the scientific areas that we think are worthy of investigation, which means we’re not going to research all areas and we don’t feel bad about that because there’s ALS Association, MDA and NIH. They can touch those areas. Our advisors, in a very focused way, pick certain areas.


We go to those specialists and we say, “We’d like you to join our group. It’s a two-page grant,” and quite honestly and perhaps crudely, I often refer to that as “bathroom reading”. We can read it fast and we can fund it fast. We generally get money within about two weeks to investigators.


On one hand, that’s important in the ALS research community because you’re speeding them up, so we’ll fund researchers from around the world in this approach, but the real twist, the most important part is if we fund someone, they must agree to the following. One, they actually must come to Johns Hopkins. If they’re from Hopkins and we fund them, they must come to a monthly meeting. Every month, they must show up.


Two, if they’re not from Hopkins and they’re from, say, UCSF or Harvard, they must come quarterly and they must at these meetings show us unpublished data. They must be willing to show what their ongoing research is and they must be willing to collaborate with others in the room. If they fail to do that, we take the money back. No one does that.


You have a grant from the NIH. You have a grant from some organization. You have it for a year or three years, and we do this because it’s actually built — when I wear my clinical hat and when I run a clinical trial with, say, Novartis or Lilly, whatever the company is, they’re going to come to me and say, “Jeff, we want to enroll patients,” and you have certain milestones. If you don’t achieve those milestones, we’re pulling out and going somewhere else if you don’t enroll a certain number of patients and you don’t give us that data quickly. Companies run that way, believe it or not; academics don’t.


And so, that model is pretty efficient in keeping us pretty on time and organized. If you take that model to my colleagues and I say, “Look, I want you to join this group,” you’re going to be around some of best junior and senior researchers, but if you’re not really dedicated, that means you’re not going to share and you’re not going to show up, I don’t want to give you money anymore. That’s how we operate and it’s worked pretty well over 14 years. I wish I could say 14 years later we found the cure or a drug to stop ALS, but we’ve built a very good collaborative community from doing this.


Seth: You mentioned the long wait time between academic research and hitting the light of day. Is the Packard Center doing anything to shorten that time?


Dr. Rothstein: Okay, so that’s like trying to challenge the United States government, only it’s called “peer review”. None of us have an influence on essentially publication delay. It’s complicated. I’m not sure we could spend an hour on this. It would be not enough. It’s a complicated equation because there are free journals which will get your data out quickly and some of us will publish occasionally there, but publications in academics are the coin of the realm, meaning that who and what journal you publish in establishes the quality typically of the science and your ability to use that to get your funding.


No matter what Packard funds, whatever money we give out, or the ALS Association or the MDA, it’s small change compared to the real government grants. Again, there are many nuances to that. When ALSA or Packard or MDA funds my lab or any other lab, they’ll pay for the younger people in my lab to work. They can’t pay for the salaries of the principal investigators. They can’t pay for the rent. It gets very expensive, and all universities require that. They’re not bad about that. That’s how the whole system works. That means you have to get the big grants, and you get the big grants by publishing in the big papers.


Knowing all of these nuances is actually how I get my colleagues to work together because they want to work with the major researchers. They want to do that cutting-edge research. They want to have an impact on both the disease, but the ways to make sure this flow of research and funds is continued, that still relies on that major publication track, which is typically journals like Science and Nature and many other journals.


I know this seems like a long answer, but what it really means is that that element to the world of communication, which is not just life science — physics publishes in these journals, chemistry — you’re bound by their rules. I’m just not strong enough to try to change those rules.


Seth: Well, we will try and support you. Thank you for that answer on the organization. If we could step back to the science really quickly, many of our listeners are new to the topic of IPS. Are these cells different in any way from a biopsied brain cell?


Dr. Rothstein: Yes. Let me go back one step because the world of media in stem cells has made this a very difficult world for all of us. Many years ago when we first dabbled — and when I say “we”, this is the medical community. I’m not the leader of this scientific approach, but when we dabbled in the switching to using stem cells or what we often refer to also as progenitor cells, they came from the eggs. Women would donate their eggs for this kind of research. Of course, there are many ethical issues about that.


