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

Dr. David Cunnington: So welcome to this episode of SCN2A Insights, your podcast talking all things genetic epilepsy. And welcome again, Kris.

Ms. Kris Pierce: Thank you. So this is the first of two episodes where we talk to Simons Foundation. In the first interview, we talked to John Spiro about the SFARI program.

Dr. David Cunnington: So John, thanks for joining us. What’s the Simons Foundation and how does SFARI fit under that?

John Spiro: The Simons Foundation is a private foundation based in New York City and has a very broad mission to advance the frontiers of research in mathematics and the basic sciences. And it was co-founded by Jim and Marilyn Simons. And the mission of SFARI, which is one of the divisions, one of the larger divisions of the Simons Foundation and SFARI stands for the Simons Foundation Autism Research Initiative, is to improve the understanding, diagnosis and treatment of autism spectrum disorders by funding innovative research of the highest quality and relevance. We have a yearly budget in the range of about 90 million US dollars per year. So that’s a quick introduction to Simons and SFARI.

And then Simons Searchlight, which I’m happy to talk about maybe a little bit later is a project within SFARI that aims to study individuals with known genetic variations to try to learn how they are similar to each other, how they’re different from each other, how these genetic events influence particular behaviors and challenges. And the hope is that by studying people in this way, we’ll learn what type of interventions might work best, what doesn’t work and those types of things.

Ms. Kris Pierce: What’s your role within that mission at Simons? 

John Spiro: So my title is Deputy Scientific Director of SFARI. I did a PhD and postdoc in neuroscience. And I worked for many years as a Scientific Editor at the journal Nature. And then I joined SFARI very close to its beginning in 2007.

Ms. Kris Pierce: So what are some of the current projects that Simons SFARI is running in SCN2A?

John Spiro: So the funding comes in sort of three broad types. And if there’s time, I thought I could mention these and then provide some more details about some of them. I should mention, first of all, that pretty much everything I’m going to say is also on our website, which is just sfari.org. There’s spelled S-F-A-R-I.org, so sfari.org has a lot of this information. Some stuff I can tell you today is a little bit more up-to-date.

But our funding comes in sort of three broad types. The first one is cohorts. We spend a lot of our money developing cohorts and I’ll tell you a little bit about that. The second type is resources. And these are resources to lower the barriers of entry for scientists interested in getting into the field. We think this is really important just to sort of draw more really smart, innovative people into the field. And then the third, which I can talk about in some more detail also is direct funding to investigators around the world for investigator-initiated projects.

At the beginning of SFARI, we funded the creation of the Simons Simplex Collection known as the SSC. And this was a collection of about 3000 families with an autism spectrum disorder. And it ended up playing a really big role in understanding the genetic landscape of ASD and related neurodevelopmental disorders. And was really the beginning of the discovery of many single genes and so-called copy number variants that are major risk factors for autism that including SCN2A. The number of genes and CNV regions now that are definitively identified as risk factors is in the range of about 200.

So the Simons Simplex Collection or the SSC is done now collecting individuals but SFARI is hard at work on a much larger cohort called SPARK. SPARK currently has about 90,000 individuals with autism spectrum disorder and at 90,000, that’s a really big number. And the goal is to do exome sequencing, that’s the coding part of the genome. So for all of the people in the collection to do exome sequencing. And those with known genetic variants, such as SCN2A, can then enroll in the sort of sister study to SPARK which is called Simons Searchlight. Simons Searchlight used to be called Simons VIP for anyone listening who might be confused by that.

So as I mentioned briefly at the beginning, this is a group that – this is a project that gathers families with the same genetic variation and sort of takes much deeper dives to learn about how that genetic event influences behavior, you know, presents particular challenges. And the hope is by studying individuals in this way, we’ll learn much more specifically about what types of interventions work best and what doesn’t work and things like that.

So I thought I could very briefly just give an update on this SCN2A group within Simon Searchlight. We have about 190 families that are registered. These are people from all over the world. About 130 of them have submitted lab reports that are gone – that staff at Simon Searchlight go over very carefully to make sure everyone really has the genetic variation that they think they have. And then about 116 or so have completed quite in-depth medical history interviews that are done by a genetic counselor that works for the program. So this is a very rich collection of individuals with SCN2A.

