1 – SYNGAP1 Research Roadmap

Event Time

June 18, 2020


Here are our introductory comments:

Dr. Rumbaugh gave a talk titled SYNGAP1 Research Roadmap on June 18th, 2020.

Webinar Overview

Dr. Gavin Rumbaugh is a neuroscientist at Scripps Research Institute doing research on SYNGAP1. In this webinar, he talks about how disrupted SYNGAP1 functions affect the way neurons connect and create networks, as well as the different variants of SYNGAP1 and what they mean when thinking about therapeutics for SYNGAP1 patients. He does a deep dive into the concept of genetic haploinsufficiency, the characteristic of patients having half as much SYNGAP1 flowing through their brain, being the root cause of 80% of SYNGAP1 patients’ brain disorders. He explains how this is an important concept when considering the different approaches for raising SYNGAP1 protein levels in the brain. Finally, he closes the webinar with the work his lab is doing to find pathways in the brain and compounds that could be used to raise SYNGAP1 expression.

Other Relevant Publications by Dr. Rumbaugh

Syngap1 regulates experience-dependent cortical ensemble plasticity by promoting in vivo excitatory synapse strengthening

SYNGAP1 Controls the Maturation of Dendrites, Synaptic Function, and Network Activity in Developing Human Neurons

Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders


0:02So we start in a few minutes. Just for the people  who have signed up early, I just want to do a  

0:12little advertising. Here you’re seeing the thing  for today’s talk which is Gavin. Just wanna remind  

0:19you in two weeks we’ll also have Shilpa talking  on July 2nd. This is on the SRF Facebook page. You  

0:27can register with that link at the bottom. And she’ll be talking about some of her specifically SYNGAP1   epilepsy research. Hey, Gavin you’re logged in  as Marta but it’s all good. And then also  

0:39Helen Bateup will be two weeks after that and  then, so Gavin I’m just doing a little general  

0:47FYIs before we get going. A reminder that we  have five days left on this “Be Kind” campaign so  

0:53if you want to get shirts again the link’s on  our Facebook but SRF kindness off bonfire.  

0:58SRF does a weekly parents meetup which is which  is always fun and generally useful. I took the  

1:05least flattering picture possible of everybody in  this one but they’re good meetings. And then just  

1:12a reminder we have the Syngap Research Fund board is now up to 12 families and we’re   always looking for people who want to help so if  you have the time to do more and you want to be  

1:21involved reach out. SRF is pretty much everywhere.  We’re on Facebook, Instagram, LinkedIn, Twitter and  

1:28SynGAPResearchFund.org is a good website  to have handy. So with that just in a minute  

1:36I’m gonna ask Marta Dahiya to introduce Gavin  Rumbaugh and then we’re going to give it to Gavin.

1:46Gavin, can you… I’ll just wait one more minute  and then I’m gonna ask you to take over screen  

1:57sharing to make sure you can do it is that  cool? All right, fabulous. And then I’m gonna,  

2:03just in case anyone’s worried when Gavin starts  talking I’m gonna for some you to everybody and  

2:08then at the end of Gavin’s talking on I will  unmute everybody so if you have questions or  

2:16concerns or things you want to say that before  we get unmuted you can just chat them to me so  

2:22in the chat function on zoom you can chat any  questions you want either to me directly or to  

2:27everybody which would probably be most efficient  so I hear a lot of people chiming in let’s just  

2:35give it another 30 seconds reminder you’re here  Gavin’s talking Shilpa will be talking Dr.  

2:43Kadam will be talking I should say in two  weeks about Syngap epilepsy. Dr. Bateup   from Berkeley will be talking about some of  her research we are selling Be Kind here feel  

2:54free to get some. We have a happy hour every week  Wednesdays at 5:00 Pacific it’s a really good  

2:59chance to talk to other Syngap parents sorry  about the picture Peter sees smirking and it’s  

3:06fair and speaking of Peter there are twelve  families on the SRF board right now we are  

3:11always taking more help. Hi Dr. Terry Jo, thanks  for coming and SRF is on Facebook, Instagram,  

3:22LinkedIn, and Twitter we try to push our content  out on all of those things so please follow us  

3:28and search for all I am thrilled so time is  precious and we’re all gonna have we’re all  

3:39gonna run out of time because Gavin is very  popular we’ll have lots of questions for him   so let me now hand over the screen sharing –  Dr. Rumbaugh and let’s make sure he can do that  

3:52and then as soon as he takes control Marta if  you want to or actually mark so why don’t you  

