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Welcome to BIOTECH NATION !!! With understandable interviews requiring no background in science, BTN attracts a wide global audience. From everyday people looking for hope in treatments in development, to bioentrepreneurs interested in the experience of their fellow travelers, to venture capitalists looking for possibilities in cutting-edge breakthroughs, to scientists simply interested in the work of others, BioTech Nation is the voice of human endeavor, driving science to new realities for everyone. These interviews are drawn directly from the public radio program, "Tech Nation", which also can be heard in numerous global radio and podcasting venues.
It's your brain. We all pretty much know that over time, we lose synapses. Depending on where you lose them, it could lead to such conditions as depression, schizophrenia, Alzheimer's, or ALS. Doctor Peter Vanderklish from Spinogenix talks about their advanced human trials in synaptic generation. Doctor Vanderklish, welcome to the program.
Dr. Peter Vanderklish:Thanks for having me.
Dr. Moira Gunn:Now there's a whole range of medical conditions that we are all familiar with and they have to do with the loss of synapses in the brain. That could be depression, schizophrenia, Alzheimer's, ALS. So let me start there. Give us a picture of our healthy brains. What are synapses?
Dr. Moira Gunn:What do they do? And how many do I have in my brain or your brain or any brain?
Dr. Peter Vanderklish:Well, synapses are physical connections between neurons that allow them to communicate with each other. And so every neuron has, you know, potentially thousands of synapses and can sort of link up with many other neurons by virtue of having that many contacts with other neurons. So neurons link up into large networks of neurons and it's a synaptic communication between them that allows them to do things like information processing. So synapses are really, an indispensable element of yours your nervous system and are involved in everything you do, everything you you think, everything you perceive, everything you say you do. And, of course, they're involved in memory formation, which is perhaps, maybe, the most important faculty of mine become over a lifetime, together.
Dr. Moira Gunn:Now how many do I have? You like it how it's all about me? Yeah.
Dr. Peter Vanderklish:Yeah. Well, you have a lot. I can sense
Dr. Moira Gunn:How many does the listener have?
Dr. Peter Vanderklish:So on average, the, you know, the human brand is about 85,000,000,000 neurons. And estimates of the number of synapses that you have range from about a 150,000,000,000,000 all the way up to, you know, pushing up towards 1 quadrillion. So that's an enormous number. To give you a sense of that that number, I I actually want to refer back to a passage from a book my, my postdoctoral mentor, the late Gerald Edelman wrote, where he he tried to relate, you know, the sort of the size or the the complexity of the number of synapses. And he said he had a great quote in there, which was, if you were to start counting each synapse 1 by 1 every second, it would take you 32000000 years before you finished.
Dr. Peter Vanderklish:Now if you then went on to actually calculate how many different ways those various synapses could be activated, the it becomes what he called hyper astronomical. So the number of potential combinations of active synapses that you can have in your brain is 10 followed by 1,000,000 of zeros. And to give you some perspective, the estimate of the number of atoms in the known universe is about 10 followed by 80 2zeros. So the complexity embedded within your brain in terms of the number of synapses and how they can be active, and that says nothing about sequences of activation which would project beyond all balance is hyper astronomical.
Dr. Moira Gunn:And pretty darn complex.
Dr. Peter Vanderklish:Yes.
Dr. Moira Gunn:I'll take that for sure. No one is gonna argue with me about that. Now from the time you were born to throughout your life to the time you age, if you have a healthy brain, how does that change?
Dr. Peter Vanderklish:Well, that's that's a great question. So, you know, I'm gonna paint a little picture for you. So early on in your life, you have believe it or not, you have too many synapses. So in early brain development, you have this explosion of synaptogenesis that creates, you know, a template, if you will, that the brain can work with as you mature and develop and learn. And once you pass that peak in early life, and I think it's somewhere around 3 years old, and mature and develop and learn, you actively prune down synaptic contacts.
Dr. Peter Vanderklish:You whittle them away, the ones that aren't used or are aren't so important. And you resolve at a plateau. You you have a stable number of synapses in your adult life for a very long period of time. Now as you age and maybe getting into maybe around 60 years old, somewhere around there, this sort of flat line that is synaptic number through most of your adult life starts to dip a little bit, but slowly, not too much. You know?
