Loss of Function & Autism

Episode 12: Loss of Function & Autism

What is the relationship between loss of function SCN2A mutations and autism? How can studying SCN2A mutations teach us about cellular mechanisms underpinning autism? To help answer these questions we talk to A Prof Kevin Bender from UCSF Center for Integrative Neuroscience.

Hosted by Kris Pierce and David Cunnington, parents of Will, who has SCN2A.

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Guest interview:

Assistant Professor Kevin Bender head up the Bender Lab team at University of California, San Francisco Center for Integrative Neuroscience. His recent research interests have included loss of function SCN2A mutations and the cellular mechanisms via which these mutations can result in autism.

You can follow A Prof Bender on Twitter: @NeuroBender

Regular Hosts:

Ms Kris Pierce RN MHSc MWellness, is a rare disease advocate and mother to Will who has SCN2A. Kris has held a range of board, project management, advocate and consumer representative roles and has been instrumental in working with local, state and federal governments to secure funding for multi-million dollar projects. Kris is highly skilled in building teams to work together collaboratively and is a co-founder of Genetic Epilepsy Team Australia (GETA) and SCN2A Australia, and a RARE Global Advocacy Leadership Council member.

Follow Kris on LinkedIn or Twitter.

Dr David Cunnington is a sleep physician and father to Will who has SCN2A. He is director of Melbourne Sleep Disorders Centre, and co-founder and contributor to SleepHub. David trained in sleep medicine both in Australia and at Harvard Medical School in the United States. David’s clinical practice covers all areas of sleep medicine and he is actively involved in training health professionals in sleep. David is a regular commentator on sleep, both in traditional and social media.
Follow David’s posts on sleep on Facebook or Twitter

Transcript:

Intro: Welcome to SCN2A Insights bringing you the latest research and clinical updates on SCN2A and genetic epilepsy from around the world.

Dr. David Cunnington: Hi, I’m David Cunnington.

Kris Pierce: And I’m Kris Pierce. Today in this podcast, we speak to Kevin Bender who is an Associate Professor of Neurology at the University of California in San Francisco.

David Cunnington: The reason we wanted to talk to Kevin is that he has been doing a lot of work on the loss of function side in SCN2A. We’ve talked in a number of episodes about the gain of function but a loss of function is equally common, if not even more common than the gain of function so we thought it’s really important to get a better understanding of some of the research going on in this area.

Kris Pierce: Thank you, Kevin, for joining us today on the podcast. We appreciate your time today, but also, we appreciate all the work you’re doing in SCN2A. I know there are lots of families around the world who are grappling with what it means, whether they’ve got a gain of function or loss of function, and just hearing that people are taking the time out to work on this specific gene provides some hope and interest as well as to what you’re learning through your work.

Kevin Bender: Well, thank you, Kris, thank you, David, for having me this morning. I know it’s relatively early for me on the West Coast of California but it’s extremely early for you. So I appreciate you getting up extremely early. I’m happy to talk about what our lab has been up to in the SCN2A realm.

Kris Pierce: What are the differences that you found between gain and loss of function mutations in SCN2A?

Kevin Bender: This work started probably three years ago with some interactions with Stephan Sanders who came to UCSF from Yale. And he is a geneticist by training and also a paediatrician by training who has been studying the genetics of early neurodevelopmental disorders. And one thing they noted was that SCN2A was one of the most commonly associated genes with autism spectrum disorder and it seemed like in those cases, it was a loss of function case where there was less protein available to individual neurons or the channel itself didn’t function as well as it should.

And so, that actually contrasted with what we’ve known for probably 10 or 20 years on the opposite side, which is the gain of function side where the channel functions more than it should and it’s a little more excitable than normal. And that gives rise to really early infantile epilepsies.

So our lab started by just asking the question, well, do these clinical manifestations where we think that there’s gain and loss of function at the level of the channel, does that actually play out at the level of an individual channel?