3:58just start talking and give your introduction I  know you’ve been you did your research on this   one I’ll tell you there yep okay you’re in  good good my can’t hear you yeah ever muted

4:22I’m you okay they are now please introduce Dr  Rumbaugh yes then I want to welcome everyone  Introduction to the work of Dr Gavin Rumbaugh

4:32today meeting my name is Marta Dahiya, I’m a Syngap  parent, everybody knows, and we are excited to start  

4:40the SynGAP Research Fund Webinars. The goal of the  webinars are to get everybody closer to science of  

4:48Syngap, make you aware of the research being done and the opportunities to participate, empower  

4:55your communications with clinicians as  you get clearer knowledge of Syngap. As a group  

5:03we firmly believe we’ll be able to improve the  quality of life of our Syngapians, find the right  

5:10treatment and ultimately the cure if we continue following the science. I want to  

5:18tell you again the name of the talk today. Syngap  Research Roadmap: behind the scenes view on efforts  

5:26to develop therapies and I want to introduce, I have the  pleasure to introduce Dr. Gavin Rumbaugh who is a neuro-  

5:35scientist at the Scripps Research Institute in  Jupiter Florida. Dr. Rumbaugh’s laboratory is devoted  

5:44to the understanding of how synapse and sit with  mechanisms contribute to cognition and behavior  

5:52may be behavioral adaptations in particular  he studies how genes that mutated caused a  

6:01defined neural node of the believer in health  disorders like Syngap. Dr. Rumbaugh has written at  

6:09least a dozen of papers on Syngap including one  that give us believe that our kids can be helped  

6:18by our therapeutically his laboratory was able  to improve function related to seizures and well  

6:27for a single protein in an adult animal Dr. Rumbaugh  work in his earlier years in a basic science of  

6:40SynGAP protein function even before SYNGAP1-  related disorders were identified in  

6:49humans. He experienced a powerful change  in his career after meeting his first SYNGAP1  

6:56patient who motivated him to dedicate his  ofcorse to find pharmaco therapeutics for this  

7:04disease. The two main focus of his research are  finding safe and effective therapeutics and  

7:12grading animal models to understand behaviors  to find effective treatments. Last forum X dr.  

7:21Rumbaugh even more specialized that he dedicate his  work to make a difference in our kids lives and  

7:29this is the introduction Profesesor Rumbaugh and  for people that just came to the webinar again  

7:37it’s Dr. Rumbaugh and the name of the talk is  think of research roadmap behind the scenes do  

7:45you own a force to develop therapies um we have to  chat in the chat you guys can formulate questions  

7:52and we’re gonna have dr. Rumbaugh give us time  by the end to answer those questions and for  

7:58the people who could not be on this webinar we  are taking the webinar and it will be launched  

8:05later on okay doctor Rumbaugh thank you thank you  for the wonderful introduction can everyone hear  

8:14me okay yes quickly Gavin I’m gonna for some  you everybody so and then I’ll unmute you so  

8:23just give me one second to do that okay Gavin  I tell you and can you see my presentation and  

8:36presenter in the main view you can and you saw  the transition there yeah yeah good and and am  

8:44I looking in the camera we can’t see your face we  can just see your screen okay great and I can’t  

8:51see you either the way it’s set up so you know  this is the days we live in so it’s a little bit  

8:56different so I’m I’m gonna try to give me the  same style talk I normally give if I was there  

9:03in person. Of course we’re limited because we’re  not physically next to each other, and so when I  

9:10give talks to to families and stakeholders to non  non you know what I call hardcore science talks I  

9:18it’s okay to interrupt me and I you know Mike is  given very clear instructions to the audience and   I think on zoom that works best so Mike if you  feel like it’s a good time to interrupt me with a  

9:28Clinton point of clarification please go ahead  and do that you know I’m a big big supporter of  

9:35that style so and I understand that you guys were  shooting for about 30 minutes you know you know  

9:44information that comes from me and then maybe you  know another 30 minutes of Q&A so that’s kind of  

9:51what I planned for but sometimes it’s a little  more organic so it’s okay to go that way – okay  

9:57so start with should start with an outline and  so but before I go into the hour and you know I  Outline of talk

10:07think it’s important that you know that you all  understand that I’m here for you so you know for   this hour you know my time is yours and and we  should use it in the way that’s best best for you  

10:20all and so the reason why I do this is because you  know I you know I’ve gotten tremendous amount of

10:27motivation and inspiration from from working with  SYNGAP1 families and patients so it’s not  

10:37just for many scientists it’s kind of an academic  exercise you know we try to solve problems but you   know it’s become you know somewhat personal for me  over the years so you know I really want everyone  

