ALS Crowd Radio S2:E2 Dr. Joseph Beckman on Stopping ALS in the Lab

Dr. Joseph Beckman, PhD

Oregon State University, Linus Pauling Institute

Interview Date: April 19, 2016

Dr. Joseph Beckman has been studying ALS for 23 years. He shares exciting results in the lab of treating SOD1 mice with a copper compound that extends their life from four months to over two years. His hypothesis seems proven: that a copper deficiency is being created in the brain of the ALS mice. Dr. Beckman treated them with copper ATSM and saw remarkable improvements.   The compound will begin human Phase 1 trails in Australia in two months, and shortly after in the US. Copper-ATSM is currently used in humans as an imaging tool which can detect brain tumors, or other damaged cells.  Dr. Beckman believes that both familial and sporadic ALS can benefit from this treatment, although much research will be needed from this point forward.  As his important research continues, he speaks with hope of turning the tide against this horrible disease.  

ALS Crowd Radio Show with Dr. Beckman

Full Transcript:

Seth: Hello and welcome to the Season 2 Episode 2 of ALS Crowd Radio. I’m your host, Seth Christensen, here today with our ALS Crowd Director of the Health Education, Lori Wangsgard. I will have Lori introduce our guest for today.

Lori: Thank you, Seth. We would like to welcome Dr. Joseph Beckman as a Distinguished Professor of Biochemistry and Biophysics in the College of Science at Oregon State University. He is the Director of the Environmental Health Sciences Center and Principal Investigator and the Burgess and Elizabeth Jamieson Chair in Healthspan Research at the Linus Pauling Institute.

Dr. Beckman received a Bachelor’s Degree in Molecular Biology and Master’s Degree in Population Biology both from the University of Colorado, and then received a PhD in Plant Physiology and Biochemistry from Duke University. Dr. Beckman served as a Professor at the University of Alabama at Birmingham in the Departments of Anesthesiology, Biochemistry and Molecular Genetics, and Neurobiology.

Before coming to Oregon State University in 2001, he was also a Guest Professor at the Swiss Federal Institute of Technology in Zurich, and also Universität Konstanz in Germany. Dr. Beckman has been the recipient of many research grants. A major research project in his lab is aimed at understanding how oxidative stress, superoxide dismutase, and zinc are involved in ALS. We would like to welcome Dr. Beckman to the show.

Dr. Beckman: Hello everybody.

Seth: Hi. Dr. Beckman, thank you for being with us. We’re honored to have you here today. Thank you for your willingness. Dr. Beckman, this is the first time we’ve had you on our show. I wonder if you could tell us what originally brought you to ALS as a career.

Dr. Beckman: I’m a researcher doing basic science in the field of oxidative stress, and I was interested in using the enzyme superoxide dismutase as a protective agent. In 1993, mutations to superoxide dismutase were discovered as the first known cause of ALS, and that created a lot of mystery of how an enzyme and a protein that’s expressed in every cell of the body from birth can cause a very selective death of motor neurons and cause ALS many, many years later. But in tracing that down, I’ve been working in the field since 1993, basically, trying to understand how does this protein cause the disease.

Seth: Amazing. All right. In those 23-odd years, how has the field progressed or changed?

Dr. Beckman: I’m sorry, there’s an echo in the background. I’m just having a little trouble hearing you.

Seth: My apologies. My question was over those 23-odd years, how has the research you’ve done progressed or changed? Have there been milestones that propelled us forward?

Dr. Beckman: In understanding the disease, I’m a Biochemist by training, so we’ve tended to work with pure proteins and with cultured cells and then we started to work with transgenic mice. I’ll talk a little bit about the transgenic mice because they’re very important for understanding ALS research, and a transgenic mouse is a mouse that a scientist has genetically engineered in some way to change the DNA or the material involved in inheritance.