So we started this collaboration by studying individual channels. And the way you do that in a dish is you generate individual channels and you have them expressed in a type of cell that actually doesn’t have any sodium channels itself because SCN2A includes this sodium channel, this brain’s sodium channel, Nav 1.2. And so you get them to express in a little cell that doesn’t have its own sodium channel so you can study the function of this newly expressed channel all on its own.

When we started doing this, we were expressing these sodium channels in what are called HEK cells. They actually come from human kidney cells and kidney just doesn’t express sodium channel itself. In those cases, you can go and then do electrophysiological experiments where you basically test the cell by running it through different voltages that engage these sodium channels and asking how well these sodium channels respond to those voltages.

And what we did is we express normal sodium channels, normal Nav 1.2 channels. And we also expressed some that are known to be associated with various forms of early infantile epilepsy, those associated with epileptic encephalopathies and those associated with benign infantile seizures. And those are the ones that we actually don’t worry about as much in the clinic because those are ones that arise relatively early in life but then actually spontaneously regress as a child is just a little bit older.

What we found on that side was that perfectly consistent with the literature is that epileptic encephalopathy associated mutations resulted in rather dramatic changes in what’s called the voltage dependence of these channels or the speed at which the channel opened or closed. And what that meant was that the channels opens – were easier to open at lower voltages. And so, that’s indicative of something called hypoexcitability where once you translated that into a neuron, the neuron would fire an action potential, fire something in a sodium-dependent way, sodium-channel-dependent way much more quickly and much more readily than it normally would. And that is very consistent with the manifestation of epilepsy at a network level.

And so, that was the case for epileptic encephalopathy. Benign infantile seizure was a less severe form of that. There were more – the channels were more excitable but certainly, not as excitable as epileptic encephalopathy. And we did both of those control just to make sure that we were doing things the right way and that we saw things that were consistent with what other people saw on the literature.

The work on the opposite side, those associated with loss of function, we really actually didn’t know what to expect. We had some cases where we knew that the channel shouldn’t be made at all because what happened was a variant introduced what’s called a stop codon and so the protein should be made just a little bit and then it reaches a stop prematurely and it – what happens is the protein is stopped from being made and actually the little bit that has already been made just goes off and is eaten up by some regulatory machinery inside the cells.

And so those ended up being cases where basically, we didn’t see any functional sodium channels at all. That made a lot of sense.

But then we had another case where we saw missense mutations associated with loss of function. And these missense mutations are much more commonly associated with gain of function. And so we didn’t actually know what would happen. Is it that there are some cases where there are missense mutations that actually we see something like extra or excess sodium and that is somehow associated with autism spectrum disorder or loss of function? Or was it that these missense mutations were somehow damaging or decreasing sodium influx to the channel?

And so, we went and expressed all of the missense mutations that were known from some studies that were done from the Autism Sequencing Consortium and the Simons Simplex Consortium back in 2012 or so. And what we found with, I think there were 7 or so variants at that time, that each of those either completely blocks the channel from conducting sodium or they decrease the amount of sodium that was allowed through for any given voltage or any given time of opening.

And so, those are going to be more consistent with loss of function. But one thing I want to stress is that on both sides of the coin here, gain of function and loss of function, it’s not really a coin. It’s not really a binary thing where either you have a variant or a mutation that gives rise to full loss of function or full gain of function. There’s actually this massive spectrum where there are different degrees of effect and we see that very easily on the gain of function side where you can have variant forms of epilepsy from relatively mild even though any form of epilepsy shouldn’t be considered mild, to something where you have an extremely severe form that lasts throughout life.

On the loss of function side, it seems like we have a similar thing occurring where sometimes we have a little bit of a dampening of sodium flux but in other cases, we have a complete block of sodium flux. And in those cases, the child is basically left with a situation where they have one normal copy of the gene from either the mother or the father and then another copy which is basically not producing enough of the channel. And so, this is a case that’s defined as something called haploinsufficiency where you have one of two normal copies and the second copy can’t – having one copy doesn’t allow you to compensate for the loss of the other.