I mentioned that Simons supports sort of three types of funding, I just told you about cohorts. And I can mention briefly, the second type, which is sort of resources to lower the barriers of entry for scientists interested in getting into the field is sort of attract really good scientists to work on this. And I can give you an example of some of the things we do.

One of them is to maintain a really curated database of all of the genes that are involved in autism and related neurodevelopmental disorders. This is called SFARI Gene. It’s a free resource, I should have mentioned, that everything that Simons does is free, there’s no charge whatsoever to enter any of the cohorts to use any of the data. This is all based on the philanthropic generosity of Jim and Marilyn Simons.

So the other type of resource that we think is really critical to put out there is to make sure that there are animal models that researchers can readily use to study genes like SCN2A. I want to make the point that for the most part, researchers are not really trying to make a model of the disorder per se, it’s a human disorder, you can’t really have a mouse with autism or with SCN2A disorder. But you can actually change the genes in mice and rats, and zebrafish. And then by doing so, and studying the biology of those animals in great depth, you can learn a lot about what the gene is doing and hopefully understand what that gene is doing in people.

So we maintain resources in rats and zebrafish and mice, where we’ve paid to have either these animals generated in the first place, or we paid to have them at a repository where people can access them. So that’s one major resource that I think has been very successful at getting people interested in working in the field.

And then the other one, which directly relates to the family’s generosity, is that we’re developing a resource for so-called iPS cells or induced pluripotent stem cells. And since it’s really virtually impossible to study the brain of people in great detail while they’re alive, for obvious reasons, iPS cells have turned out to be a really amazing new tool to do this, these have only been around for a decade or so. And that works by taking a person’s skin cell or now we’ve found that blood cells actually probably work even better and are easier to collect, and turning that blood cell back into what’s called a pluripotent stem cell. And that’s a cell that can then be coaxed to become a brain cell or other types of cells in the body.

So that’s been a really, really interesting way that researchers have been studying SCN2A and related disorders by making these so called iPS cells, and then turning them into neurons. For SCN2A, we have in the range of 20 blood samples from different individuals, 20 different individuals that are ready to go. And we are in the process of reprogramming about 11 of those into iPS cells, which were then made available to the full research community essentially at no cost, just for the cost of shipping and things like that. That work has been slightly delayed because of COVID-19 but we expect that to be back up and running.

Dr. David Cunnington: So that’s really interesting. I didn’t realize the Simons Foundation had such a broad mission. And you’ve done a really nice job of explaining to us how all that fits together and the different aspects of that. What are some examples of the investigator initiated research that the Simons Foundation is funding?

John Spiro: I was kind of really pleased to see, I was going through some notes in preparation to talk to you and me – there are even more grants that we’ve funded in this area than I had originally realized. Over the last few years, we’ve funded something in the range of nine or 10 grants. These are grants that come in through a very competitive open call for proposals that they’re rigorously evaluated both by the internal science team and in collaboration with an external panel of scientists there. Some of them are up to about 300,000 US dollars a year for somewhere between two and four years, depending on that.

Some of the grants that we fund investigate a large number of genes that are known risk factors for ASD and neurodevelopmental disorders, all at the same time. So they’re sort of asking questions across a number of genes. But what I thought I could focus on is a number of genes that focused entirely on SCN2A that we funded and I can tell you a little bit about those. Once again, if you’re curious to read more about these grants, summaries of the proposals, and of the investigators themselves are on our website, sfari.org.

So the first grant that I’d like to mention is a grant that was to Al George, who’s a professor at Northwestern in Chicago. And it’s called High-Throughput Functional Annotation of Human SCN2A Variants. It’s a really important and interesting topic. So we know that about half of the SCN2A variants that have been identified are predicted to truncate the encoded protein, which is the sodium channel. That means they sort of take it out so that that one copy of the sodium channel gene is not turned into protein. But many other variants in SCN2A, we don’t really understand what their functional consequence will be. So the gene may still be read through and turned into protein but we don’t know how the genetic variation in that gene changes the protein function.

So the study from Al George that we funded several years ago, and we’re just about to make a new award to him to sort of ramp up this work is basically to use an automated electrophysiological platform, where he puts these various variations into cell lines, and then uses tools of electrophysiology to actually measure the protein function, which is it’s a sodium channel. One of the great things about SCN2A is we know exactly what it does. So we know how to measure what the protein does with a very high level of resolution. So what ordinarily would have taken years and years to do to measure each one of these one by one, each one would take a graduate student a while to make, and then quite a bit of time to measure this, Al has developed essentially a high-throughput pipeline to measure these.