Dr. Peter Vanderklish:And and that is one of the contributors, not the only one, but one of the contributors to normal age related cognitive decline. It's not the type of precipitous decline that you see in diseases such as Alzheimer's and other forms of dementia, But it, you know, it's measurable. And so, you know, healthy brain aging, normal brain aging does involve at some point a reduction of synapses from a stable plateau that you have in most of your adult life.
Dr. Moira Gunn:Now these medical conditions, I mentioned, depression, schizophrenia, Alzheimer's, ALS, from the outside, they all look different to us and yet they all share loss of synapses. How are they different from each other if we look at it through the lens of synapses?
Dr. Peter Vanderklish:At a basic level, one of the main differences is that you're losing synapses in in different regions. Now a lot of these diseases have a lot of commonalities. So, you know, they have overlapping patterns of synapse loss in terms of what brain regions you've seen synapse loss in, but they also have important differences. So for example, in Alzheimer's disease, you see a lot of synapse loss in a region called the hippocampus and the neuronal cortex are involved in memory formation. Frontotemporal dementia, you've seen it more on the frontal cortices, temporal cortices.
Dr. Peter Vanderklish:In ALS, you've seen it in in the motor cortex. And additionally, in ALS, you know, there are some people who have frontal temporal dementia like cognitive issues and you see synapse loss in those people in the frontal cortex. And so, you know, regionally these diseases differ. In schizophrenia, for instance, is as well you you have loss of synapses in the frontal cortex. So regionally they differ but also at a mechanistic level it's kind of the same picture.
Dr. Peter Vanderklish:There's there's a lot of mechanisms that are involved, pathological mechanisms involved in synapse loss and at least to some extent these diseases share some of those, but they also have important differences. So from an anatomical perspective and from a mechanistic perspective, they have overlapping but different properties. So in your brain and Alzheimer's, you know, what you would be seeing is a pattern of synapse loss that is occurring, you know, predominantly at first in the hippocampus and then spreading to other regions. In a disease like ALS, which is a motor neuron disease, you're going to see synapse loss primarily in the motor cortex. And in disease like schizophrenia and frontotemporal dementia, you're going to see a pattern of synapse loss that mostly involves the the frontal pre and prefrontal cortical regions.
Dr. Moira Gunn:Well, what about depression? Are there many kinds of depression?
Dr. Peter Vanderklish:That's a great question. So, you know, depression actually, it turns out that you're losing synapses to a degree, in some of those same regions, in the hippocampus and the prefrontal cortex. Those are particularly important areas for not just memory formation but emotional regulation as well and stress regulation.
Dr. Moira Gunn:Now if you hear anything about Alzheimer's, you often hear about a theory which is some combination of the presence of amyloid beta causing plaques and tau tangles within neurons and it all, you know, to the lay listener, it all all kind of sounds the same. Is this theory accepted science?
Dr. Peter Vanderklish:Oh, that's that's a great question. So I I think a lot of it is. I think, you know, you know, the amyloid theory of Alzheimer's disease is core in its most basic form just posits that the generation of a small protein fragment called amyloid beta, is causing is a central player in the pathogenesis of the disease and kind of accounts for for most of the the pathology you see and the symptoms you see. It's and it's thought that this peptide, this short protein fragment is is toxic to both synapses and neurons and increases inflammation and does other things. It's a decent theory but, you know, it may be, you know, it may be wrong.
Dr. Peter Vanderklish:And this, you know, this you know, a lot of people have seen, you know, data in the popular press, you know, about how the the effects of new medications that have been approved are are very modest, and some of them come with a nontrivial risk for serious adverse events as well. And there's also been reports that you've heard about, of course, about allegations of scientific misconduct by major figures in the field. This has brought some doubt more doubt into the theory. But I think when you, you know, when all the smoke clears, you know, it does carry some weight. And I do think, you know, it can be safely concluded that amyloid beta is at least a stressor on neurons, and synapses.
