ALS Therapy Should Target Brain, Not Just Spine
A recent Northwestern Medicine study published in Nature Gene Therapy has shown that the degeneration of brain motor neurons in ALS is not merely a byproduct of the spinal motor neuron degeneration, and is a target for future treatments for the disease. Lead study author, P. Hande Ozdinler, PhD, associate professor of Neurology and director of the Ozdinler Lab in the Les Turner ALS Center at Northwestern Medicine, explains the importance of these findings.
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Learn more about Hande Ozdinler, PhD
Hande Ozdinler, PhD
The Ozdinler Lab is interested in understanding the cellular and molecular mechanisms responsible for early vulnerability and progressive degeneration of upper motor neurons. These neuron populations are clinically relevant as their degeneration leads to diseases such as HSP, PLS and when their degeneration together with spinal motor neurons, leads to ALS.Learn more about Hande Ozdinler, PhD
Transcription:
ALS Therapy Should Target Brain, Not Just Spine
Dr. Andrew Wilner: Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Andrew Wilner, Associate Professor of Neurology at the University of Tennessee Health Science Center and Division Director of Neurology at Regional One Health Memphis, Tennessee.
Today, we're discussing a Northwestern Medicine study that was recently published in Nature Gene Therapy. This landmark research led by Dr. Hande Ozdinler indicates that degeneration of brain motor neurons in amyotrophic lateral sclerosis is not merely a byproduct of spinal motor neuron degeneration, but is an independent process. Consequently, these cortical upper motor neurons may be therapeutic targets as well as the lower motor neurons in the spinal cord.
Joining me today is lead study author, Dr. Hande Ozdinler. Dr. Ozdinler is an Associate Professor of Neurology and Director of the Ozdinler Lab in the Les Turner ALS Center at Northwestern Medicine. Welcome, Dr. Ozdinler
Dr. Hande Ozdinler: Thank you so much for the invitation. Thank you.
Dr. Andrew Wilner: Okay. Before we get too deep into your research, can you tell us a little bit about ALS and what causes it. Is it genetic, environmental, both?
Dr. Hande Ozdinler: So ALS is amyotrophic lateral sclerosis. It is a rare neurodegenerative disease in which the motor neuron circuitry degenerate. So the motor neuron circuitry has components both in the brain and in the spinal cord. And ALS is very complex. It's very heterogeneous. There are numerous underlying causes for the disease. And, yes, some of it is genetic, but there are also unknown environmental factors. And it may be a combination of both. So we are trying to understand the underlying causes of ALS. And every day, in each and every day, we realize how complex it is.
Dr. Andrew Wilner: Now, let's talk about your research. I read your paper in Nature and, frankly, it was pretty technical even for a clinical neurologist. Can you simplify it for me? What were you trying to determine?
Dr. Hande Ozdinler: So in the field of ALS, there was this notion that the upper motor neurons, the cortical spinal motor neurons, which resides in layer V of the motor cortex, degenerates because there is an ongoing degeneration in the spinal motor neurons, so that their death was actually a consequence of what's going on in the spinal motor neuron. Therefore, people believed that targeting upper motor neurons for ALS was a wasted effort because they were going to die anyways. And most of the effort to understand the ALS pathology focused on spinal motor neurons and the cortical component was left underinvestigated and not very well understood.
So we wanted to see if that is really the case, if upper motor neurons degenerate just because spinal motor neurons degenerate, or this is an independent process that we have to target upper motor neurons together with spinal motor neurons if you want to develop an effective treatment strategy.
So that's why we first developed a technique where we have the disease either only in the cortex or only in the spinal cord. And then, we looked at the degeneration of the motor neurons, both in the cortex and spinal cord. And we found that the cortical degeneration is not dependent on the spinal motor neuron degeneration. So the belief, the dogma that the spiral motor neurons drive upper motor neuron degeneration is not correct. So the brain now becomes the attention for developing treatment strategies. And I think that's very important as we move forward.
Dr. Andrew Wilner: Well, of course, clinically, ALS has been very frustrating for physicians and, of course, for patients because our treatments are not very effective. So now that you know that the cortical neurons play an important role, what can we do about that?
Dr. Hande Ozdinler: Oh, I think there are many things that can be accomplished. First of all, I would like to tell you that especially for the drug discovery studies, can you believe that none of the compounds that are in clinical trials right now have ever been considered for their impact on improving the health of upper motor neurons?
So this is a big, you know, untouched territory and the movement starts in the brain. The upper motor neuron degeneration occurs very early. There is hyperexcitation in the cortex, which begins to occur even six months prior to any symptom onset. So if you leave the brain out of the equation, I think we can never develop effective treatment strategies. So to include the cortex into the program, I think one way is to develop gene therapy approaches.