10:46to know that this is something that I care about  very deeply so you know my goal is to is to help  

10:53parents figure out the best way to use their voice  for helping for helping their kids so okay so

11:01maybe for parts of the talks at how to genetic  variance known to cause developmental disorders  

11:08impact brain function so how what is the current  state of understanding of what SYNGAP1  

11:14variants do to the brain? So that’ll be maybe  five or ten minutes and so the next part of the  

11:25talk will be how do we group SYNGAP1 patients?  So we don’t necessarily see all the SYNGAP1  

11:34kids the same way biologically and there’s  an important reason why we do that and so we  

11:41will talk a little bit about that and then the  last part of the talk is gonna be on strategies  

11:48for treating SYNGAP1. Now this isn’t just my  my preferred strategies I’m gonna try to give  

11:54you a synopsis of the kind of consensus of the  academic labs and biopharma so commercial entities  

12:05on the the most promising and fastest routes  to getting treatments for SYNGAP1 and then  

12:14also some more longer-term visions to optimize  and to come up with alternative therapies for  

12:20SYNGAP1 and then of course the Q&A and again  mic feel free to interrupt me at any time ok so  What do we know about SYNGAP1 disorders?

12:28what do we know about setting up one disorder  so you know I’m gonna I’m gonna I’m trying my   job when I communicate to the public is to take  the science out of the science and to just try  

12:39to get the ideas across and the reason why I do  that is is you know I think on how to communicate  

12:46these complex ideas to people who aren’t training  neuroscientists and so the way that I approach  

12:53this is you know if my if my nephew had sing up  one disorder how would I explain and how would I  

13:02braised the most critical issues you know to to my  brother or sister and so that’s what I’m gonna try  

13:07to do so this was I’m trying to imagine that you  know that the the my child is affected so what are  

13:12the key things that you need to understand because  there are so much information out there there’s   more information than even I can assimilate right  or anyone any scientists can assimilate so you  

13:22have to be able to filter and pick out the most  important things for the problems that you want   to solve and so what I’m going to try to do is  to still the most critical issues and concepts  

13:31that as parents that are interested in helping to  accelerate treatments you know what you should try  

13:37to pick out and what you should try to focus on  so when it comes to the actual biology sing up you  

13:42need to know very little and and and so you know  you just need to understand that sing up one is a   gene and genes encode proteins so can you see my  cursor Mike no you can’t see my cursor all right  

13:57let me try that’s too bad let me try to go back  here all right let’s try this again how about now  

14:06can you see it now yes yes okay all right great  so so what you need to understand is that SYNGAP1  

14:12is a gene and so this is the gene here  and and of course you know a lot of this you  

14:17guys already know but I just want to put it into  into a complete story so sing up one is a gene and   genes and coat proteins okay and these proteins  are there many different proteins or 20,000 genes  

14:29and each gene makes basically a protein with those  proteins can come in different forms and different   flavors and those proteins assemble inside of  cells to assemble into machines and those machines  

14:39do work and that’s what carries out life the  business end of life inside of cells or proteins  

14:44and so in the brain which is the most complex  organ in the body the brain brain cells or neurons  

14:50and their supporting cells glia assemble and  connect to each other and those create circuits   and networks and those networks are where memory  planning behave or everything that we can do  

15:00everything our brains can do they can do because  neurons do connect to each other and create brain  

15:07circuit so you can see this would be one synaptic  connection and the human brain has billions of   neurons and trillions of synaptic connections  and right and this is what you end up with is  

15:15a complicated biological wired machine okay and  and so what happens essentially is that SYNGAP1  

15:26gene and encodes SYNGAP1 protein  and it’s important for the way that these neural  

15:32networks are assembled in development and how they  change with experience so what do I mean by that  

15:41so first thing to think about is is that these  are the connections and SynGAP lives inside of   these neurons right and so as the brain develops  these connections are formed you know we’re born  

15:51with you know very few brain circuits and as we  develop we get more of these circuits and more of  

15:57these networks and then our capabilities improved  throughout life and so the big unknown in general  

16:02in any genetic disorder but it but especially in  Syngap is is that how does disrupted SYNGAP1  

16:07function affect the way the neurons connect in  creating networks right because with the a what  

16:14the end result is and what what you really need to  understand is that the lot loss of SynGAP protein   results in an alteration in the way that these  networks form and that is what causes altered  

16:25memory planning language motor function sensory  function behavior seizures everything that you can  

16:31associate and so what’s the consensus of the thing  of when biology is over the past 10 to 12 years a  