I mentioned that there are mutations, genetic causes to a protein called superoxide dismutase. Mark Gurney and his colleagues in 1994 had a major accomplishment where they could take the DNA from a human that encode this gene and put it into a mouse, and now that mouse inherited the human gene and it developed ALS in about four months. And what’s remarkable is these mice really do recapitulate the human disease pretty well. The mice died very consistently in four and a half months, and we’ve had the mice for over 20 years but no one has been able to effectively treat the mice. They even offered a million-dollar prize if you could extend life by 25%. In other words, add a month of life to the mice.

That’s been a huge puzzle in the field. Why does this protein, why does this mutation to a protein cause the disease and why the heck can’t we treat it? Why can’t we stop it? I’ll be happy to stop there and we can expand further.

Seth: Wonderful. Yeah. We have to have other guests to speak about the SOD1 mouse model. We’re eager to understand them further. Is it the only mouse model in ALS?

Dr. Beckman: No, but it was the first and it recapitulates the disease better than any other mouse that’s been created so far. In the ‘90s, there was just a little progress that momentum was building to discover new genes that cause ALS. But after that, a lot of different genes have been identified and people have made mouse and rat models, and they’re studying those at this point. But the mouse model, the SOD1 mouse, is still the best model we have of the disease, and it recapitulates the disease. And the question is, why can’t we figure out how to treat it effectively? In many ways, like being run over by a Mack truck, it’s just so severe that it’s very hard to stop.

Seth: Yes. This brings us to the meat of our interview today. We have all heard rumors that you have been able to make progress in treating the SOD1 mice. I’ll allow you to talk about that.  All callers who have a question for Dr. Beckman out there, after his explanation, dial in 516-590-0362 and press the number 1 if you have a question. We’ll now give Dr. Beckman the chance to explain about his progress.

Dr. Beckman: I’ll start by explaining a little bit about the paper we just published and what we showed. Basically, my colleagues in Australia at Melbourne, at the Florey Institute, they came up with an interesting compound that contains copper, and they were getting as good a protection as anybody had gotten in the SOD mice. We had taken a different attack, instead of asking, how do you cure the disease? We were investigating what makes the disease worse. So if you understand what makes it happen faster, what accelerates the disease, I can give you other clues of where to look. And that’s where we made the progress.

Dr. Elliott and son in Texas had shown that there was a very unusual finding. There’s a protein that associates with SOD that helps insert copper into the protein. They had this remarkable and surprising result that if they took the human CCS gene and put that into a mouse, the mice were just fine. But if that gene was co-expressed at the same time with the mutant SOD, the mice die ten times faster. This acceleration was really dramatic and never seen to that extent in any other way.

We figured out that there was probably a copper deficiency being created in the brain. So we tried the Australian compound and to our surprise, the mice responded remarkably well. And what we published in January was that the mice had actually lived for about two years. So the life extension had gone from four months to over two years.

Now, we’ve argued that this mouse model, in many ways, represents what goes on in humans more because humans do express both the CCS protein and the SOD1. And that gives us hope that we could take this compound and actually try it in humans and see if we’d be able to treat ALS with it. So that’s the progress so far. The compound has actually been made and clinical trials for safety should start in about two more months. That was the latest word I got this morning.

Seth: Thank you for that explanation. Since the publication of the paper, we have all begun to eat three more pennies to get the copper, but I’m told that is probably not the right way to go.  Can you tell us what the magic of copper is and how you get that across the blood-brain barrier?

Dr. Beckman: Okay. You raised an excellent point. The question is, copper is a micronutrient, and why not just take free copper? Why do you need this compound? The problem is the copper itself is required in small amounts but it becomes toxic in larger amounts. It’s required by every cell in the body in order to be able to use oxygen. All the energy we get from taking in oxygen, breathing it, is only possible because there’s a copper atom that’s interacting with the oxygen in a place in the body, an organelle called mitochondria.