Especially for rare diseases, gene therapy offers many advantages. Imagine that you know the mutations that are present in the patient. You know the genes that are affected, we can actually take a corrective study and apply gene therapy so that the mutated genes or the mutated proteins can be corrected specifically in the upper motor neurons that degenerate. So these studies have a huge potential as we move forward for personalized medicine especially for ALS, other rare diseases and motor neuron diseases. This is what we would like to accomplish in the future.
Dr. Andrew Wilner: Well, that's pretty exciting. Are there any candidate drugs? Are we close at all to finding something that might help patients?
Dr. Hande Ozdinler: Yes. That's also the result of our collaboration with Dr. Richard Silverman who is the inventor of Lyrica. And now we're working on a novel compound which we identified to improve the health of diseased upper motor neurons. It is an NU-9. And that paper was also published last year. And we identified the first compounds that improves the health of upper motor neurons that are diseased due to mutations in SOD1 gene and also TDP pathology, two different and distinct underlying causes of ALS. So that's very exciting because we are developing gene therapy approaches, we are developing treatment approaches and we are also developing high throughput drug discovery platforms, which will incorporate the upper motor neuron health in drug discovery. And we are approaching with multiple different pathways all at the same time, because our goal is to incorporate the brain component of ALS into developing effective treatment strategies. And I think the future is very bright for ALS patients.
Dr. Andrew Wilner: Now, if I'm right, so far, all of your volunteers have been very small and have a tail, right? You're using mice. Now, how transferable is that information to human beings?
Dr. Hande Ozdinler: This is a very good question. So mouse has been used as a model system for many different diseases. And especially if you look at the motor neuron circuitry, there are differences between mice and humans. So then when you compare mice and human, it is not one-to-one translation. And I think that was one of the reasons why some of the previous clinical trials failed because the goal was to improve the health of the mouse. And yes, you can improve the lifespan of the mice, but this did not translate into improved lifespan in humans. So, you know, the translation is not between mice and humans.
But let me tell you this, if you focus your attention or our attention to the diseased neurons, it's a cellular level. So if you look at the upper motor neurons in well-characterized mouse models and the upper motor neurons in ALS patients, they are identical. And we show this with electromicroscopy analysis, with molecular markers, with many different cellular analysis that they show the same underlying cause for degeneration, same pathology. So if we can make the neuron happy, we can make the motor neuron circuitry happy. And if we can make the motor neuron circuitry functional, then this is the way forward for developing therapies in patients.
So it all boils down to the health of the neuron. And at a neuron level, at a cell level, the upper motor neuron in the mouse and the upper motor neuron in patients are identical. So that's why we don't translate between mice and human, but we translate between upper motor neurons versus upper motor neurons at a cellular level.
Dr. Andrew Wilner: Now, I'd like to expand on this just a little bit. There are, of course, many neurodegenerative disorders that affect motor neurons. Stroke, for example, can affect motor neurons. And would any of this treatment for ALS possibly be transferable to other diseases like Parkinson's and Alzheimer's and other neurodegenerative treatments?
Dr. Hande Ozdinler: This is also an excellent question. So upper motor neurons are critically important and clinically very relevant neuron populations. Their degeneration is observed in ALS, but also in hereditary spastic paraplegia, in primary lateral sclerosis. And in patients of HSP and PLS, there's also upper motor neuron loss. And as you mentioned, in spinal cord injury patients, the long-term paralysis that we observe in spinal cord injury patients is mostly because the upper motor neurons degenerate. And improving the health of upper motor neurons will have implications, not only in ALS but also in HSP, PLS and spinal cord injury patients And as well as stroke patients, and potentially Parkinson's disease patients as well.
Dr. Andrew Wilner: Well, that's pretty exciting. So tell us what are you working on now? What's the next step?
Dr. Hande Ozdinler: So, we are trying to develop biomarkers that would inform us about the timing and extent of upper motor neuron loss, because that information is very important especially for phase II of clinical trials for NU-9 and maybe other drugs that we identify.
In addition, we are developing personalized medicine approaches using gene therapy, so that we can actually alter a gene expression profile of key genes that cause the disease in select patients of ALS, HSP and PLS. And we are also developing drug discovery platforms so that we can incorporate upper motor neuron survival as the readout for success. And I think this is going to improve the overall success rate of clinical trials for ALS and for other upper motor neuron diseases.
Dr. Andrew Wilner: Dr. Ozdinler, this is fantastic. I want to thank you very much for sharing your research and insights about ALS pathogenesis and potentials for therapy with the audience.