Dr. Peter Vanderklish:It may not be the the central player in the disease processing, but it's not something you want a lot of in your brain. I think probably the bigger problem with the amyloid theory is that it's just insufficient. So in Alzheimer's disease, we know that it's tremendously heterogeneous from a clinical perspective, and from a mechanistic perspective. So patients will present, you know, with different profiles of dementia. And there's also it's also known that there are a lot of different pathological processes going on in the Alzheimer's brain that may differ in their relative contribution to symptoms from one person to another.
Dr. Peter Vanderklish:So I think as people go forward in this area, trying to parse that heterogeneity and attack the disease from multiple angles, you're gonna find more success. And of course, we think synaptic regeneration is gonna be a great therapeutic value.
Dr. Moira Gunn:Which leads us to the theory that Spine Genetics is pursuing.
Dr. Peter Vanderklish:Yeah. And so we're pursuing synaptic regeneration as a therapeutic approach to address the larger set of what we call the synaptopathies. So all these diseases that you mentioned at the outset that are you, having common a loss of synapses. And in particular, our compounds are are geared towards regenerating a subset of synapses called a special type of synapses called glutamatergic synapses. These the amino acid glutamate is a neurotransmitter.
Dr. Peter Vanderklish:And these are the dominant, the most abundant type of synapses in your brain. And so we think by regenerating synapses through a mechanism that is actually, we think to a degree, disease agnostic, You can actually offset synapse loss in these different diseases in different areas of the brain, and hopefully slower, maybe even possibly reverse, the course of symptoms in different diseases.
Dr. Moira Gunn:What exactly, are you doing? Yeah.
Dr. Peter Vanderklish:So we've developed, a compound which is called SBG 302. It's a small molecule, which basically means it's something that you can formulate into a pill and take by mouth and it gets into your brain where it works to regenerate synapses. And we're using this as a therapeutic approach to treat a spectrum of diseases that are termed the synaptopathies, which encompass many of the diseases you mentioned at the outset, Alzheimer's disease, schizophrenia, frontotemporal dementia, ALS, on and on. There are many synaptopathies and we think that regenerating synapses in these conditions has the potential to slow or potentially even reverse, some of the symptoms of these diseases.
Dr. Moira Gunn:I think what strikes me is that I've always heard about synapses dying, but I haven't heard about synapses regenerating. Can you give us any examples of that?
Dr. Peter Vanderklish:Yeah. So in your adult life, you're you do have synaptogenesis. You know, it's not just a as we talked about earlier, it's not just a a downward curve the whole time. You're things are at a stable plateau for quite a while. You know, you're losing synapses, you're generating synapses and they're roughly offsetting in most brain regions for a long period of time.
Dr. Moira Gunn:So that's the flat line.
Dr. Peter Vanderklish:Exactly. Yeah. So, you know, regeneration and gen synaptogenesis and regeneration are alive and well for a lot of your your lifetime. But as you age, a lot of these diseases are have too many components to them. They have degenerative processes, obviously, which are very multifactorial.
Dr. Peter Vanderklish:But with age, you also lose the ability to regenerate. And we think our compound is coming in and coaxing a particular molecular process that is allowing synapses to, you know, or neurons to sort of wake up, if you will, and and to be able to regenerate synapses where they're needed. And, you know, a good example of where this this happens in nature is, you know, under conditions of stress, is in in hibernating animals. You know, there are there are studies that were done on hibernating ground squirrels, for instance, where, you know, they do because of a scarcity of food, these animals, you know, evolved to go into a state where they they use less energy because they don't have as much food. And so and then you get to survive the winter as well.
Dr. Peter Vanderklish:So they they hibernate. They go into a state of torpor, low body temperature. They lower their metabolic rate all in an effort to sort of survive the stresses of winter and and and low intake of food. Now this is a big challenge for the brain, which is very metabolically active, to to weather this. And and one of the things that the brain does is to retract some of its synapses.
Dr. Peter Vanderklish:Now these studies in ground squirrels are very interesting because when they go into hibernation, it turns out that their brains actually, show evidence of, Alzheimer's like changes. They, they develop, you know, tangles of tau, the hyperphosphorylated tau protein that you see in the Alzheimer's brain. They lose some of their synapses. But by the time, you know, within hours after them coming out of the hibernating state, their synaptic density, comes back to normal. Now the the the percentage of synapses that they've lost has returned to a normal state.