16:39lot of it you know I say that my lab is driven to  try to understand when you lose SYNGAP1 or at   least one copy of seeing that one the closest  approximation an animal model we could have to  

16:49try to understand brain function and rodents and  how it may be affecting human brain function isn’t  

16:54it’s that SYNGAP1 or lost to SYNGAP1 does two basic things at least two basic things  

16:59and one of those things is it affects plasticity  so the way that you store memory the way that you  

17:06learn and store memories is that these connections  here can change with experience so when you learn  

17:11something you actually can physically make  new connections or existing connections can   grow bigger in size and then those connections  become stronger and that’s one way that this  

17:20organic neural network or supercomputer can  store information okay and so SYNGAP1 or  

17:27SynGAP protein and that comes from the SYNGAP1  gene is critically important for those   processes that that that that allows synapses to  grow and shrink to store and erase information  

17:38okay and so the other thing that sing gap one does  is this during development it helps to facilitate  

17:45the growth and maturation of developing neurons  and that’s you know initially we’re born and our  

17:52brains are small and it’s because we have very  few connections and as our body grows our brains   grow and as they grow they develop more and more  connections and that’s why you know you’re you  

18:01know in first grade you have limited capabilities  and by the time you get to high school you can do  

18:06calculus and a lot of that’s because your brain  just has more processing power because it has   more connections and so what SynGAP does is it’s  completely separate job from this plasticity jobs  

18:16it’s a role that that we can differentiate there  they’re completely different functions of the   gene and it’s to facilitate this wiring ok now  smart Tallulah – you know I and I got a series  

18:28of questions that that were posed in anticipation  of this talk and one of them in rightfully so is  

18:38is to what extent can deficits in  a SYNGAP1 brain be rescued after childhood and  

18:46so we recently shown a couple of years ago now  that these plasticity mechanisms or the or the  

18:54mechanisms in the brain that allow you to learn  and remember and store information appear to be   non-developmental functions of SynGAP. Meaning that  they’re they’re used in development but they’re  

19:03also used in the adult brain meaning that if you  can rescue the SYNGAP1 gene   or fix the SYNGAP1 gene then you may be able  to recover some of this plasticity and we have  

19:12another paper that’s been uploaded to by archive  that will be published soon where we show that  

19:18this happens this plasticity happens at the level  of what are called cellular ensembles and they  

19:24saw their ensembles what actually store memories  and we show that we can that these are disrupted  

19:29and SYNGAP1 haploinsufficiency and a bacon  and then these ensembles can be restored and this   plasticity of monks cells can be restored when  you put SYNGAP1 back into the brain so we’re  

19:39very excited about that and we and we think that  those capabilities don’t depend necessarily on  

19:47what are called developmental critical periods and  therefore therapies these SYNGAP1 therapies  

19:53could be beneficial even after childhood. Okay so  that kind of wraps up the SYNGAP1 what we  Types of variants and how they relate to therapies

20:03know about SYNGAP1 biology and now I want to  transition to the variants and so a lot of this  

20:09talk has been driven by conversations I’ve had  with many parents some of you that are on this  

20:17call as well as people in the biotech industry by  the pharma industry and other scientists and so I  

20:27think it’s important to discuss the different  types of variants and what they mean for  

20:34thinking about therapeutics excuse me so there’s  really two kinds of variants we can we can put  

20:45variants in two different kinds of buckets if  you will there’s the clearly pathogenic variants  

20:51here and what are called the VUS or variants of  unknown significance and so the clearly pathogenic  

21:02variants are the ones that have received the most  attention over the years is because as you’ll   see is that they made while they may be different  individually in terms of how they actually affect  

21:13the SYNGAP1 gene at the level of the bases  or the level of the SYNGAP1 gene structure  

21:18they’re biologically similar or the same in a lot  of ways and so these clearly pathogenic variants  

21:27are nonsense variants or what are called base  changes that lead to premature stop codons small   indels large deletions and what these types of  variants have in common is that they essentially  

21:39cause what’s called a frame shift inside the  SYNGAP1 and that will inactivate one copy of the  

21:44gene and we’ll go into this a little bit more and  why that’s important so the variants of unknown   significance and some of you may have seen  these on the genetic reports and so these  

21:55unknown variants are typically missense variants  where you have an amino acid change inside of  

22:02Syngap so you don’t necessarily destroy the  function of the of the copy of Syngap what  

22:08you do is you change the amino acid or the or  the individual building blocks that go into the   protein the and you change one of those and so  often what that can do is destroy the protein so  