And one of the goals of the current project, the one that’s just about to start, that’s a continuation of another grantee had, is to try to get this data directly into the clinical databases that are used by clinicians around the world, one of the most used one is called ClinVar. So that when someone has an SCN2A variant detected on a genetic lab report, they’ll be able to go into this database, and immediately see what that variant does to the function of the protein.

Another group of grants that I’d like to mention come from a team of investigators at the University of California, San Diego, this is Kevin Benders, Stephan Sanders and Dr. Ahituv. This grant is to do a very detailed analysis of what happens when the SCN2A gene is missing in a mouse. So they make a mouse, they’ve made a mouse that models the human condition, it’s called haploinsufficient, which means one copy of the gene is inactive.

And they’ve done very, very detailed recordings and behavioral analysis of the mouse. And they’ve found some unexpected things about how not only does the sodium channel act early in development to initiate action potential or nerve impulse signaling it, but it also is active in the arbors of the nerve cell called the dendrites, and seems to be involved in some processing in the dendrites that extends throughout lifetime. A really interesting part of this grant is not only to study this mouse, but to try to use the technologies of gene therapy to reintroduce, or essentially tweak the parts of the gene that control its expression. So actually, let me say that…

Dr. David Cunnington: Sure.

John Spiro: Let me say that in a slightly different way. So in addition to characterizing the mouse in a very detailed way using tools of electrophysiology and quantitative behavior, one of the goals of this grant, which is really cool, is to use the tool CRISPR, which has received a lot of attention recently. This is a tool that allows one to go into the genome and very precisely edit parts of the genome.

So the idea here is to use a modification of this CRISPR called CRISPRa. And what they’re trying to do is to get it to tune up the regulation of the intact copy of the SCN2A gene. So remember, the situation in humans that have an SCN2A condition is that one of the copies is inactive, but there’s another copy that works. So the idea of this proposal is to use this CRISPRa technology to upregulate the good copy, the functional copy of SCN2A to correct for this so-called haploinsufficient condition. And there is some sort of very exciting early work showing that this strategy might be working. There’s a long way to go before one could move such a strategy to humans but this provides a really important proof of principle that such strategies might work. 

Dr. David Cunnington: And we had a chance to talk to Kevin Bender about some of his work on loss of function and feedback mechanisms at a neuronal level that may give insights into autism. And yeah, it’s great to work. So, really excited that SFARI is funding the further development of that research line.

John Spiro: It’s very cool stuff.

Dr. David Cunnington: It’s really interesting. Thanks for telling us about a lot of different projects. So, SCN2A in some respect has been leading the way in developing platforms for some of the other genes that aren’t as well understood. So we are in a somewhat fortunate position as it’s a well-understood gene. And a lot of the researchers in this area with their knowledge of SCN2A are developing ways of then learning more about other genes. So hopefully that also means we’re leading the way in terms of the development of treatments and access to helpful therapies.

One of the things I wanted to ask you, John, is about the Simons Foundation’s overarching sort of idea of using maths to solve complex problems. You’ve talked to us a little bit about the frontend so the data comes in, and you have the cohort studies and you accumulate that data, and certainly, researchers can then sort of access that at a sort of a profile sort of level. What’s under the hood? Are there things that SFARI is doing in a math sense under the hood to try and sort of tie together all these different gene variants with the behavioral and human data that you’re collecting?

John Spiro: The way we’re set up at the foundation is that we’re primarily going out and looking for the best and brightest people around the world to both collect the data and then as you said, we make all of this data as available as possible to any interested researchers, and to sort of coax researchers to sort of squeeze it for even more value. We organize a lot of meetings and workshops, where we bring people to the foundation for the sort of debate on different issues and to try to generate new ones. We had a meeting in January on gene therapy approaches to neurodevelopmental disorders and SCN2A focused very, very high on that.

We don’t do a lot of direct in-house research on the data within the SFARI team. But interestingly, Jim and Marilyn Simons a few years ago, started a computational research institute, just across the street from the Simons Foundation. It’s actually part of the Simons Foundation, called the Flatiron Institute, I think it was formed in 2016. And they’ve hired something in the range of about 200 data scientists who work and they sort of divide their – the data science is divided into an astrophysics group and a quantum material Science Group. But there’s a big group of biologists and geneticists as well that are doing some computational biology.