That’s long gone. These are cells that come from your skin. They can come from your hair. They can come from your fat. They’re with special chemicals or molecular tools. We can sort of reverse the aging of these cells and turn these cells into early cells that we have in our body when we start as embryos, and these are called progenitor cells. It’s like going back in time. If you remember HG Wells, you could go all the way back in time with his time machine. It’s taking a piece of your skin, you go back in time to when you were a little embryo, and now with another set of drugs, we speed you forward again just to turn that skin cell now into a brain cell.


In fact, there are even very new methods where you don’t even have to go back in time. We can take your skin cell and just with a few chemicals, turn it right into a brain cell. Those brain cells are pretty simple or perhaps not identical to the brain cells in your body. Now, I should say we have no reason to think they’re thinking brain cells because they’re only a few cells compared to your brain, which is are gazillion billion cells. It’s my new unit, by the way.


These cells, though accurately reflect people, my lab and others have shown that they pretty accurately reflect what’s going on in an ALS brain. So it’s a way of taking your skin or your blood — we usually start with skin. Now, we can even do it from a simple blood draw that anyone has when they go to commercial labs and convert those cells now into brain cells, and that becomes a fundamental starting point then to understand the disease.


Seth: Now, once a newly-minted IPS brain cell is created, is there any fundamental difference between that and a naturally generated brain cell?


Dr. Rothstein: Superb question, questions that we face now because you could say, “Well, this was a skin cell. Now, it’s a brain cell, but it didn’t live in my brain for 50 to 60 years, so how can it be the same?”


It’s the equivalent of doing a fingerprint. We can do genetic analyses of these cells and then we can do genetic analyses of the brain of our patients. In fact, the best is actually to have someone who’s donated their body and before death, we make IPS cells from them and then after death, we look at their brain and we make the comparison. There have been very few studies of that yet.


So far, generally when we look at things, we see — and I’m going to make this number up, so I’m not sure if it’s really accurate — let’s just say a 90% similarity between the IPS cell and the brain cell, but there’s no way they’re going to be perfectly identical and live a life — they don’t have the memories of a brain cell, but we think they’re going to be a better platform than a mouse and that’s the gamble. So we’re going to spend probably the next ten years using these, perhaps in addition to mice, and at some point we’re going to go back and stop and look back and say, “Who won that battle? Who’s better? Do we need both?”


My suspicion is we’ll still need both, but my suspicion is that these cells, the way we play with them over the next few years will turn out to be a better way, an easier way to study the vast majority of our patients.


Seth: Excellent! Where are we at in the timeline of IPS research? Is this your theory? You mentioned a couple of hundred of cell lines. Are we yet doing drug trials on those cell lines?


Dr. Rothstein: I know of two examples where we’re just putting our first feet into the water of that. I’ll tell you, and I know them both pretty well. One, a colleague of mine — in fact, the very colleague who I set up this IPS bank with, Kevin Egan at Harvard — has begun to use a handful of these cells to characterize some of their physiological properties. Neurons in our brain fire; they charge and discharge. That’s normal for cells and they’ve begun to study these cells in cultures, and this was published just recently.


He found that ALS cells have a different firing property than non-ALS cells. Based on some of those principles, some of those analyses that they did with those cells, they came up with a drug that might calm down that fire or misfiring of the cells, at least in a dish. That drug will soon go into trial and it’s a drug called retigabine. And so, there’ll be a trial of other drugs based on this initial analysis of those cells, so that’s an early attempt to use the cells in a very general way for ALS.


The second is we’ve got a group here at Hopkins where we’ve used specifically C9 cells. Here we know the exact mutation and the cause of the disease, and here we found a class of drugs that will essentially turn off the mutation, turn off the bad thing that it does. We’re working now with a drug company to essentially optimize that drug to bring to patients as fast as possible.


That approach, which is going after subsets of patients, we have really great hopes for because now we know exactly what starts the disease and we found a drug that exactly stops that defect, so two different approaches; early stages in ALS research, but two different labs essentially beginning this foundation of how we use these cells to discover drugs for our patients.


Seth: Because we are interested in generating hundreds, if not thousands of cell lines, it makes me think that we’re not looking at all ALS as the same starting point. Are we testing a hundred different diseases or why the number of cell lines required?


Dr. Rothstein: A very important question and this gets back to the Answer ALS initiative. We don’t really know. Many of us who have been following ALS patients for years strongly believe on one end clinically that there are probably different kinds of ALS, but probably more importantly, we know that scientifically because we already know that there are 20 different genes that can start ALS, so that means 20 different kinds of ALS in a small familial population, meaning 20 to 25 different starting points, so ALS must be different. There must be different forms of ALS, but we always lump them together clinically because we couldn’t do it any other way.


