Research funded by The ALS Association recently identified a potential therapeutic target in the accumulation of a protein called CHMP7 that is connected to TDP-43 mislocalization and development of ALS.
Connecting ALS recently talked to Dr. Jeffrey Rothstein, professor of neurology and neuroscience and the founding director of the Robert Packard Center for ALS Research at Johns Hopkins University School of Medicine, and Dr. Alyssa Coyne, a postdoctoral fellow at Johns Hopkins about their research.
This transcript has been edited for brevity and clarity. You can listen to the entire conversation HERE.
Can you walk us through your findings and what it means for ALS research going forward?
I'll start off by introducing TDP 43 as it relates to ALS. TDP-43 is an RNA binding protein that regulates different aspects of RNA metabolism, regulates protein expression in the cell, ultimately. Previously in ALS and ultimately other neurodegenerative diseases like Alzheimer's, frontal temporal dementia, this normally nuclear protein is found present in the cytoplasm and disaggregates. And you can actually see that in end stage post-mortem tissues in ALS, Alzheimer's disease and frontotemporal dementia.
While that was identified about 15 years ago, no one really understands why that happens or how that happens. My work as a post-doc in the lab is really focused on identifying defects in the nuclear pore complex, which is sort of like the control center of the cell. And it forms a gate between the nucleus and the cytoplasm to regulate the compartmentalization of different proteins and MRNAs between the nuclear and cytoplasmic compartments of the cell.
TDP 43 is one of these proteins that can actually shuttle through this complex. We have hypothesized for a while now that perhaps an injury to the nuclear pore complex or control center could perhaps contribute to the mislocalization and dysfunction of TDP 43 that is seen in ALS-related neurodegenerative diseases.
CHMP7 is a protein that is involved in multiple cellular pathways, but it's predominantly known for its role in nuclear remodeling; and recent work from our collaborator, Patrick Lusk at Yale, has identified a role for CHMP7 and ESCRT-III complexes -- its protein partners -- in remodeling nuclear membranes and surveilling the nuclear pore complex to maintain homeostasis, to ultimately maintain trafficking and compartmentalization between the nucleus and the cytoplasm.
In ALS, this protein, CHMP7, actually accumulates in the nucleus and can initiate an injury to the nuclear pore complex structure, and this can ultimately be the loss of TDP 43 function within the nucleus and mislocalization of the TDP 43 protein itself from the nucleus to the cytoplasm.
Our previous research identified how the nuclear pore was defective. It was missing pieces, we'll call it. I like to use the term -- probably not properly -- as the pores being disassembled, and our most recent study explains the mechanism, how it becomes disassembled in ALS and then downstream of that, how that then affects TDP 43.
We want to emphasize, this is a pathology. It's come to all sporadic patients that is both the nuclear pore defect, but previously the defect and TDP-43, this loss of nuclear TDP-43.
How do these findings point to a potential therapeutic target?
ASO's, or antisense oligonucleotides, are elements of the nucleotides, the elements that the building blocks of either RNA or DNA, and they're complimentary,that is, they're matching partners. And when you add them to a cell artificially, as you can do with an ASO therapy, they cause a degradation of the endogenous RNA in the cell, and that's a way of essentially eliminating a toxic species in the cell. So, it's the earliest starting point in many diseases where there's defects in the nucleotide sequence. The ASO essentially eliminates that very first starting point. To use an old cliche, it’s like a domino.
This has actually been done for a while in ALS. It started with the SOD1 antisense trials, which are still now well underway, because exciting results have been reported in the last year. Quite honestly, it began there first, but sometime later that same kind of therapy, a different version of this drug, was used in spinal muscular atrophy. And it is what I consider the penicillin of the 21st century. It essentially stops the disease in those children, and they regain normal health. This has become a very powerful therapy that we can use.
And finally, the most important part, we know therapies take a long time to develop. It often takes 10 years to build a new molecule therapy. ASOs much faster. This research that Alyssa and I just published, we're already working with the drug companies to develop that ASO therapy. It will be, of course, their therapy to use, but it moves easily half the time a normal drug goes to development to a patient.
What are the next steps in the development and in the research process?