David Cunnington: So that’s how you found the cells behaved when you were testing them in the dish if you like. What happens when you then took that learning into an animal model like a mouse model?

Kevin Bender: We had this major question now. We have these two sides of the coin, gain of function and loss of function at the level of the channel. Now, the big question was, well, if we see the loss of function, how does that actually relate to something like autism spectrum disorder or developmental delay when you translate that loss of half of a certain population of sodium channels into something as complex as a human brain? It would be lovely to be able to study this inside human brains and actually interrogate individual circuits and cells and systems. And some people are starting to do this with induced pluripotent stem cell lines where you can actually transform stem cells or any type of cell into brain cells in a dish and you can actually make a lot of discoveries that way.

Unfortunately for SCN2A, there turn out to be some rather interesting developmental quirks that we’ve identified in mouse that would suggest that if you wanted to study this in a human equivalent, you would actually have to let those cells grow up for about a year or two. And so, we’ve actually shied away from that approach and instead have used mouse models. And mice are extremely useful because you can purpose breed them for this approach and you can generate mice that actually have the exact same genetic makeup as what is found in a child neurodevelopmental issue.

So for example, you can find mice that are haploinsufficient for SCN2A, otherwise known as SCN2A heterozygous where they have one functional copy and one lost copy. Now, it turns out that these mice were actually made way back in 2000 really to study what happens in a basic biological sense, what happens when you lose Nav 1.2 channels? And so the original study reported that OK, if we get rid of half the channels, the mice look largely normal and then the rest of the study started to focus on what happens if you get rid of all of the channels. And actually, what happens there is that the mice die right around birth because SCN2A is actually important for driving your diaphragms so the mice just weren’t able to breathe.

Obviously, this is an extremely important sodium channel. But at that level back in 2000, nobody knew it was associated with autism so the heterozygous and the SCN2A haploinsufficient case, was basically thought of as, “Well, it looks largely normal so we are just not going to study it.” And so, these mice were basically put on the back burner until the field progressed and autism genetics moved forward.

And in 2012, we discovered that this was one of the most important genes in autism. And so at that stage, it became a realization of, “Well, those mice actually are extremely important. I wonder who still has them. Has anyone actually held on to these mice for the last 12 or 15 years?”

And so we started asking around. We contacted the original authors of that paper and it turned out that they got rid of the mice back in 2007 because they just hadn’t had a need for it. Suggested a few other people, contacted those people. They didn’t have it. It ends up being that I had to scour the internet and find a lab through actual research of who was doing active research in this realm and it turned out that there was one colleague of mine down in Louisiana State Health Sciences that happened to have these mice. And he finally sent them over to us. I think he sent like three mice, a couple of them died in transport. So we ended up starting a colony for I think one or two males and resurrecting SCN2A in our lab.

And now, thankfully, we’ve been able to share this with other groups and get this shared with the community. So we are actively sharing this with the permission of Mauricio Montal who originally developed them.   

We finally got our hands on this mouse model. We had to ask the question of, well, what happens when you have a loss of function? What does it look like in a mouse? And we have this original prediction and it’s basically the flip of gain of function. We know with gain of function, we have hypoexcitability. With loss of function, we would expect hypoexcitability or less – fewer action potentials generated per neuron.

And what we found was that yes, indeed that was the case. But a bit to our surprise, we found that that was present only in really, really early life in a mouse. It actually was present really within the first postnatal week in a mouse, and that corresponds to since mice grow up a lot faster than humans, it actually corresponds to about the first year in a human.

Now, in some respects, that actually made a lot of sense to us because if you think about the benign infantile seizure, one of the prevailing hypotheses in the field is that the reason benign infantile seizure shows up early in life and then disappears is that some early developmental switches that go on within certain neurons in your brain.

So early in life, it’s known that the outermost portion of your brain, the neocortex, inside there, there are excitatory cells that express Nav 1.2. And very early in life, it’s known actually from Stephan Sanders’ lab that these cells only express Nav 1.2 and no other form of sodium channels.