I’m frank and honest because we’ve quite frankly failed at finding drugs by doing that lumping process. Maybe it’s time we un-lump. And so, one plan — again, this is the answer of ALS initiative plan — is that we do make IPS cells from every patient, ideally everyone at minimum 500 or 1000 patients, and then we analyze those cells in a very detailed manner.


What are the gene abnormalities of those cells? What are the protein abnormalities of those cells? What are the metabolic abnormalities of those cells? This will lead to many, many gigabytes, terabytes, and umpteen bytes of data, so much data that we’re going to probably have what we refer to as big data somewhat to help us analyze all that information coupled to all of the clinical information for each of those patients.


We begin to look at that. We step back to look at it and say, “Oh, look at this. This is what we’ve hoped for.” There are actually clearly defined, different subgroups of patients that will come out of that and we believe that’ll be in part the starting point to then better define drugs for those patient subgroups. So there’s a fair amount of legwork here to build up that information.


Now, we would actually hope that those cells from each patient might even be usable to begin drug screening. There’s a program in our Answer ALS initiative that talks about drug screening, but I can’t go too far into that not because I’m trying to hide anything, only because this is where the team getting together has begun to chew at this problem, how do we do it properly with a team of now about 45 different investigators with a wide range of expertise.


By the way, this plan that I’m talking about scientifically and is a future plan, it’s not limited to academics. When you talk about something on this scale, no academic lab can handle this properly. We’ve actually identified various clinical research organizations, companies that are experienced in stem cells that will actually help us increase the throughput and the quality of what we want to do.


Seth: Amazing. How do we start as ALS patients to support your work?


Dr. Rothstein: First, think about what I said. Think about this whether it’s exciting or worthy and come back with criticisms and ideas. That’s very important. Everything that I’ve described to you is well beyond the typical funding of an NIH grant or even a typical ALSA or MDA or Packard Center grant, so this is going to require collaboration of organizations.


The initial plan for this is perfectly well into the scope beyond this. It’s Team Gleason, ALS Association, and Packard Center to come together and to find ways to fund this large initiative, which will involve many clinics around the country and many scientists around the country, so it’s no one university. It’s no one organization. That’s what’s on the table now and I believe Team Gleason is working very hard to trying to find ways to make this happen.


The plans there, if you will, we’ve drawn the home plans, the blueprint, and now we’re looking to go to the piggy bank to try to find ways to make this happen. Soon we’ll be announcing this to our other clinical colleagues who haven’t heard much about this. This has been mostly a pre-clinical consortium.


Seth: With that, we will let you rest your voice for a few seconds while Amy invites callers.


Amy: Callers, please use the number 516-590-0362. Press 1 to indicate you have a question for Dr. Rothstein.


Seth: Excellent! My mind is a little swollen right now, Dr. Rothstein. You’ve given us a lot to think about. Could I ask what other trials you are currently involved in?


Dr. Rothstein: Over the years — so my group at Hopkins, I try to distribute my trials to all of my other faculty, so they all get a chance to learn how to do trials.


There’s an exercise trial now, an exercise that’s long been an interest in ALS. Does it help patients? All too often, patients come to me and my colleagues, and are warned that, “Don’t exercise. It’s bad. It’ll speed up the disease,” and there’s absolutely no good evidence for that. There’s very good reason to believe that it could act in a beneficial way, but no one’s really studied that, so Nick Maragakis here has been working on finishing the exercise trial.


Soon, we’ll be hopefully carrying out the retigabine trial that I mentioned to you earlier, a drug from I believe Glaxo, a drug on the market already. There are great plans by Dr. Maragakis to carry out a glial stem cell trial and he’s been working closely with a small biotech company to bring that forward and that’s just a handful.


I think one of the things I didn’t talk about and that’s critically important for ALS as well in the future is not just our drugs because we do face this problem of bringing patients in and having failures and this concept of can we subgroup patients better. One, you might say, is genetics, genetic approaches. Some of my patients might say, “Well, that could be a really small subset of patients. Are there other ways in which we can divide our patients?”