Dr. Hande Ozdinler: Thank you so much for the invitation.
Dr. Andrew Wilner: And that wraps up this episode of Better Edge, a Northwestern Medicine podcast for physicians. To refer your patient or for more information, head on over to our website at breakthroughsforphysicians.nm.org/neuro to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. For updates on the latest medical advancements and breakthroughs, you can follow us on your social media channels. I'm your host, Dr. Andrew Wilner. Thanks for listening.
ALS Therapy Should Target Brain, Not Just Spine
Dr. Andrew Wilner: Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Andrew Wilner, Associate Professor of Neurology at the University of Tennessee Health Science Center and Division Director of Neurology at Regional One Health Memphis, Tennessee.
Today, we're discussing a Northwestern Medicine study that was recently published in Nature Gene Therapy. This landmark research led by Dr. Hande Ozdinler indicates that degeneration of brain motor neurons in amyotrophic lateral sclerosis is not merely a byproduct of spinal motor neuron degeneration, but is an independent process. Consequently, these cortical upper motor neurons may be therapeutic targets as well as the lower motor neurons in the spinal cord.
Joining me today is lead study author, Dr. Hande Ozdinler. Dr. Ozdinler is an Associate Professor of Neurology and Director of the Ozdinler Lab in the Les Turner ALS Center at Northwestern Medicine. Welcome, Dr. Ozdinler
Dr. Hande Ozdinler: Thank you so much for the invitation. Thank you.
Dr. Andrew Wilner: Okay. Before we get too deep into your research, can you tell us a little bit about ALS and what causes it. Is it genetic, environmental, both?
Dr. Hande Ozdinler: So ALS is amyotrophic lateral sclerosis. It is a rare neurodegenerative disease in which the motor neuron circuitry degenerate. So the motor neuron circuitry has components both in the brain and in the spinal cord. And ALS is very complex. It's very heterogeneous. There are numerous underlying causes for the disease. And, yes, some of it is genetic, but there are also unknown environmental factors. And it may be a combination of both. So we are trying to understand the underlying causes of ALS. And every day, in each and every day, we realize how complex it is.
Dr. Andrew Wilner: Now, let's talk about your research. I read your paper in Nature and, frankly, it was pretty technical even for a clinical neurologist. Can you simplify it for me? What were you trying to determine?
Dr. Hande Ozdinler: So in the field of ALS, there was this notion that the upper motor neurons, the cortical spinal motor neurons, which resides in layer V of the motor cortex, degenerates because there is an ongoing degeneration in the spinal motor neurons, so that their death was actually a consequence of what's going on in the spinal motor neuron. Therefore, people believed that targeting upper motor neurons for ALS was a wasted effort because they were going to die anyways. And most of the effort to understand the ALS pathology focused on spinal motor neurons and the cortical component was left underinvestigated and not very well understood.
So we wanted to see if that is really the case, if upper motor neurons degenerate just because spinal motor neurons degenerate, or this is an independent process that we have to target upper motor neurons together with spinal motor neurons if you want to develop an effective treatment strategy.
So that's why we first developed a technique where we have the disease either only in the cortex or only in the spinal cord. And then, we looked at the degeneration of the motor neurons, both in the cortex and spinal cord. And we found that the cortical degeneration is not dependent on the spinal motor neuron degeneration. So the belief, the dogma that the spiral motor neurons drive upper motor neuron degeneration is not correct. So the brain now becomes the attention for developing treatment strategies. And I think that's very important as we move forward.
Dr. Andrew Wilner: Well, of course, clinically, ALS has been very frustrating for physicians and, of course, for patients because our treatments are not very effective. So now that you know that the cortical neurons play an important role, what can we do about that?
Dr. Hande Ozdinler: Oh, I think there are many things that can be accomplished. First of all, I would like to tell you that especially for the drug discovery studies, can you believe that none of the compounds that are in clinical trials right now have ever been considered for their impact on improving the health of upper motor neurons?
So this is a big, you know, untouched territory and the movement starts in the brain. The upper motor neuron degeneration occurs very early. There is hyperexcitation in the cortex, which begins to occur even six months prior to any symptom onset. So if you leave the brain out of the equation, I think we can never develop effective treatment strategies. So to include the cortex into the program, I think one way is to develop gene therapy approaches.
Especially for rare diseases, gene therapy offers many advantages. Imagine that you know the mutations that are present in the patient. You know the genes that are affected, we can actually take a corrective study and apply gene therapy so that the mutated genes or the mutated proteins can be corrected specifically in the upper motor neurons that degenerate. So these studies have a huge potential as we move forward for personalized medicine especially for ALS, other rare diseases and motor neuron diseases. This is what we would like to accomplish in the future.