But then about a year in life in a human and about a week in life in a mouse, there’s another sodium channel, SCN8A, which is associated with other forms of epilepsy and which it really is a paragroup associated with that.

SCN8A is upregulated. And SCN8A has properties that encode a sodium channel called Nav 1.6 and that has properties that are slightly different than Nav 1.2 and it’s thought that the upregulation basically allows the cell to switch from having Nav 1.2-dependent action potentials to Nav 1.6-dependent action potentials, and that helps you get rid of this benign infantile seizure form where there’s basically very small changes in voltage dependencies at 1.2 that are completely subsumed by the normal voltage dependencies of Nav 1.6.

Flipping back to the loss of function side, what we saw was we had early hypoexcitability in mouse models where they lacked one copy of Nav 1.2. But then that went away. And so thinking about it from the opposite side, we thought, well, maybe that’s because Nav 1.6 is upregulated. And that looks like it’s the case.

So really within a mouse, we have hypoexcitability, hypoexcitability early in life that disappears once the other sodium channels are upregulated. And at that point, we are wondering, well, OK, if we have this early developmental loss but then it’s restored pretty quickly, how can that actually lead to a life-long issue of developmental delay and autism spectrum disorder?

And so, that led us to look a little bit more carefully at the excitability of the neurons. And one thing that we noticed was that yes, action potential initiation was intact and propagation down neuronal axons was relatively intact as far as we could tell.

What we found later in life is that Nav 1.2 channels lost their role in the axon but actually found a new role in another part of the cell called the dendrite. And so before I explain that, I just want to explain a little bit of how neurons are organized. They typically have a cell body that is sitting right in the center, that’s called the soma.

And on the output side, there’s an axon which integrates a lot of information from the soma but also integrates information from another part of the cell called the dendrite. And the dendrite looks like a big oak tree standing on top of a tree trunk and you can imagine all the leaves are individual inputs into that cell. And those leaves actually in a neuron are things called spines because they look like little pokey things. These spines are sources of excitatory input onto these cells, and each of these spines can be strengthened or weakened depending on whether or not you want some sort of learning process to go on within an individual pathway that’s connecting to certain spines or other spines.

And it’s through this process of strengthening and weakening these synopses that we think learning occurs. This is one of the dominant theories in neuroscience for how learning manifests at an individual cell level.

One of the ways in which learning occurs at these individual spines is by knowing when the neuron integrated all the information and fired an action potential. If an individual spine can somehow compare and contrast information based on its input and the output, it might either strengthen itself or it might weaken itself, sometimes depending on the timing of those things, and often, depending on whether or not an input gave rise to an output. And so, one way to think about that is cells that fire together, wire together. They tend to strengthen those connections, and that can give rise to a long-lasting memory.

How does this relate to SCN2A? Well, it turns out that the way a spine can pay attention to its output is through something called backpropagation of action potentials. And that’s the case where an actual potential initiates in the axon and then propagates back into the dendrite and if it gets to a spine, that spine now has some sort of mark or memory that an action potential just occurred and it can compare in a fancy biophysical way or biochemical process whether or not it just had an input that helps give rise to that output. And so, at the level of an individual spine, that’s one of the ways in which you can have plasticity and you can give rise to learning or memory in individual cells.

So what we found in SCN2A is that backpropagation was severely impaired and it was because the dendrite seemed to have lost many of the sodium channels that help support backpropagation. And so, what we thought here was that this actually makes a lot of sense. The children have a lot of issues with learning especially with long-lasting learning. So sometimes you can work with these children and actually get them to learn a new process within one day. And then the next day, they will have forgotten and you have to start again. It’s an unfortunate situation but it actually is consistent with what we are finding in individual cells.

And so here, what we saw was that backpropagation was impaired and then if we tested whether or not we could have any case where we could have back propagation-dependent reinforcement or plasticity of these synapses, we found that the back process was impaired as well. And then we found other metrics such as – you can look at the morphology of these spines and you can look at other physiological properties of these spines, and they all looked in many cases just like very immature spines that had never had a chance to develop.