There’s an area of ALS that has not grown until recently, and that’s using various imaging tools. Our exam teaches us something about patients, but are there different ways we can look into the patient’s brain to find out if there are different reasons or different pathways that are dysfunctional?


To address that, we’ve built what’s called the PET ligand, positron emission tomography. It’s a way of lighting up different parts of the brain and teaching us which areas of the brain are defective in ALS because not all ALS patients have the same defects in their brains. That approach, using these imaging tools, is also we believe at the forefront of ALS so we can better identify subgroups of patients.


Seth: We just had Dr. Nazem Atassi from MGH on our show and talked a little bit about this exciting space. We hope to hear a lot more in the future about imaging.


Dr. Rothstein: Yes. In fact, both Nazem and my younger colleague here, Lyle Ostrow, are using one of those ligands. It’s called mGluR5 to begin to look at patients. We spent ten years building another ligand, looking at a different component of ALS, and we think the future of ALS will include this approach. I think many of us do.


Seth: Now, when we have talked about ALS research, many in our population gets a little nervous to hear 10-year and 12-year timelines. Is there anything in your mind that indicates we are making progress and speeding up research?


Dr. Rothstein: What you refer to is the time it takes to get a new drug evaluated and eventually through clinical trials and eventually FDA-approved. You can break those steps down. At the end, what I’m about to tell you is there’s a definite answer.


The discovery phase, which is the phase you can use things like IPS cells, may — wait a minute. Before I get to that part, on top of that, the other complication is that in neurologic disease alone, 70% of drugs fail to get FDA approval. I don’t mean they fail because the FDA says “no”. They fail because they’re just not good drugs, 70%. That’s a horrible rate.


In fact, that’s 70% after phase two, so just to remind the audience, a phase one trial is when we have a brand new drug and we’re trying to understand how to even give it to a human being, and there’s never been humans before, so those are just small trials, often short, one or two weeks, five to ten patients. They’re not about whether the drug works clinically. It’s just how do we give this new chemical to a person and not stop their heart or make them vomit or all kinds of other things that can be pretty bad for you.


Once we have that idea, we go on to a phase two trial. In a phase two trial, the first attempt is to try different doses of the drug and begin to see if the drug might have some clinical efficacy. They’re typically larger trials, 60 to 100 patients. Typically in ALS, they’re a year in duration. Obviously, you have known this from some of your other speakers. If the drug looks exciting there, this is where you often hear about a drug in the news.


“A small biotech company finds a new drug” and they get all excited. They do all these press releases and everyone thinks, “Oh my God! This is the next fantastic drug. I can’t wait to get that.” They want it right away, but the FDA requires two positive trials and quite honestly, although that’s very disappointing at the patient’s side, as a scientist, you really need that because when I tell you that those phase two positive trials, 70% of them fail when they go to phase three, that tells you something.


In ALS, we’ve had only one that’s passed both phase two and three, meaning riluzole. We’ve had a handful we all got excited about in phase two and bombed horribly in phase three. The most recent was dexpramipexole, which looked kind of exciting and sort of borderline in results, but we don’t get borderline positive results too often in phase two. Boy, at the end of phase three, 60 different measures of how good the drug could be and they’re all negative. That’s the reality.


We hope we could change that not because we can change that. We’d like to pick better drugs. Well, picking better drugs comes back to what I mentioned to you earlier. If we knew the drug was really working in the brain, you would be surprised at how often a company comes to the ALS community and says, “We’ve got a brand new drug we want to try.” We’ll ask the company, “Do you know if the drug gets into the brain?” “Oh, we don’t know that.”


Are you kidding? You want to run a drug trial and you don’t even know if it gets into the very tissues the drug is supposed to work at? Most of us, they’ll carry out those trials. That’s another discussion because we know the trials are still good for patients overall, to be part of a trial, but it’s bad science.


Two, the company comes to us and says, “We’ve got a great drug,” and we’ll say, “Do you know if the drug is really working in the brain? Not even does it get there, but does it do something in the brain that it’s supposed to do?” They’ll say, “We don’t have a marker for that.” Those are called pharmacodynamic markers. These are the things that we want to change in ALS.


I know you’re asking for the timeline and I’m equally excited to make sure that when I carry out our trial, I have a better chance of being successful not that it’s five years rather than ten years, but this could be more successful. I need hits that are positive. So these changes, the demands to know if the drug gets into the brain and that they have what are called biomarkers give us greater confidence that we have the possibility of finding a positive drug.