22:20the proteins made and it becomes unstable when  it gets destroyed but but sometimes it doesn’t   do anything and sometimes it can actually create  a protein with a different function so because  

22:30of that and the only way to differentiate those  three possibilities is to actually do experiments  

22:35in the laboratory to determine how the base  change affects Syngap function whereas in  

22:41the case of the clearly pathogenic variants  because you have what’s called a frameshift   and you have early early termination of SYNGAP1 reading basically we know that those proteins  

22:54never get made into mRNAs get destroyed so we  can group them into the same same category and  

22:59so here you can see I expand on this idea a little  bit more as here’s a map of all the no nonsense  Clearly Pathogenic Variants

23:04variants in the SYNGAP1 patient population  a colleague of mine Al George has recently put   this together because we’re getting ready to  undertake an exciting collaboration on how to  

23:14how to fix these nonsense to have potentially how  to fix these not these nonsense variants first in  

23:22animal models and maybe someday in patients and  so but the the the the concept that I want you  

23:28to take take away from this is that while all  of these are different nonsense bearings here   on this map okay that means they’re all premature  stop codons and they all have different individual  

23:38and all your genetic reports are by and large all  the genetic reports will say something different   in terms of the base effected they’re biologically  all the same and that they caused in any capital  

23:47insufficiency meaning that you have two copies of  Syngap but one of them doesn’t work so you’re   only left with one copy of Syngap okay  and as I mentioned these things are  

23:56less clear for the for the variants of unknown  significance and where you have to actually do  

24:01research on every variant to know how the missense  variant or even a splice variant so a splice  

24:08variant would be our spliced mutation would be in  the same category you have to do experiments on  

24:14these on these individual variants or mutations  to figure out what they’re doing in some extent  

24:21you know that’s being done I know that you know  some of us are working on these these types of  

24:26NIST sensors place variants to understand exactly  what they do. Now so why is this important and so  Why is haploinsufficiency such an important concept for parents, clinicians, and biologists?

24:32why is it so important? Why do people focus  on haploinsufficiency? Why do people focus   on these these clearly pathogenic variants?  And what do the families that  

24:43don’t have these variants you know what can they  take away from this and what are they supposed   to think because I get these questions a lot. So  the reason why haploinsufficiency is so important  

24:52and why it’s such an important concept for all  parents as well as clinicians or biologists is   because it’s the glue that keeps us together  so the unique genetics of Syngap and one of  

25:02the things that’s very very important is it’s  what’s called an autosomal dominant disorder   and where you have what’s called genetic capital  insufficiency in in the majority of the patients  

25:10and you and you can think about and I get this  question a lot and I think it’s sometimes it’s  

25:17difficult to comprehend exactly what we mean by  this so I spent some time this morning and came up   with three slides to try to show this graphically  so what exactly does haploinsufficiency mean why  

25:27is it important and how can you visualize it so  you can see there’s three panels here follow the   blue arrows so you have a genome you have lots of  chromosomes and inside of all those chromosomes  

25:37you have your 20,000 genes within one chromosome  you can unravel it like a like a spool of yarn and  

25:42you can see that there are genes in green okay and  you know I’m so like this would be sing gap one  

25:48and this could be PhD ninety five and this could  be some other gene here okay and so from when they   unravel they can be it can be translated basically  what that means is that that sing gap one gene is  

25:59then made in a message which can be seen here and  you make this message okay and then the message  

26:05can be so that’s transcribed in a message and  that can be translated into protein sing gap  

26:10protein the the that’s the part of the single  in gene that actually does something inside of   cells okay and so that that protein I think the  best way to think about protein inside of cells  

26:20is the way that cells work is they’re made up of a  bunch of large protein complexes and what protein  

26:25complexes are is think of each protein is a year  and one think of any complex machine you have a   lot of gears that were put together and the sum  of the parts is what equals the machine okay so  

26:35that’s the best way to think about proteins  Syngap is just one gear, one part of a large machine  

26:41that comes together okay but like any complex  machine you have some parts that are absolutely  

26:46essential in some parts then you know you can get  away with not having that part work like imagine   your car so you have windshield wipers right  and so you only really need windshield wipers  

26:55like in Florida you need them a lot but in a  lot of places you don’t need them very often   and you can even get away if one windshield wiper  isn’t working right so you can imagine like these  

27:03green gears here are proteins that are made  from the genome and so maybe they’re a little  

27:08less important to the overall function of a cell  or a neuron but this red one here if you imagine   that this is part of a large complex you can see  that this gear here is important to turn all the  