You have to have copper, but copper is pretty reactive and it can catalyze, it can cause a lot of different types of damage, and there’s certainly a number of diseases that are caused by copper overload or copper mishandling. If you just try to take free copper, it’s not going to help. One is it will cause some damage, and two, the brain really strictly regulates the way copper is taken up. And that was what we discovered from our work in the mice was just how careful, how slow copper is taken into the brain, and how getting the right amount there is critical.

Now, the compound is actually already used in humans for imaging experiments. There are experiments that use PET scanners, that use radioactive copper to detect tumors, and also to diagnose Parkinson’s. And this particular compound was know to leave copper in tumors or in damaged regions of the brain, because of the way the copper gets released from the compound. So it’s extremely fast at crossing the blood-brain barrier. It doesn’t need a protein or anything to do it. And usually, it carries the copper back out of the brain harmlessly. It’s only released in cells that are damaged and seem to have a need for the copper.

What we found was this compound, Copper-ATSM, worked really well. But if we removed one methyl group, one carbon atom, the compound no longer works, and in fact, it could become toxic. So the structure is really important to its function, and you have to be really careful in how you dose and how you use it in order for it to work.

Seth: For a context, how long ago did you begin to first dose SOD1 mice with this compound?

Dr. Beckman: We started about three years ago. It was just a trial set of experiments and we had some pretty amazing results of the mice responding very quickly. But then we designed much more complex experiments that were blinded, which means that we didn’t know which mouse was getting which treatment, and started to see how long they would survive and they kept living and living. So after they have lived for about a year, we started to try to publish the studies, and then there is enough skepticism in the field from one or two reviewers that it took over a year to get the data published.

Seth: Please go ahead with the background.

Dr. Beckman: I’m sorry, I had trouble understanding you.

Seth: I interrupted you. You were saying the background.

Dr. Beckman: I’m sorry I still couldn’t quite understand.

Seth: That’s all right. We understand that, in the SOD1 mouse model a developed breakthough like this has never happened before. I wonder how a research staff react when they begin to have mice live beyond the four-and-a-half-month period. Are you able to get excited in the lab or do you feel like you need to reserve excitement for a later time?

Dr. Beckman: I’m sorry I’m still having an awful time understanding what you were saying. There’s kind of an echo that we weren’t getting earlier. You’re asking about, is this the first time the mice have lived beyond four and a half months?

Seth: Yes. We can start there.

Dr. Beckman: Okay. Yeah. There have been one or two reports of mice that have lived substantially beyond four months but they were never repeated. And then if we treat the standard model with our compound, they only live to be about a month longer, a little longer than that. They hit 25%. So it’s only when they have the combination of the chaperone protein in the SOD, both human proteins together, that the copper compound is protective.

Now, the good news is that humans already have the human CCS gene, the copper chaperone expressed. So in many ways, I believe our result more closely represents what would happen in humans than the mouse model. And we’ll have to just tell it by clinical trials and see whether or not the compound works.

Seth: Thank you for that. Can you talk to us for a moment about that timeline for clinical trials?

Dr. Beckman: Okay. When we knew we had the protective results, the mice were living for a long time, we started to contact people. My colleagues in Australia, actually, had already licensed the compound to a company called Procypra. So I contacted the CEO and we’ve been in contact for quite a while now. So they are the company that’s involved in actually doing all the work that’s needed to get a molecule like this for mouse studies into humans. And it takes a fair amount of money and resources and it has to be done in a very strict way.

I’ve tried to explain the process but they’ve worked down through the steps. So the first is, how do you make the compound? How do you make the chemical in a way that’s safe and that it’s known to be pure and it’s not contaminated? And that’s a very detailed and complicated process. We can make the chemical in our lab but we have to be able to prove it would be safe enough to get to humans and you could make more of it. Then you have to figure out how do you put it together as a pill or a drug or how do you actually give it. Then we have to figure out, is it toxic to mice and rats? And then is it toxic to larger animals before you go into humans?