The actual timeline for clinical trials could be shortened if we had better readouts. How do we know that drug is working? Maybe at some point, we’ll be able to do some kind of physiological measurement or a spinal tap and we’ll say, “Oh my God! Look, the drug really worked and we know this change tells us the drug is slowing the disease down.” That would shorten a trial. We don’t yet have those kinds of markers, just to name a few things that we need to do to change the field.


Seth: Well, I know that it is October and a 30% hit rate is acceptable in baseball, but in ALS that has to be daunting in the way pharmaceutical firms consider an investment. Does IPS have a short test towards having the investment dollars required for a three-phase trial?


Dr. Rothstein: Yeah, a very good question. The simple answer is no one knows that because they haven’t really been put into the pipeline properly. Clinician-scientists and companies all believe that’s possible because of the following. One, it’s not a mouse you’re studying your drug in. It’s a real human cell. Now, it’s not a whole organism, but it’s a real human cell.


By the way, I’ll stop by saying that before 1995, we have discovered drugs using mice. The vast majorities of drugs we use in human beings were actually discovered in culture dishes or studying patient material itself, so we know there’s a history of finding drugs this way, but it’s the human cell that counts. It’s the real defect in patients.


Also, because these are real human cells, we can measure things in those cells, those markers that say the drug is working, which we can’t really get from the mice. And then we can go to our patients and say, “We gave you the drug. We know the drug works in the cell and we have a marker that tells us that the drug is working,” so we learn that from using IPS cells. So we think the IPS offers several advantages that are not possible in other systems, but I use the word “we think”. We just don’t know and we will not know until we really dig in and spend the time to develop these processes.


Seth: Excellent! Thank you for that answer. We now have a little time for callers.


Amy: I’m going to give that number one more time. It’s 516-590-0362.


Seth: Thank you, Amy. We will go to our first caller ending in 1034. You are on the line with Dr. Rothstein.


Caller: Hi, Dr. Rothstein! Thank you so much for doing the show today. It’s been very, very informative.


Dr. Rothstein: My pleasure.


Caller: I’m curious about your approach. I love the collaboration and moving things forward in a better way, a faster way. As I look at ALS and these other diseases that are terminal and have short time spans, I’m just wondering how patients can get involved.


I think Seth has a great example of how patients can really make a difference for other patients and to help advance research, so I’m really impressed with what he’s doing, but I’m wondering if there are any other thoughts that you thought of about bringing patients as the most motivated group to pitch in and help driving for a faster pace.


Dr. Rothstein: I’m a very practical person, so my first pass is boy, I’d love to have extra people in the lab, maybe having sons and daughters in high school and college help out labs as a real hands-on experience quite frankly. Now, that’s not going to apply to a lot of people, but we’ve done this in the labs here at Hopkins and I’m sure other researchers have, so that’s as proximate as you get to speeding up research. Quite honestly, the other end, of course, is helping clinics. They’re both equally important to the patient. That’s one extreme, so that’s truly trying to help advance the science.


There are even smaller ways. Maybe someone who has skills in web development can help their local clinics to get the word out. Of course, the other extreme is helping in fundraising. That’s not my base of experience, but we all know that’s as important. Although people could say, “Oh, the Ice Bucket Challenge brought tons of money,” that would go away eventually and we’ll need more. I’m quite certain about it. I’ve been doing this long enough to know.


There are novel ways that are out of my experience base, of course. I think one of the ones I’ve seen over the years that has been just phenomenally interesting to watch and evolve is [0:52:03] [Indiscernible] patients help one another by exchanging information, and they’re not the only organization or website that does that. By the way, I have the links to that. I’m just thinking of ways in which patients could help one another.


My first thought about that is what do they do to help me and my clinic or basic science research program? Obviously, not all of you could do that, but I tap on people locally to do that and I think there’s great effort there. Beyond that, I’m not that creative, I have to tell you. I’m very focused on getting the program moving forward.


Caller: Well, those are some great ideas, so thank you so much for taking my call.


Dr. Rothstein: Thank you for asking.


Seth: Thank you, Caller 1. We’ll go to our next caller ending in 0360. Please go ahead.