Dr. Peter Vanderklish:And also some of the the Alzheimer's like changes that you see in their brains are reversed. So there is this ability to have the brain to rebound and regenerate after, states of severe metabolic stress, which is a component to neurodegenerative disease, and to do so in short order and in an appropriate way. Interestingly as well is the fact that in hibernation, you know, the additional studies were showing that memories that were encoded in ground scrolls shortly before hibernation actually, remained intact after hibernation. There could be a lot to explain that. One of the explanations could be that even though some of the synapses have been lost, when synapses were regenerated, they were regenerated at the right level and in the right places.
Dr. Moira Gunn:Wow. That's all I gotta say. Hey. I remember where my acorn is that that I buried over here in the fall.
Dr. Peter Vanderklish:It's important. Yeah.
Dr. Moira Gunn:It's very important. And I think what's so important here is is not just that they can be regenerated, but that we naturally have a regeneration process that may be what was affecting and it's not so much the decline in synapses, which we all have, but the fact that we're unable to regenerate them. You know, there's any number of combinations here again because it's very complex, but it's it's a it's a much different way, I think, of of thinking about how to go forward. Now, you, of course, are already in phase 2 with this, but I wanna, talk about what did you do in phase 1, that first study to make sure that it's safe? But, you know, we always learn things in phase 1.
Dr. Moira Gunn:What did you do in phase 1 that when you started studying it in humans? And what did you learn?
Dr. Peter Vanderklish:Yeah. So phase 1, involved healthy volunteers, over 80. And what we do in those studies is we test our our drug at a single dose of our drug at multiple dose levels, and they called a a single ascending dose, portion of the trial. And we tested, you know, what we think would be low levels to give people and and and levels that we think exceed what you need to achieve therapeutic value. And then we also have a cohort of people where, they receive multiple doses, either multiple low doses over days or multiple high doses.
Dr. Peter Vanderklish:And we found that that the drug is very safe and well tolerated. It doesn't seem to induce any severe adverse events. And we also found that at relatively modest doses, we achieved blood levels of the compound that are associated with, efficacy and regenerating synapses and improving symptoms in animal models of neurodegenerative disease.
Dr. Moira Gunn:So in fact, you're seeing that it's it's at some point is something is being delivered here.
Dr. Peter Vanderklish:Yeah. Yeah. So it's it's it was doing everything you would want for a drug of this nature. It's getting it quickly. It's achieving plasma blood levels that are associated with the biological the intended biological effect in preclinical models.
Dr. Peter Vanderklish:And it's not it appears to be not causing any harm.
Dr. Moira Gunn:Now now let's go to phase 2 because now now you're starting to separate out which disease are we working on. They're different arms of phase 2 here. Let's start with the Alzheimer's. How many people are you studying? Who are they?
Dr. Moira Gunn:What are they doing? How how how is everything being measured?
Dr. Peter Vanderklish:So we have an ongoing phase 2 trial in Alzheimer's disease. It's enrolling patients with mild to moderate Alzheimer's disease up to 24 patients. And, you know, the trial is designed as follows. So there's an initial period that is placebo controlled, meaning that some will get the drug and some will get a placebo. And that period is followed by a longer period after that and during which patients can elect to stay on the drug if they'd like to and know they're getting the drug.
Dr. Peter Vanderklish:And in the trial, we're we're measuring 2 general things. So one, we're measuring we're using multiple tests to get a gauge of their patient's cognitive status, the same tests that are used by many others, testing other types of candidate Alzheimer's therapies. In addition to that, we're using, we're doing measures of of proteins in the blood that are, you know, biomarkers of the disease process. One of them's a measure of neurodegeneration in general. And then there are other biomarkers that are are decent measures of of degenerative processes that are more specific to Alzheimer's disease.
Dr. Peter Vanderklish:And then on top of that, we are adding, neurophysiological measures, you know, actual EEG recordings, different types of measures that allow us to get a sense of whether or not our compound is actually changing, the number of synapses in the brain. And there there's sort of, you know, ensemble activity that you can record, from the outside of the brain, from the skull.
Dr. Moira Gunn:How about the ALS trial? Is that very different?