27:18other gears and so if this gear doesn’t work right  you can imagine the whole complex machine doesn’t  

27:23work right and so if you take this what’s called  complex protein complex of a bunch of machines and  

27:30you have many of these complexes and they fit  together and even more complex machine and so  

27:35this machine will turn all these gears and then it  will turn this one and I’ll turn this one and this   is your flow of energy okay now so what happens  in haploinsufficiency so this is your sing gap  Haploinsuffiiciency results in too few SynGAP proteins, or gears, made in the neuron

27:45one gears and in a normal neurotypical genome or  person you have two copies of this single one gene  

27:53so any any gene that’s not on the X chromosome X  or Y chromosome you have two copies one from mom  

28:01one from dad and so each gene is functional each  gene copy is functional so you know mom’s copy of  

28:06sing gap one mixing up one mRNA dad’s copy of SYNGAP1 make SYNGAP1 mRNA both of those mRNAs  

28:13make proteins you get basically 2x of the protein  but an halo insufficiency because of the de novo  

28:20variant that happens you know basically when  you know a conception or shortly after most of  

28:26the time you have that that variant landed Syngap that destroys one copy and it can no longer   make mRNA and so what you end up with is half  of the SynGAP protein okay so your so the  

28:36neurons only make half of the number of sing got  one gear so why is that bad? SYNGAP1 is one  

28:42of those those proteins or one of those gears it’s  essential for the way the neurons work so it’s not  

28:48the windshield-wiper it’s the transmission or or  the or the radiator something that’s fundamental  

28:53you can’t really live with if you don’t have an  enough of it so you can imagine that this is this  

28:59complex machine that I showed you that this is the  critical gear and it turns all these other gears   and then and then it turns this gear and then  you can see the energy flow this way, okay. But  

29:10when you have SYNGAP1 haploinsufficiency  this is Syngap, this is where Syngap fits, but   you only have half as much SynGAP, but you have  all the correct number of all the other proteins.  

29:18So the machine assembles but you don’t have SynGAP here to help turn the energy in which you  

29:23end up with is a breakage or a disruption in the  flow of energy or the function of the cell okay   so what we really need to do is to get these  sing out proteins back because sing gap does  

29:33more than one thing it doesn’t just do one job it  does many jobs and that was the the point of my   first three slides is that it not only affects  plasticity or the way the brains change with  

29:43experience but it also changes the way they they  organize in development okay so this leads into  Approaches for giving back SynGAP protein to brain cells

29:50the approach is to giving back to gap one protein  so haploinsufficiency is eighty percent of the of  

29:56the known SYNGAP1 patients sing got sing up  kids have are thought to have haploinsufficiency  

30:03meaning that that they the root cause of their  brain disorder is that they have low levels of  

30:11functional SYNGAP1 protein and that’s what  leads that’s what causes their disease and so what   what nearly everybody is focusing on currently and  for good reason is is to try to figure out ways  

30:22to bring these levels back to normal and that’s  some of the work that I did in mouse models is  

30:28this show that when you put the protein back in  using genetic tricks that only work in mice but  

30:33it’s proof of principle that if you could put the  protein back in even after development you can   restore function so now people are trying to take  known biological mechanisms and to try to exploit  

30:44them to try to trick the cell that only has one  copy of Syngap and makes half the protein to trick  

30:50it into making twice as much single and so by the  idea would be now you give all the gears back and  

30:56now you can recover function of the neural okay  and so there are a couple of strategies and so  

31:05there’s a couple of strategies related to putting  giving the sell back it’s its amount of sin-debt  

31:10okay and so plan a is is what you’ve probably  heard a lot about and rightfully so or ASOS  

31:17or antisense oligonucleotides and so these are  synthetic RNA or DNA is basically that trick one  

31:29copy of Syngap into making either twice as much  mRNA message or to make the message that’s there  

31:38a make to make twice as much protein out of it  okay and there’s a lot of interest in ASOS because  

31:46they these a SS have been successful in raising  protein and other genetic disorders is the most   most notably spinal muscular atrophy in the ASO  new Sanderson and so there are academic labs that  

32:00are investigating ways to exploit ASOS to race and  got protein and there’s also commercial entities  

32:05several commercial entities that are exploring  ASOS to regulate SynGAP okay so what what the  

32:15point I’m trying to get across and this is what  my lab works on is ASOS may or may not work and  

32:22we have to be honest with that it’s experimental  no one ASOS may work for Syngap and they may  

32:27work for some kids and they may not work for  others and you think of epilepsy medications or   even medications that treat depression so 60% of  patients don’t respond to depression medications  