All of those studies have been completed now, and the compound is ready to go to what’s called a Phase 1 study. And usually, Phase 1 studies are done in healthy male volunteers to see whether or not the compound has any toxicity or any side effects. The company went forward and they got permission to actually go directly into ALS patients and test the drug in patients. And they’re going to do the first studies in Australia, for a number of reasons, but they could actually get them together a little bit faster than the United States, although they’re working on that too. In the Phase 1 study, we’ll be giving the compound starting with very small doses and they’ll be given for 28 days and the doses will be increased if there’s no risk of damage, if there’s no sign that people are getting sick from taking the drug.

That’s where the studies are now, they’re trying to figure out, is the compound safe enough to give to humans? Are there things that we just don’t know that start to happen in humans that you don’t see in other species? And that’s a possibility. Then from there, they start to do more studies that will be called Phase 2 or possibly Phase 3 to start to test these compounds. Are they still protective? Do they have any protection in ALS? Do they have any benefits? And so those will take probably one to two years to complete and decide whether or not there’s a benefit there.

Actually, from the announcement of our success in mouse studies, we’re much closer to getting into humans than previously. But I also realize that it’s still too damn slow for a lot of people who suffer from the disease now. So I’d be happy to expand further if you like.

Seth: Thank you. We will pause for a moment and allow Lori to invite callers.

Lori: If you have a question for Dr. Beckman, you can call in at 516-590-0362 and press 1 to indicate that you have a question so we can connect you with Dr. Beckman.

Seth: Thank you, Lori. We have callers from all over the country at this point, but none that have indicated that they have a question. We will continue for a moment to allow those to press the number 1. Dr. Beckman, do we know whether this compound is effective in non-SOD1 cases of ALS?

Dr. Beckman: We have no idea, and this is one of the big arguments I get into when I write grant applications. Only about 3%, anywhere from 2% to 7% of people with ALS have SOD mutations. So the question is, would a drug that treats SOD actually have an effect in people without the mutations? A lot of people say, “Well, they could be completely separate diseases and the drug will have no effect.” And they may be right.

I tend to believe that the mutations don’t really cause the disease. They just make it more likely for the protein to malfunction, and that they’re an indicator of what goes wrong, and the same thing could go wrong in sporadic patients. And we have some evidence that the processes are closely related. The flipside of it is, I would argue that the drug might work better in sporadic patients than familial patients, people with the SOD mutations. But that’s purely a hypothesis, a conjecture or what my colleagues would say a wild-ass guess. The only way to tell is actually give the drug and see if it works, which fortunately, the drug company is going to do sporadic, as well as familial patients, and we’ll see how that turns out.

Seth: Yeah. I love to hear that. Thank you. Again, callers can press the number 1 if they have a question. Dr. Beckman, while we are waiting the Austrailian trials, how does your work continue in Oregon?

Dr. Beckman: We are continuing in a couple of directions. One is there’s a chance that there’s something with copper-ATSM, that it may not be the best chemical to test. So we’ve made lots of different versions changing the structure, and we’re trying to see, can we find something that works better? We’re trying to understand how does the drug really work, which will give us the insights into how you could test it or how you would know it’s working in humans. We’re working on trying to test the compound in dogs because it turns out that many breeds of dogs have mutations to SOD1 and they develop a disease that looks very much like ALS.

And then we’re also testing other types of compounds, and one of the ones that we’ve been working on is something called masitinib. And the exciting news is that in Phase 3 trials in Europe, and an interim analysists suggests that this chemical, actually, was effective in ALS patients in slowing the disease.

There is a lot of different things happening in ALS and people have been talking about making progress, and I think you’re starting to see the first fruits of it come now. It’s not just the compound we’re working on but there are other things that are maybe turning the tide and offering some hope.

Seth: Thank you. We feel that hope and are thrilled to have researchers like yourself on the team. With that, we will take our first caller. Caller ending in **35. You are on the air with Dr. Joseph Beckman.