So there are some groups looking through some of the genetic data that the SFARI is collecting, and trying to use new methods of machine learning and AI, in particular, to look through the genome. One of the big questions right now in the field, and there are a couple of people at Flatiron that are focusing on this, is the area of the genome, or the percentage of the genome that codes for genes like SCN2A is only about 1% of the whole genome, and the other 99% or 98% or so, it’s still quite mysterious how these regions that probably have strong influences on regulatory functions and modifying functions of other genes and changing expression. So, there’s a lot of computational work being done on that. But we’re also supporting some purely computational work from people all over the world.

Dr. David Cunnington: Yeah, that’s great. And that can be such a helpful strategy. I know, in my clinical practice, I see patterns, you know, I’m very much about pattern recognition and that’s what we do often as clinicians. But sometimes we don’t know how those patterns relate to each other, we just know they traveled together. And so having someone underneath that, being able to look at mathematical associations, and then give the basic scientists or the more basic researchers an idea about, OK, we had to start looking for those things to then bring it back to the clinic can be really helpful.

John Spiro: Exactly. And a key component of that, of course, a key ingredient is making sure the data is clean and readily available to people who have good ideas that that’s not always the case but, we put a lot of effort into that. We have a group, an informatics group that works with the SFARI team that spends quite a time, quite a bit of time sort of curating all of this data and cleaning it, making sure it’s sort of put out there for the masses to use.

Dr. David Cunnington: Yeah, congratulations! That’s just a fantastic resource that really is going to continue to drive research forward. 

Ms. Kris Pierce: Thanks for all that, John. If researchers or in fact, patient groups want to undertake some research on SCN2A or other genes in collaboration with Simons, what should they do? What’s the best way to move forward? 

John Spiro: The best way to learn about the foundation is to sort of dig through our website. We have a newsletter that goes out every month that has announcements about new funding opportunities.

One of the things I would really like to see in the coming years, and I think we haven’t quite advertised to the researchers around the world, just how terrific these resources are, the Simons Searchlight platform has this really rich data, medical data, genetic data about all of these families, the families who have been generous enough to donate all of this data, and in many cases, blood and other biospecimens. So we really want everyone, you know, researchers and scientists around the world to realize what a rich source of information exists already for mining.

But one thing that I’d like to really point out is that we really encourage researchers to come to us both to use these databases and to apply for funding, of course, but to use these days, databases in new ways. So we have a program called Research Match, where if a researcher has a project they want to do – I’ll just mention one type of example that I’m particularly interested in.

Because we all know that sleep is really critical for cognitive function and a lot of people with neurodevelopmental disorders have pretty significant problems in sleep rhythms and sleep structure, I think it would be really cool to go into some of these Searchlight groups, and actually do measure sleep and other types of activity with wearable devices and other kinds of gadgets. And that’s the kind of thing we’re really set up to do if someone has a really great idea. And they say, I want to compare sleep patterns in people with SCN2A versus, for example, some other genetic variant that’s known as you know, CHD8, or something like that, this would be just an incredibly rich opportunity to do that.

So we both have, you know, we’re neutral players on the field, too. We’re not a pharmaceutical company. We don’t really have a vested interest here other than to push the science for it as quickly and as deeply and as rigorously as possible. So I think there’s just an enormous opportunity for researchers and patient groups as well. I think one thing that we’ve learned from attending a lot of family meetings and interacting with various patient groups is how much the moms and dads really know that the researchers would benefit from knowing. So really, making sure we’re collecting data and insights from the families as well as to what are really the most important challenges and sort of some of the most interesting areas for research. 

Dr. David Cunnington: Thanks very much, John for outlining what the Simons Foundation is doing and what SFARI is making available and developing in this area.

John Spiro: My pleasure.

Ms. Kris Pierce: That was a really interesting interview with John Spiro and a lot of work going on in SCN2A and we look forward to continuing our conversation with John and the Simons Foundation and hearing more about SFARI.

Dr. David Cunnington: If you’re looking to hear more about Kevin Bender’s work, check out the previous podcast episode and I’ll put a link to that in the show notes.

Ms. Kris Pierce: If you want to learn more about SCN2A, you can follow our podcast on any podcast channel, and you can follow us on Facebook or Twitter @SCN2A Australia.

Dr. David Cunnington: Thanks a lot.

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.