In the past, many therapies were first developed in a model, a rat or a mouse, for example. This gene product is very different than mice versus humans. And this is why the platform that Alyssa used, induced pluripotent cells, essentially a human neuron from our patients is the ideal platform to discover this drug in and to use this drug.
And so, we began without a mouse model, if you will, we went right to the human cells. We tend to refer to this as like the equivalent of a human biopsy from our patients.
We've worked this out with the help of Ionis, the pharmaceutical company that has been a real strong collaborator in this project. And so, we've worked at a molecule that works very good in the laboratory. They then as well as any commercial partner, whether they develop it for a drug or some other commercial partner have to then optimize it and we'll need to still do some testing in animals just to make sure it's relatively safe in animals, and of course we all know that ALS is a terrible disease and safety to some patients becomes a minor player when you have such a terrible disease, but they need to know before they'll ever bring it to patients that you can give it to a mouse and suddenly the analysis and dropped dead in two hours.
So, there are simple things that we need to know first and that's in their hands. We'll help them out a little bit, but it really ultimately goes to their hands. But in my past experience, an ASO moves within a few years to patients. Now, I can't tell you there'll be a few years for this molecule, but in my past experience, it's been more like a decade. This is going faster. If in fact it is a good molecule, that's where the next set of experiments are.
How much earlier are we talking about in terms of being able to think about earlier interventions in terms of earlier treatments? Is that something that we can conceptualize?
We believe that the nuclear accumulation and mislocalization of CHMP7 from the cytoplasm to the nucleus might be perhaps one of the earliest initiating events pathogenically in ALS.
We also know in a subset of ALS, such as C9 ALS for instance, that the initiating domino there is actually a genetic mutation in the gene, but we think we've landed on a very early event, at least in cultured IPS neurons.
Translating that to patients is a little harder. We don't really know. There have been very few studies of patients where brain tissue is examined before they actually had ALS --accidents, things like that. From the limited data that's available, it looks like that a very early event is this mislocalization followed by an event that many other labs have studied, which is this aggregation of TDP-43 outside the nuclease in what is known as the cytoplasm. Studies of real human neurons teach us that, that clearance is really likely the first event.
Now, can we translate that to the time we actually intervene in the clinic? I don't think we're ready to do, and no one is ready to do that yet. So, all we know is the earlier we get in ALS, the more hope we have that we will be impactful.
I've run clinical trials since 1995 and I can tell you when we looked very late in the disease, we haven't done so well in terms of drugs.
What's important to point out herethat we didn't mention yet in terms of translating this therapeutically is, when I did those ASO studies in these cultured neurons, I actually treated these neurons at a time point where the pathogenic cascade had already occurred.
These neurons already had nuclear pore injury. They already had TDP-43 dysfunction. They already had nuclear accumulation of CHMP7 initiating this all. And when I treat at that time point and now reduce CHMP7 protein levels, I can reverse the injuries that had already occurred.
So, the point being, it's not past the point of no return. We can still repair an injury once it's occurred, at least in this human cell line, which we hope recapitulates what goes on in patients.
What are the next steps in this particular line of research?
My future directions in terms of looking at CHMP7 research is we have been talking about identifying that first domino and identifying the initiating event. And so we know that nuclear accumulation of CHMP7 can initiate this pathogenic cascade, but this is a protein that's normally found in the cytoplasm and not the nucleus.
My open questions that I'm interested in pursuing, or one of them moving forward is, what actually initiates bringing CHMP7 into the nucleus and keeping CHMP7 and the nucleus to, quote unquote, disassemble the nuclear pore complex and initiate this pathogenic cascade, especially in sporadic ALS, where there's no known genetic mutation.
We have a few hypotheses that I'm working on testing and I'm interested in looking further into, in the future, just sort of identify this initiating event that initiates CHMP7 initiating nuclear pore, complex injury.
And one of these might be actually genetic variants in nuclear pore complex proteins or nuclear envelope proteins themselves that may act as a damage signal recruit this surveillance and homeostasis protein at pathway. That's a particularly exciting idea that we have in the group.