Caller: Hi, Dr. Beckman. My name is Stephen Finger. I’m in South Carolina. When you think about what you’ve seen in mice and if you think the mechanisms work similarly in patients, would you anticipate this slowing progressions or do you think if everything works perfectly, you would see improvements?

Dr. Beckman: Okay. The question is if the drug worked, a huge if, would it just slow down the further progression of the disease or would you see improvement? To be honest, I would be dancing a jig if either happens. We have been able to do the experiment in a mouse. We can take the drug away and let the mice develop the disease and then start the treatment again. And you’re not able to replace motor neurons that have already died, but what we did see is the mice did show some improvement in how they moved. They started to gain weight. So we’re able to actually stop further progression for a long time.

Unfortunately, the mice, after about eight months, they did start to progress further and got sick and eventually died of ALS symptoms. Our hope is that we can understand what stops the progression of the disease and stops to spread. And we’re not going to be able, with this type of therapy, to actually reverse a huge amount of the injury, but the goal would be to do something like happens in post-polio syndrome where people have lost a lot of motor neurons. They can have very severe mobility issues and challenges but they have a good quality of life and the disease doesn’t progress. That would be our goal.

Caller: Thank you.

Dr. Beckman: Okay. Any other questions?

Caller: What would you expect to see in terms of endpoints in the trial?

Dr. Beckman: I’m sorry, the question was what are the endpoints in the trials?

Caller: Yes. If you expect, it would simply slow progression or halt progression, what do you think would be an appropriate endpoint?

Dr. Beckman: That’s really not my expertise, and I won’t be involved in actually designing the trial. And there’s certainly a lot of different debates as to what it would be. Generally, they’re following the progression of the disease using various scales that monitor the further progression of the disease. And the challenge with that has been that it’s usually presented ALS is a relentless progressing paralysis, but there are periods where it slows down for some patients and then accelerates in others.

All of that has to be taken into account in the design and making sure that you follow enough patients long enough that you know that the drug is working. There’s a huge surge now for surrogate markers or biomarkers that would tell you whether or not the drug is actually engaging a target and whether you can tell you got enough of the drug in. And even that in itself is a pretty tough problem that we spend a lot of time working on and still don’t have a great answer for it yet.

That’s a great point. The success of the trial depends very much on the endpoints you’re searching for, and that is a continuing debate as to how do you treat with this compound or any compound in ALS.

Seth: Go ahead, Dr. Beckman.

Dr. Beckman: I’m sorry, was there another question?

Seth: No. You were saying you would add one point.

Dr. Beckman: Oh, okay. Yes. I’ve been very impressed with how the medical community has come together to study and work with ALS. I’ve watched this evolve over 20 years and there’s a huge amount of knowledge that’s been gained about how you test drugs in ALS, what are the difficulty with it. And it’s basically, there haven’t been successes in drugs that really treat the disease to speak of, but there’s been a huge amount learned about how you test it and how do you evaluate it. So there is progress in studying the disease and there’s been huge progress in how you manage the disease, which also helps with the quality of life quite a bit.

When I say that that’s not my expertise, that’s in part because there are a couple of hundred physicians that debate that and think about it very carefully.

Seth: Thank you for that. How can our listeners support your research?

Dr. Beckman: Well, I think the ice bucket challenge in many ways helped a lot of people. In Oregon the ALS Association has provided a grant. It’s just helped raise the awareness of the disease enough that it’s become higher profile. So I think that was a success and it’s trying to figure out how do you keep the momentum going? How do you keep awareness about ALS improving? And then what I’m hoping that the results we publish show is that we are making progress. It was actually very frustrating when people were dumping ice on their heads that we knew we had compound that worked really well but they were all locked in the laboratory. And you just had to keep going, keeping the experiment blinded and progressing.

And I think there’s a lot of different people. I know there are a lot of different projects and a lot of different approaches to treating many different aspects of the disease. Keeping hope up is really the key part in understanding that the work that people have done to support this disease is helping in making a difference.