32:37and only only a certain proportion of patients  that have any type of epilepsy response Apple  

32:44XE medication so there’s no reason to think  that every single child would respond to an   and so if they do work and and I think that they  probably will work but the question is will they  

32:56be able to penetrate the brain areas that need  SynGAP expression how well and how well will  

33:04they work across the different that the broad  SYNGAP1 patient population so because of  

33:10this and in any disease I mean think about blood  pressure medications so there are many different  

33:16ways to treat blood pressure and so there’s  usually the reason is is because between the  

33:21side effect profile and the different types of  biology for each patient you need more than one   therapy you need more than one arrow in your  quiver to be able to attack disease so what’s  

33:34plan B if a after am so so in the issue is is that  there to raise protein expression and the fact is  

33:40there really is no there really is no plan B  right now and so what why lab is trying to do  

33:45is to find these alternative plans to be able to  racing singing up expression so one thing I’m not  

33:51going to talk about our alternative strategies to  raising Syngap expression and those would be you   know repurposed drugs that alter the rest pathway  like statins and other related drugs because at  

34:00the end of the day those don’t treat the route  so those are interesting strategies and they’re   important but they’re probably not going to work  as well as therapies that racing that protein  

34:12expression and the reason why is because the SynGAP protein has many jobs and so it’s difficult  

34:18to imagine that a drug that works downstream of  the sing sing gap function could fix all of the  

34:24things that sing that one does so what a lot of  us have agreed on in the in the community in the  

34:29scientific community is the best way to attack  a disorder where you have low sing out where you   have low protein is to try to put the protein back  and so that’s why there’s so much emphasis on that  How to find “Plan B”, “C’, etc.

34:38and there’s just a two or three more slides  so what we hypothesize and we know this from  

34:45just neurobiological principles and neuro and  neuronal cell biology is that there’s probably   lots of ways to go from the SYNGAP1 gene  to SYNGAP1 protein and so there are likely  

34:57many many many different biological pathways that  regulate ultimately the amount of SynGAP protein  

35:02that’s in a cell. So you can make more message you  can make each message make more SynGAP. You  

35:10can make the message more stable, and load more  of that message into the ribosome to make more   protein. And also we know from neurons is  that that each SynGAP protein or any protein in  

35:20the cell doesn’t live forever. So most proteins  only live in the cell for 12 to 24 to 36 hours  

35:27and so these proteins degrade and they degrade  through biological mechanisms. So if you were able to  

35:33regulate the way that they degrade, you maybe  also be able to raise SynGAP protein expression.   The issue is is that we don’t know anything about  how SYNGAP1 is made, or how SYNGAP1  

35:43is degraded so we literally don’t know  any other biology. So for some genes we do know   some things, but for Syngap we don’t know anything  and so one of the things that I’ve been trying to  

35:53trying to encourage people in the community,  especially parent organizations that have  

35:59interests in funding research, is to try to find  people and support people that want to understand   how SYNGAP1, how the SYNGAP1 gene is  regulated how the protein is made and how the  

36:09protein is degraded because those can lead to what  are called druggable pathways that might lead the  

36:15drugs that raise SynGAP protein. So what does my lab do  well my lab because we don’t know anything and so  

36:21there’s a trick that you can do in biology that if  you don’t know anything you can do what’s called a   nun by up screen what that is is that you say okay  well I think that you can regulate single single  

36:30protein but but I don’t know how so what you can  do is invent a system that shows you how much SynGAP  

36:37is present in a cell and so what we did is we  created using our tricks and our tools for Mouse  

36:43genetics as we created a mouse a series of mouse  lines that can everytime is sing up one protein  

36:50is made and actually that SynGAP protein its  present in a cell can make life and so so neurons  

36:56will glow when they have SynGAP in them because  the SynGAP proteins themselves glow and and the  

37:03amount of glow that is in the cell is directly  proportional it’s the amount of SynGAP present   and and this type of glowing if you will it’s very  easy to measure across many tens of thousands of  

37:17neuronal what are called neuronal culture well so  we have many neuronal networks and because you can  

37:24screen many many many thousands of them if you can  put different compounds and all these different  

37:29Wells the idea is that if you screen enough of  these compounds you’re gonna find that compound   that does what you want which is to make the cells  glow more which is the to make more sing up so  

37:39what how you know how can you do that so it’s  it’s not that hard frankly to to to make these  

37:44systems that that tell you how much they got this  president but what is hard is the screen the tens  