We all have normally acting proteins, but slight variations. If you look at all of us, we have slight differences in our face, eyes. And this surveillance pathway may pick up those slight differences over time, leading to the injury, as opposed to a strong genetic mutation like C9 mutation. So that's at least one way to explore this in sporadic ALS.
The other very important point, and we've seen this a lot now with things like COVID research, this fundamental research program, aside from giving us a fundamental understanding of cell biology, does begin to lead to new candidate drugs. When we started this years ago we were hoping to fix the nuclear pore. We didn't know this pathway would be the direction. It was a sequential series of basic research that led to this point. Continuing along those lines almost certainly will lead to those new opportunities.
As we continue to understand what initiates this whole cascade, we'll continue to refine and find new therapeutic opportunities for intervention, perhaps even earlier on.
This sounds very hopeful. Thank you for all the good work you’ve done and are doing!
My daughter, Keri, died from ALS in January, 2008. Only 25 months from the first symptom. Keri was 27 years old when the first symptom (right foot dropsy or dragging) appeared. She became pregnant in 2006 and gave birth to my granddaughter in March of 2007. She stopped breathing in January, 2008. My wife (now deceased) started the non-profit Keri's Crusade for ALS. We help sponsor the North Carolina annual conference on ALS and are affiliated with the NC ALS Association. So I am very interested in any discovery, treatment, or research on ALS.
My son Louis Bowman had ALS, that started when he fell from a high place and landed on his back. That fall started with pain, soreness that charopatric treatments did not help. Finally my son consented to see an MD. Dr. Smith. My son was not even thirty years old! So trauma in my opinion is a real culprit in ALS. Now I wonder also if as his mother, I will have memory problems, because is a gene in my system? But none in my family or his father's family had or has had ALS. nor my other two living sons. If you need samples of me let me know.
I have never heard of your theory but in my fathers case it could very well apply. He was a paratroopers in the Army 82nd Airborne when his parachute failed to launch. The parachute finally opened but had holes all in it so he was extremely lucky to be alive. Nevertheless, he had major back and neck problems the rest off his life which resulted in multiple surgeries. He too developed ALS in 2017 and passed in 2018.
My mom of ALS in 2019
3 months prior to her first symptoms she fell backwards on her back and hit the left side of her skull on concrete. She did not break anything and never told us until we were at a doctor’s appointment is when they asked if she had fallen in the last 3 months.
The neurologist did not think there is a correlation. I have always wondered if there is. Praying for a break through in ALS research
I do not believe that they mean a physical injury to your body.
I was diagnosed with Progressive Bulbar Palsy (PBP) in May 2018. I have not manifested any signs of ALS thus far, though anything is possible since well over 90% of all PBP patients do develop ALS. if things stay where they are with my progression to ALS, would I be a candidate to receive this therapy or would I have to be displaying signs of ALS?
Hi Maureen, so sorry to hear about your diagnosis. These researchers have not yet developed an available therapy, even for people who are living with ALS.
This is wonderful news! I lost both my sisters to ALS, my mom had frontal temperal lobe dementia . Myself and my niece both carry the gene for ALS. Thank you so much for this information.
It must be so exciting to get down the micocellular level and hopefully find possibilities on how to control the progression of ALS. I want to encourage you all to keep going. Perhaps there is a vaccine(mRNA) that will control it? Just offering my encouragement(that is what I do) and some ideas I have.
Exciting news but, as the sand continues to exit the top half of the bottle, many of us will move on without being able to experience any advanced treatment..
I am delighted to read this so well written and exciting article.
As a geriatric nurse practitioner, recently retired, and the widow of Blair Clark, who died of ALS November 2017, getting to follow this thread of exciting research feels rich with hope.
Very interesting. I’ll get the scientists in my family to explain it to me but this is exciting work. Blessings on you. It matters!
This is very interesting. A little over my head but understandable. My cousin has ALS. I would be interested in info on trials.
Thanks for this helpful information
Thank you for sharing this exciting work!
This is very exciting research! Pinpointing the origin of this catastrophic cascade is really the holy grail for ALS research, and I congratulate you on this very promising detective work. (This appears to be a machine translation, and the transcript could use a little editing.)