And so, our theory at this point is that autism spectrum disorder, at least associated with SCN2A may be associated with this failure to develop normal functioning synopsis in these dendrites.

David Cunnington: So sometimes we think about autism as a manifestation of hypoexcitability. Kids can’t switch off. They can’t go to sleep at night. They have difficulty with distraction. So how does loss of function translate to those sorts of behaviors?

Kevin Bender: You definitely see that with the kids that are on the loss of function side. Sometimes they have trouble with distractions. They have trouble attending to – they’re easily distracted. They’re easily startled. And it’s a situation that actually doesn’t make sense when you think about hypoexcitability and especially this case with learning in the dendrites.

And so, one thing that we have been thinking about is well, one, can we model that in a mouse and whether or not the mice have certain levels of hypoexcitability or an inability to cancel out or just ignore distractions? And so that’s something we’re actually actively testing in the lab right now. We don’t have an answer unfortunately yet.

But at the level of the child, one possibility there, again, becomes – it becomes an issue with learning. So often, what you and I are capable of doing is eventually learning to adapt to distracters and learning to focus. And if you’ve lost the ability to learn and if you’ve lost the ability to actively forget or actively ignore certain processes, then everything in the world is novel. And that becomes an issue because you can’t easily remove those distracters and it becomes an issue of attending and it becomes an issue where any sort of contact or any excess visual stimuli become overwhelming.

And so often, you will find that the parents can deal with this by introducing certain visual stimuli that are pleasing to the child or some headphones to remove all those extra distracters and we see that all the time.

David Cunnington: Yeah, it’s interesting. In my role as an adult sleep physician, when I work with people with autism spectrum disorder, often, it’s the failure of self-soothing. They haven’t learned to self-soothe. So I really like that learning hypothesis that it’s not a hypoexcitability so much at the cellular level. It may actually be that there’s not that learning of the social skill of self-soothing.

Kevin Bender: Yeah, that is entirely a possibility. Now, one of our big questions is, with SCN2A, it’s an outrageously important gene on its own and understanding how SCN2A gives rise to these things not only helps us understand how we can hopefully better treat these children with SCN2A disorders but also, possibly help us understand autism as a whole.

And so, this is something that we are starting to explore as well is, do these issues that we see with backpropagation or potentially with hypoexcitability at an animal’s level, are these really failures to learn within individual cells or failure to extinguish nonrelevant sensory inputs, and how common is that across other genes associated with autism spectrum disorder? What else can SCN2A tell us, is this a big question in the lab?

David Cunnington: Yeah, and sometimes you get insights into these things by correcting those defects. And you presented a paper in neuroscience early this year where you’d gone on to do that. What did you find?

Kevin Bender: This is work that we’re actively pursuing with Nadav Ahituv’s lab at UCSF and also with Stephan Sanders’ lab. We’ve taken advantage and I should stress that this wasn’t a paper. This was a poster. So this is still a work in progress but we’re pretty excited by this work. We are taking advantage of a technique that Nadav has helped push forward called CRISPR Activation to help rescue cases of haploinsufficiency. This could be considered a form of gene editing without any editing. We use a lot of the same techniques that those who are working towards gene editing use but it’s actually a technique that doesn’t do any editing itself.

So a couple of things I need to explain in the process. First, what we – our major goal was to get SCN2A levels back to their normal full level in a case of haploinsufficiency where you only have one of the two genes working and you have a protein truncation in the other gene and that’s leading to a complete loss of that set of proteins. So we are 50% and we have to get back up to 100%.

One way in which you could do that if you’re thinking about gene editing would be, well, you could just introduce extra copies of SCN2A. Unfortunately, the current state of the art using viral techniques just wouldn’t work for SCN2A. SCN2A genes are simply too large to fit inside the viral packages that we could use for gene therapy currently. And so that’s really not an approach.