Seth: Thank you. We have one final question for you but do not want to cut off questions from our callers. Callers, please press number 1 if you have a question for Dr. Beckman. Caller ending in **32, you are on the air.

Caller: Hi, Dr. Beckman.

Dr. Beckman: Hi.

Caller: You mentioned earlier that they used copper in other sorts of treatments. I wondered about your research if you’ve seen side effect, adverse side effects. I don’t know how you can do that with mice, but if you can project any side effects with this treatment for humans as well.

Dr. Beckman: It’s a great question. If you’re giving copper, what are the side effects and can you reduce the toxicity? And that’s actually where a lot of our researcher is going now, is trying to understand what they might be and how might you counter it. One way that you can counter copper toxicity is giving zinc. We know that zinc is also important for the disease and zinc is important for the SOD1 gene. We’re also investigating ways of giving zinc and keeping the balance of the two chemicals together.

The other part of what other side effects there are, basically, we have to determine what they would be in larger animals because there’s very few effects in mice and rats. But larger species, including humans, handle copper quite a bit differently than smaller animals, which is key because we live much longer and effects can have much longer consequences. We’re just going to have to see what happens when you do those experiments and it becomes really costly and you have to think very carefully when you’re using large animals as to what the effects would be. Did that answer your question?

Caller: Yes, thank you, and thank you for your research. This is really interesting and exciting.

Dr. Beckman: We’re very thrilled with it too. It’s a horrible disease but it’s a great puzzle to be working on, and very challenging. I didn’t expect it to be this hard.

Caller: Well, thank you for your effort.

Dr. Beckman: Okay.

Seth: All right. Dr. Beckman, wrap-up question is always the same. What is the greatest opportunity you see today for our listeners to help solve the ALS riddle?

Dr. Beckman: What is the greatest challenge or the greatest work?

Seth: Greatest opportunity for us all to help?

Dr. Beckman: Oh, what’s the greatest opportunity? I don’t have a great answer for that. I do think that what I try to encourage people that are newly diagnosed with ALS is get in touch with either the ALS Association or the Motor Neurone Disease Associations around the world because there’s a huge amount of knowledge about how you manage the disease that’s come along. And then it’s working through local groups that can help a lot of people make further progress. It doesn’t hurt to let your federal government senators and representatives know that ALS is still on the radar and it is important to continue research.

I think the last thing I’d say about it is that doing research is something that we seem to be losing sight of in this country as being not valuable. It has to produce goals and we have to have an immediate societal impact and show the significance, and it’s really important that we also continue basic research. If you remember from Lori’s introduction, my PhD is in Botany and yet I’m working in ALS. And everything that I studied that turned out to be fairly important in this was for things that nobody thought was very important at the time.

The dollars that are donated for research to the different associations, they helped enable people like myself who are at the edges of the field come into it and bring in new insights, and that’s really important for making progress in the disease. There’s an old saying of, if the federal governments went off to cure polio, what we would have today are portable computer-controlled iron lung machines instead of a Salk vaccine.

I think that’s also true for ALS. A lot of seed money allows people to try things. And 99.9% of the things that are tried are going to fail. But the one in a thousand chance still can unlock the disease and help make further progress. So a bit longer than I thought but —

Seth: No. Thank you. Before we sign off with you, we’ll have Lori share the information about our next botanist. 

Lori: Thank you. Next week on ALS Crowd Radio, we will be talking with Dr. Paul Cox, PhD from the Institute of EthnoMedicine about the environmental causes of ALS. It will be Thursday, April 28 at 1:00 Mountain Standard Time.

Seth: Thank you, Lori. And thank you, Dr. Joseph Beckman for his ongoing service to the ALS community. It has been an honor to have you with us today.

Dr. Beckman: It’s been my pleasure. So good luck.

Seth: Thank you. Goodbye.

Dr. Beckman: Okay. Goodbye.

 

 

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