Caller: Hello, Dr. Rothstein. My son is a patient of yours and was tested positive with the C9 gene, and also the NIH is part of the research that’s going on. Well, it’s not quite been a year since he’s seen you, but you had mentioned then about being able to go in and turn off the C9 gene or be able to treat that. What you said here earlier, of course, is very encouraging.


Are there any plans to go ahead with that and bypass the FDA? I know that there’s something in the works in certain states that you can actually bypass the FDA if the doctor or the drug company and the patient all agree. Is that something that’s possible to speed up the therapy?


Dr. Rothstein: It’s an interesting question. One, I’m grateful that your son is participating in the clinic. Remind me to answer different parts of your question. One, you brought up something that’s very important, one is clinic.


To advance research and make sure that we move faster — because that was an earlier question, Seth, that you had — one is actually to try to set up these clinics that are specific for specific subsets of patients. Now, it eventually becomes impracticable, but at the beginning, we’re actually doing that because there was a trial several years ago by a very brilliant colleague of mine, Tim Miller at Washington University, to turn off the gene for superoxide dismutase, a very rare subset of patients.


You would think that this trial would get as many patients as quickly as possible, and yet we only got approximately ten or so patients per year to enroll in this trial. Part of that was getting the word out, getting patients actively identify so they could participate in these trials. We realized if we’re going to go for a much bigger subset of ALS, meaning C9, we better darn well be prepared for this and collect information, collection information about patients and collect information in the communities, so we’ve begun to set up C9 clinics around the country; the NIH is the first one.


The whole idea there is not just to understand the disease, but to be perfectly primed so when that trial starts, bingo, we can move fast and really make sure we get an answer about this drug and how we approach the disease. So again, it’s a bit of a long answer, but the clinic I think is very important to that.


Now, to your fundamental question — and many patients ask me this — is can you bypass the FDA? I think my simple answer is no, not to the best of my knowledge, and I’ll tell you why, at least one reason why.


One, when a company comes up with a new drug, you don’t own it, I don’t own it, only they own it, and they have complete say on what they want to do with it. It’s their drug. It’s sort of like saying, “Look, that neighbor next door, he’s got a much better car than mine. You know what? I’m just going to take his car and use his instead of mine,” just because I think it’s the right thing to do or I want to do it or I need to use it.


So the brand new drugs are not owned by us as academics. They’re owned by a company, and the C9 drug is no different. It’s owned by, in this case — well, a number of companies probably are building them. I know of only one. First and foremost, they have to decide if they’re going to give a drug without FDA approval. I have to tell you, I’ve never heard of that happening in part because there’s nothing known about these drugs.


This is a conversation I’ll often have with patients. Everyone is excited to always try a new drug when they want to enter trial. I’m very careful to make sure, as much as I want to use the drug, every drug trial has three possible outcomes. One, the one I want and my patients want, which is that, “Yes, the drug works. It slows the disease down. It stops the disease,” whatever that’s positive. Two, unfortunately common, the drug doesn’t do anything at all. Three, despite of all the research that’s taken that drug to a human being, it actually speeds up the disease, and I’ve seen that happen.


Several years ago, Columbia University ran a trail of a drug and all the research and animals made it look like the best drug ever, but in patients, it accelerated the disease by 25%, and granted that’s the patient’s choice, but my point is you have to be fully informed. So this C9 approach that we have, these drugs that we’re trying to build, I don’t know if it’s going to work the way they’re working in the IPS cells.


Part of that is I don’t know the outcome. That said, I know very well that there are plenty of my patients who would say, “I’m willing to gamble,” and I’m willing to go along with them as a physician, but again, there are rules. We can probably cover all of those issues, but no matter what, it’s always up to a company to make that decision if they own the drug.


Caller: Okay. Thank you, Doctor. I appreciate your answer.


Dr. Rothstein: You bet.


Seth: Thank you, Caller, for that question. We have time for one more caller ending in 5044. Please go ahead.


Caller: Thank you. Doctor, you talked about stem cell trials and there seems to be very few stem cell trials out there with only small patients involved. Is it cost or risk or FDA that’s holding these stem cell trials back? What can you tell me?


Dr. Rothstein: There are a couple of different ways of looking at that answer. On one hand, I can tell you stem cell research is very much in its infancy, very much. Patients lump the term “stem cells” together, whereas we know that there are all different kinds of cells you could study if you’re going to bring them to patients quite frankly whether it’s ALS or Alzheimer’s or any other neurologic disease. There are all different kinds of cells that make up our body.