And so we had to think about some other approaches. And one of them was called CRISPR Activation. So CRISPR is this relatively new thing that we have discovered as a field that bacteria invented a millennia ago. And CRISPR is this way for one to target specific regions of DNA. And in bacteria, they use it to cut out new bits of bad DNA, that viruses that are introduced into the bacteria. And so, it’s an immune response in bacteria.

For us, what we have used CRISPR to do is instead of making cuts, we’ve used it to target a little bit of DNA and basically use CRISPR as a chaperon. And what CRISPR is doing in our case is bringing along an extra transcriptional regulator to a bit of DNA that’s upstream of SCN2A called its enhancer and we are asking CRISPR to put this little transcriptional regulator on the enhancer and tell that enhancer to enhance.

So, it’s a case where you can regulate SCN2A upstream. Basically, hitting the gas pedal a lot harder. And so in this case, we are targeting both the normal copy and the damaged copy. But since the normal copy is the only one making protein, we can tell that copy to express a lot more and in this case, compensate for the loss of the damaged copy.

And so, this is something called CRISPR Activation where you don’t actually make any cuts into the DNA but it can be useful in a case like this where you have haploinsufficiency and you have a gene that’s simply too big for traditional gene therapy. And so, our poster at SFN was asking the question of, well, can we get this to work in cells? Can we get this to work in a mouse? And if we get it to work on the level of an individual cell, can we actually restore some of these learning deficits that we identified in the mouse models that have lost SCN2A?

So now that we have all that background, now that we have this technique where theoretically we could upregulate SCN2A, we just had to ask whether or not we could do it. And it looks like with this work, with Nadav’s lab, we were able to get some pretty healthy upregulation in what are called neuro-2a cells, which are these neuron-like immortalized cell lines. And it looked like it was working there. So we actually ended up packaging it into viruses and injecting it into little mouse models that are heterozygous or haploinsufficient for SCN2A and what we found again was actually, the cases of excitability and backpropagation were restored but more importantly, we saw a case where we are actually able to rescue some of the synoptic defects. And so, it looked like at the level of individual cells, we are starting to get back to that normal level of learning.

And so, this was really exciting to us for a couple of reasons. One, it looks like it actually can work if we try it all, but two, it actually ended up working even if we did inject them relatively late in life. So in this case, we started with mice that were about 4 weeks old. That’s equivalent to about a 12-year-old child. And we saw that we were actually able to rescue some aspects of excitability and synaptic plasticity even at that age.

And so, it’s a situation where my hope is that if we could translate this into something that could work in a child that could be delivered in a clinical setting, we might be able to administer it relatively late in life and see some benefits. It’s not going to be a perfect cure. I think it’s going to be relatively hard to get a perfect cure with SCN2A but I think it might be a case where we see some benefits, some restoration of normal function.

David Cunnington: Thanks. And your explanation of the process you have to go through with CRISPR Activation rather than just a gene editing and substitution just highlights that even as a community, we are expecting someone just going to come up with this – put in a good gene, take out the bad gene, problem solved forever. It doesn’t look like it’s going to be that simple.

Kevin Bender: It’s a complicated process and actually, it’s complicated by the different types of mutations that are in SCN2A and the different manifestations whether it would be gain of function or loss of function. So actually, I’m really excited about the different approaches that are being pushed forward within the field for a lot of different approaches. So what we are working on is a case where it would work – it could work for loss of function that’s associated with the protein truncation.

Unfortunately, there are other cases where there’s loss of function where there is a missense variant. Unfortunately, the way we are approaching this would not work in its current manifestation but maybe if we push it forward, we could design something that works with and selectively targets one allele over the other or one copy of the gene over the other copy and actually upregulate that way.

It could actually work on the flipside. You could have a case where you could have downregulation. It’s just called CRISPR Inactivation or CRISPR Inhibition instead of CRISPR Activation. And so, you can do the flip side with this.