Dr. Peter Vanderklish:It's it's different in some ways. So and that has some similarities. So, it's fully enrolled for one thing. And, we had our, you know, last patient enrolled very recently. It also has in the beginning a placebo controlled phase where, you know, some patients will get drug and others will get placebo.
Dr. Peter Vanderklish:And then after that, it also has that extension phase where patients can elect to to stay on drug and and know they're they're on the drug. Now, in this trial, you know, again, we're using some of the standard outcome measures that are used by people testing other candidate therapeutics for ALS. But in addition here, again, we're using neurophysiological techniques that we view as objective, quantitative outcome measures of neural function. In this case, we have not only are we using EEG like we did in Alzheimer's disease, but we also have the the added benefit of being able to use a technique called transcranial magnetic stimulation or TMS. And what's interesting about this this technique is it allows you to position a magnet basically right over the skull, right over an area of the cortex called the motor cortex that's degenerating in ALS.
Dr. Peter Vanderklish:And it's the region of your brain that's con you know, it's kind of one of the master control areas of movement. And you can apply a magnetic field and evoke a motor response. Now in ALS patients they find that a lot of patients even early on in a disease they can measure the sort of excitability of the motor cortex with this measure and the patients have what's called a hyperexcitable motor cortex, and you can quantify that. And so we will be able and this and this is linked to, we believe, the density of synapses on the motor neurons that are degenerating in the condition. And so we can measure this degree of hyperexcitability and and see if we're having a benefit at the neurophysiological level and the neuro level in the brain in ALS patients.
Dr. Peter Vanderklish:At the same time, we're measuring basically function with other outcome measures and and blood biomarkers of neurodegeneration.
Dr. Moira Gunn:Well, again you're going into many areas here, but I think some of the takeaways for me is that you're able to see changes, and you're able to do it pretty quickly, non invasively. And, we can then hope to follow those down as we go forward. But that's quite different than having to say, do you feel better? Do you get a little more? How many months from now?
Dr. Moira Gunn:I mean, you're able to see changes pretty quickly in the body.
Dr. Peter Vanderklish:Yeah. It's it's you know, we're fortunate to be able to leverage these measures, you know, these neurophysiological measures as objective readouts of a therapeutic phenomenon that we think will have a rapid, you know, has the potential to have a rapid onset. We're not just relying on patient reports and other measures of functionality.
Dr. Moira Gunn:And earlier we were speaking of this, not just the synapses but the ability to regenerate them. Do we know if the ability to regenerate them may in fact be kicked in? And I'll tell you exactly where I'm going here. Do we know if people would have to take this medication for the rest of their lives or that possibly some portion of their own body might just restart?
Dr. Peter Vanderklish:Yeah. That's a really good question. I I it could be completely, forthcoming. I I don't think we have the answer to that. So, it's interesting a couple ways.
Dr. Peter Vanderklish:So, yes, the intent is that people would take this as a once a day pill that you would just simply swallow. It's not, you know, it's not hard to administer. But is it is that going to be needed in every disease for every patient? And there's a question mark there. And the question mark comes from the fact that we have data speaking to the fact that when we regenerate synapses in the absence of any underlying disease process in preclinical models, we see that they persist.
Dr. Peter Vanderklish:They can actually persist for weeks or more. Now it's anybody's guess, you know, how that persistence is going to change in the context of, you know, one Alzheimer's patient versus another, Alzheimer's versus ALS, frontotemporal dementia versus those, etcetera, etcetera, etcetera. And that's not something you can really adequately model in preclinical studies. And it's we're just going to have to find out in the clinic. But for right now, we think we can do benefit without doing harm with once once daily dosing.
Dr. Peter Vanderklish:We may find out later that you don't have to take it all the time.
Dr. Moira Gunn:Well, doctor Vanderklish, this is fascinating. I hope you'll come back and see us again.
Dr. Peter Vanderklish:Oh, that'd be great. Yeah. Thanks for having me, Maura.
Dr. Moira Gunn:Doctor Peter Vanderklish is the chief scientific officer of Spinogenix. Spinogenix is currently recruiting participants for clinical trials in Alzheimer's, fragile x syndrome, and schizophrenia. More information is available on the web at spinogenix.com. That's spi nogenix spinogenix.com.