Agreed! We do need to understand the catastrophic cascade, especially the initiating event. And, yes, I thought this must have been a machine translation that needed at least one person to proof read it! Maybe this happened in the shortening for length, but it did make the information less clear to understand.
Prior to my mother's ALS Bulbar Onset diagnosis, she would communicate with the doctors trying to diagnose her inability to speak that she felt that it was associated with her recent Shingles vaccine. My Mom was healthy and was only taking vitamins in her daily regimen. Every doctor would dismiss it and refer her on to the next doctor. After my mother was finally diagnosed, she was asked to join a research study where she was required to answer at least 25 questions every week. By this point, Mom couldn't speak and was on a feeding tube (otherwise physically she was okay). Every week I would ask the nurse to write down that my Mom felt that the Shingles vaccine could be a contributing factor. None of us are anti-vaxers, but felt that it was relevant to determining the cause of ALS. The nurse would put it in the comments section, but told us it would "go nowhere". Mom was part of the research study through a local ALS chapter that was focused on finding a cure. We never understood why this question couldn't be asked to future respondents. Mom died 6 months ago. We live in California. Last week a friend called me to let me know that a close friend in Iowa had died of ALS and while she was speaking with the wife of the deceased, she told her that her husband had thought that the Shingles vaccine could have contributed. I saw this article and was prompted to write something. None of us are anti-vaxers, but we do not understand why this cannot even be considered in the numerous questions that are asked of someone who has been diagnosed. We believe that vaccines are given for the "common good". We also believe that if you can find the cause of ALS, then maybe you can find a cure that can at least stop the progression. We are not suggesting that the shingles vaccine needs to be eliminated, but if in some way the vaccine is causing a small portion of the population to be diagnosed with ALS, then wouldn't you be closer to finding a cure?
My Mother died from ALS inheritance 70s. So the inheritance I guess is in my family. Is there a test for possible ALS due to inheritance?
Hi Rudi. Learn more about genetic testing for ALS here: https://www.als.org/understanding-als/who-gets-als/genetic-testing
I lost my brother to ALS a couple years ago, he had the bulbar form, which progressed very rapidly. It was 10 months from diagnosis to death. Such a devastating disease. If any samples from me would be useful, I am more than willing. Thank you for your dedication and the hope you bring to all of the people affected by this disease.
I am so grateful for your work and continued dedication! This sounds incredibly hopeful! I lost my husband to ALS 5 years ago, and was also a Physical Therapist for Early Intervention for over 35 years. To think you may be able to reverse damage sometime in the future for some diagnosis’s and prevent progression of neurological damage is and answer to the prayers of millions. Thank you for such hope!
My husband was dx with PLS about two months ago. Also told possible ALS. If you do any trails he would be very interested in participating. This is such a devastating disease and we are praying for something that will help slow progression or even a cure. Thank you for your continued work.
I found out in March that I have ALS. I had 2 cousins die with the SD01 mutation of ALS their Mother (my aunt) was tested & was a carrier but never contacted ALS. There is further family history of ALS. My SD01 did not show mutation but I do have ALS which is progressing quickly. I fell in December & got 2 black eyes, however had signs of twitching & weakness before that. I am going to the ALS clinic in Indianapolis, IN & would willing be in any testing that would help this dreaded disease.
This is promising news and I congratulate the researchers. My brother Peter was 46 years old in 2006 when he lost his precious life to bulbar ALS. (For what it is worth, our family's theory is that undiagnosed Lyme's Disease may have been the trigger.) Peter was a patient of Dr. Rothstein and I cannot pass up this opportunity to express my profound hope that -- in the intervening years -- Dr. Rothstein has developed greater sensitivity toward his patients. While I do not doubt Dr. Rothstein's dedication, his manner toward my brother at that time was a source of added grief for my brother and our family. ALS patients deserve support and understanding as they wrestle with this uniquely cruel disease.
Thank you for this information. It offers hope to those of us with this devastating disease.
Iam a 73 year old who was dx. in late 2019,definitive dx delayed until 2020 because of Covid. I went from being very active,still working,caregiver of 2 to now only being able to walk short distance with walker, long distance in a wheelchair.
I pray for your success.
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