But again, unless we can target individual copies, you’re going to run into some troubles. But it’s one of those things where we’re at the point where people are making dramatic strides and basic research to understand how to control these genetic elements. And this is a case where there’s an obvious need. And so, we are just pushing forward as much as we can and the field is pushing forward in many ways in terms of delivery of these compounds, in terms of more precise editing or more precise targeting of individual DNA elements where I’m pretty darn hopeful.

And honestly, there’s a bunch of other approaches that one could take. On the gain of function side, you could have small molecules or antisense oligos that are showing some real definite progress and promise in the future.

And then there are other people that are taking an ASO approach on the loss of function side. And so hopefully, all of these will move forward and we will see some progress very soon.

David Cunnington: So thanks for that learning where you’re at now. Where is your lab going and what are you working on looking forward?

Kevin Bender: So we are very excited about CRISPR and we are going to keep pushing on that. But there’s also some other major questions that we have with SCN2A. Everything that we’ve done so far in mouse models has been to understand what’s going on in neocortex. But honestly, even though that’s obviously an important part of your brain, it’s just one part of your brain and there are many other parts. And SCN2A is expressed throughout your body or throughout your brain and it’s important to know what its function is in these other cells.

So we are starting to do some work in cerebellum. We would like to do some work in brain stem because obviously, one of the hardest things with children with SCN2A disorders are the sleep issues, the gastrointestinal issues, just everyday day of life working to help these children. It’s tricky. And if we can get situations where we can understand what SCN2A does outside of the neocortex and actually in more sort of basic autonomic function, we think that might help the families as well. And so, that’s going to be a major push for us.

And then we have various lines in the lab, various mouse lines in the lab, where we can ask the question of, well, what is the therapeutic window frame eventually? When do we need to see restoration of SCN2A to restore certain aspects of behavioral or learning at an individual cell level? And so, those are the major questions that we are going to be pushing forward on.

Kris Pierce: Thanks, Kevin. We really appreciate your generosity in sharing your work and obviously, giving up your time today and we look forward to hearing where your work goes and the impact on that for all our families with SCN2A.

 

Kevin Bender: Oh, thank you. It has been a real pleasure talking with both of you. I really appreciate the opportunity. Thank you.

David Cunnington: So what did you find interesting?

Kris Pierce: For me, the biggest drive home that Kevin talked about was that their recent work and their on-going work is that they are looking at not only changes in young mice but they are also seeing it in older mice as he talked about, a 4-week-old mice, which was equivalent of 12 years and they are seeing some reversibility in how SCN presents and its impact. So that’s really exciting for those of us with older children and it provides us some hope that there may be some help for our older kids out there.

What about you, Dave? What did you find interesting?

David Cunnington: He brings out a bit the geek in me. I found really interesting some of the basic science and how Kevin’s lab really over a number of years been using that ability to look at what’s happening at the cellular level in a mouse model to better understand what the SCN2A gene does and the various mutations then translate to in terms of abnormal function.

And then particularly interesting, the work they are now doing with the CRISPR Activation to give more insights into the role of that back propagation and when you modulate that, what does that do to learning and behaviors. So I think will not only hopefully lead to treatments that maybe relevant across the lifespan of people with SCN2A but also, a better understanding of what the Nav 1.2 channel does and what SCN2A mutations do, which in turn will guide development of other treatments and other targets.

Kris Pierce: Yeah. And it was also interesting he talked about that their work in understanding how – what happens at the cell level has to do with autism and that that learning can be translated across autism in general. And that’s a really exciting work being done and exploiting field where this information will be helpful to many.

Keep up-to-date with the latest on genetic epilepsy and developmental epileptic encephalopathies by following this podcast.

David Cunnington: Or get your updates on SCN2A through SCN2A Australia’s Facebook or Twitter @SCN2AAustralia. And thanks a lot.

Kris Pierce: Thank you for joining us.

Outro: This podcast is not intended as a substitute for your own independent health professional’s advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider within your country or place of residency with any questions you may have regarding a medical condition.