One way of looking at that is if you went to your — I don’t know where you live, but if you went to your CVS, your Walgreens, your standard drugstore, and you said, “I’ve got an infection. Could you give me one of those white pills I see on the shelf over there?” you know very well that would be ridiculous because there are 3000 different white pills.


That’s where stem cell research is right now. We don’t know what the right cells are to use. The cells that we’re using today — the science is so immature. Even all the stem cell trials that I know about anywhere, whether it’s in the United States or elsewhere, those cells can’t become motor neurons. Just to recall — we didn’t discuss this — that a motor neuron is the very core cell of a dying ALS. No stem cell today that’s being studied can turn into a motor neuron, not possible. The science is not advanced yet, so it’s very immature science. That’s part of the answer. Quite honestly, the science is immature.


Now, that doesn’t mean we don’t try to move it ahead. Stem cell is a therapy. It’s not like the pill that you take when you go to the pharmacy or a physician gives you a pill and it gets absorbed by your stomach and it’s distributed to your blood and eventually gets to your brain. These cells will be directly stuck into your nervous system with a needle. That’s today’s technology. Maybe tomorrow it’ll be different. Well, tomorrow meaning ten years or more from now, and which means it’s a major surgical operation. We can only implant them in a very small area of your body. And in ALS patients, their entire spinal cord and a whole section of the brain is involved, so it’s a tiny area that these could be put in.


Now, if we’re going to do that successfully someday, we have to figure out how to do that. Probably the best example of that today is the trial at [1:00:31] [Indiscernible] University. We’re trying to work on that.


To put it into the large view of what’s necessary — my patients know that I like car analogies — if half the car is all rusted and you want to fix that just like half of your brain or spinal cord and you might have ALS, you want to fix that. If you only paint a quarter-size region on the side door, the passenger’s side door, put an anti-rust, you’d say, “Great! That area is cured,” but the rest of the body is not cured or the rest of the car is not cured. That’s the level of stem cell research today. It’s at its very primitive stage.


Caller: So do you see that as the science advances, do you see stem cell as the answer for ALS?


Dr. Rothstein: No. I see this as just one answer. To gamble on one approach would be foolish in medicine. If medical history has taught us anything, you must make sure you have multiple ways of approaching a disease. I definitely think we should be paying attention to it. I definitely think we should work on it, but I would never think that that should be the only approach. And so, I’m excited that we’re doing it today in the United States with rigorously done trials, but I’m equally excited that we’re making sure that we do other approaches to the disease as well.


Caller: Okay. Well, thank you. Thank you for your time.


Dr. Rothstein: You bet.


Seth: Thank you, Caller. Dr. Rothstein, any closing thoughts you’d like to leave us with?


Dr. Rothstein: Well, patients — as evidenced by the calls — everyone is of course always frustrated by the lack of an effective therapy. I think at our end, we’re extremely excited — well, we’re disappointed, too. There’s no way we’re not, but we’re not disappointed enough to not think that this is an exciting time for ALS and it has nothing to do with the great notoriety about the disease because of the Ice Bucket Challenge, which by the way has been fantastic so the world knows about this disease, it’s really about the level of science that’s going on, things like IPS cells.


We’ve only touched on some of the science that’s exciting, new genes like C9 and others, new companies. I didn’t tell you that almost every pharmaceutical company I’ve talked to is now reenergized and is very interested in ALS largely because of the C9 mutation, but who cares? That means they’re willing to put their feet into the sand of getting involved and build the foundation of a research program. It may not happen tomorrow, but that means tomorrow’s patient is going to benefit.


Seth: Excellent! Thank you so much for spending an hour with us.


Dr. Rothstein: My pleasure.


Seth: Your answers have been exceptionally helpful.


Dr. Rothstein: All right. Well, thank you very much.


Seth: You’re welcome. For our listeners, a full transcript of today’s show will be available on our website in the next few days. We look forward to our next show, but for now, I want to again thank you, Dr. Jeffrey Rothstein.


Dr. Rothstein: Thank you.

About Author

Seth Christensen

Seth is an ALS patient and founder of ALS Crowd, a division of the CrowdCare Foundation. As host of the ALS Crowd Radio show, he interviews top ALS researchers and focuses his efforts on the aggregation of big data to help researchers and patients find clues that will drive to a cure.


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