Dr. Andrew Wilner: Well, that's pretty exciting. Are there any candidate drugs? Are we close at all to finding something that might help patients?
Dr. Hande Ozdinler: Yes. That's also the result of our collaboration with Dr. Richard Silverman who is the inventor of Lyrica. And now we're working on a novel compound which we identified to improve the health of diseased upper motor neurons. It is an NU-9. And that paper was also published last year. And we identified the first compounds that improves the health of upper motor neurons that are diseased due to mutations in SOD1 gene and also TDP pathology, two different and distinct underlying causes of ALS. So that's very exciting because we are developing gene therapy approaches, we are developing treatment approaches and we are also developing high throughput drug discovery platforms, which will incorporate the upper motor neuron health in drug discovery. And we are approaching with multiple different pathways all at the same time, because our goal is to incorporate the brain component of ALS into developing effective treatment strategies. And I think the future is very bright for ALS patients.
Dr. Andrew Wilner: Now, if I'm right, so far, all of your volunteers have been very small and have a tail, right? You're using mice. Now, how transferable is that information to human beings?
Dr. Hande Ozdinler: This is a very good question. So mouse has been used as a model system for many different diseases. And especially if you look at the motor neuron circuitry, there are differences between mice and humans. So then when you compare mice and human, it is not one-to-one translation. And I think that was one of the reasons why some of the previous clinical trials failed because the goal was to improve the health of the mouse. And yes, you can improve the lifespan of the mice, but this did not translate into improved lifespan in humans. So, you know, the translation is not between mice and humans.
But let me tell you this, if you focus your attention or our attention to the diseased neurons, it's a cellular level. So if you look at the upper motor neurons in well-characterized mouse models and the upper motor neurons in ALS patients, they are identical. And we show this with electromicroscopy analysis, with molecular markers, with many different cellular analysis that they show the same underlying cause for degeneration, same pathology. So if we can make the neuron happy, we can make the motor neuron circuitry happy. And if we can make the motor neuron circuitry functional, then this is the way forward for developing therapies in patients.
So it all boils down to the health of the neuron. And at a neuron level, at a cell level, the upper motor neuron in the mouse and the upper motor neuron in patients are identical. So that's why we don't translate between mice and human, but we translate between upper motor neurons versus upper motor neurons at a cellular level.
Dr. Andrew Wilner: Now, I'd like to expand on this just a little bit. There are, of course, many neurodegenerative disorders that affect motor neurons. Stroke, for example, can affect motor neurons. And would any of this treatment for ALS possibly be transferable to other diseases like Parkinson's and Alzheimer's and other neurodegenerative treatments?
Dr. Hande Ozdinler: This is also an excellent question. So upper motor neurons are critically important and clinically very relevant neuron populations. Their degeneration is observed in ALS, but also in hereditary spastic paraplegia, in primary lateral sclerosis. And in patients of HSP and PLS, there's also upper motor neuron loss. And as you mentioned, in spinal cord injury patients, the long-term paralysis that we observe in spinal cord injury patients is mostly because the upper motor neurons degenerate. And improving the health of upper motor neurons will have implications, not only in ALS but also in HSP, PLS and spinal cord injury patients And as well as stroke patients, and potentially Parkinson's disease patients as well.
Dr. Andrew Wilner: Well, that's pretty exciting. So tell us what are you working on now? What's the next step?
Dr. Hande Ozdinler: So, we are trying to develop biomarkers that would inform us about the timing and extent of upper motor neuron loss, because that information is very important especially for phase II of clinical trials for NU-9 and maybe other drugs that we identify.
In addition, we are developing personalized medicine approaches using gene therapy, so that we can actually alter a gene expression profile of key genes that cause the disease in select patients of ALS, HSP and PLS. And we are also developing drug discovery platforms so that we can incorporate upper motor neuron survival as the readout for success. And I think this is going to improve the overall success rate of clinical trials for ALS and for other upper motor neuron diseases.
Dr. Andrew Wilner: Dr. Ozdinler, this is fantastic. I want to thank you very much for sharing your research and insights about ALS pathogenesis and potentials for therapy with the audience.
Dr. Hande Ozdinler: Thank you so much for the invitation.
Dr. Andrew Wilner: And that wraps up this episode of Better Edge, a Northwestern Medicine podcast for physicians. To refer your patient or for more information, head on over to our website at breakthroughsforphysicians.nm.org/neuro to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. For updates on the latest medical advancements and breakthroughs, you can follow us on your social media channels. I'm your host, Dr. Andrew Wilner. Thanks for listening.