37:50of thousands of assay wells and so that’s what  makes Scripps very very unique so Scripps Asst   has 13 FDA approved drugs and one of the reasons  why there’s 13 FDA approved drugs that came from  

37:59Scripps is because we have this ability to screen  tens of thousands of compounds across many many  

38:08many a say Wells using these high throughput  robotics that you see here in this video and  

38:13these robotics are basically what you would see at  Merck or any other large Pharma but we have these   at Scripps in script Florida and what that allows  is researchers like me to work with experts in  

38:23in high throughput automation to figure out new  ways to look for drugs and one of those methods  

38:29that we’re using is to use this SynGAP blowing  assay to try to find the probes or compounds that  

38:34raise SynGAP protein so that’s something that  wasn’t able to be done in the past but because   of working using you know our understanding of  the SYNGAP1 disorder and our knowledge in  

38:46Mouse genetics and and the knowledge of the Scripps  screening Center we’re now able to do this type of  

38:52high-throughput screening to try to find those  compounds that raise the a SynGAP expression   and so I want to caution you that this this is a  longer term solution to discover non-obvious ways  

39:02that manipulates and gap expression so the ASO  pathways work and SYNGAP1 is in theory one  

39:08of those genes and proteins that can be regulated  by ASOs you know but again we don’t there are  

39:14probably dozens of different ways to regulate  SynGAP protein and so one of the ways to do  

39:19this is to find these compounds and then once we  find the compounds that can raise SynGAP protein   colleagues at Scripps have this amazing ability to  work backwards from the compound to figure out the  

39:30biological mechanism that made SynGAP go up and  then the idea is that those those pathways that we  

39:36find starting from that compound that was from  the high-throughput screen those will we think  

39:41that those will be the pathways that will be used  to racing gap protein in the future so with that I  Acknowledgements

39:47just want to give a few acknowledgments so of  course the the screening facility at Scripps  

39:52is run by Tim Spicer in Lewis Camp AV I’ve been  working with them for 10 years they were gracious   enough to listen to my ideas and to think outside  the box because most screening facilities don’t  

40:03screen in neurons and and have no interest but  these guys wanted to tackle this problem and and  

40:08I think it’s it’s gonna bear fruit also the NIH  spend instrumental in keeping my lab going over  

40:14the last twelve years they’ve been very generous  in supporting supporting my laboratory Scripps is  

40:20given me tremendous for sport support also  various parent driven advocacy foundations  

40:29SRF Leon and Friends and bridge the gap have are  game changers I think in the way that parents can  

40:36interact with researchers to really drive research  forward and and and I and I encourage everybody to  

40:45keep doing what they’re doing because it really  is having a real impact because you’ve only been   at it for a few years now and you know imagine  imagine where we can be in a few more years so  

40:56thank you very much awesome Gavin thank you very  much and I’ve got I just got one question that  Questions & Answers

41:06came through so I’m gonna hit you with that right  off the top um the question was about the neurons  

41:13you’re using in your high-throughput screening  using human neurons or other you want to clarify   that since you where the mouse guy yeah well so  we stopped sharing my screen we so we we are we  

41:25can use both so we have we have glowing neurons  from both human iPS cells and from mouse and so  

41:32you know if you want a scientific if you want  a science explanation you can read we have a  

41:39paper on this and and you know I can send you  the reference but to make a long story short is   that human neurons what’s the difference between  human development and mouse development right at  

41:49the level of neurons their neurons are basically  the same honestly what’s different is the number   of neurons in the way in the way they connect  in the brain right but the mouse brain and then  

41:57human brain are very similar right it’s just the  scale is different but what’s the difference so   a mouse gestation is 21 days and its development  is they’re sexually mature within six weeks okay  

42:10a human gestation period is nine months and sexual  maturity happens you know twelve years of age or  

42:16whatever and so when you model neurons in a dish  you have to keep human neurons growing much longer  

42:23before you get synapses where sin gap lives we’re  talking a couple of months to be able to see real  

42:30synapse biology okay where as an amount Iran you  can see just 12 days you can start to see the type  

42:37of biology that you need the glowing that you need  and so the difference between 12 days and 2 to 3  

42:45months is millions of dollars in reagent costs the  idea would be if we use human neurons we could and  

42:53and we will and I’ll get at that in a second but  you would be able to screen far fewer compounds  

42:59in order of magnitude fewer compounds and so in  order for high-throughput screening to work you   have to look at but we’re planning on looking at  200,000 compounds right so 0.2 million and you  

43:10need that because they’re rare it’s a needle in  the haystack and in order for it to work you have   to screen tens and tens and thousands of compounds  and what we’re gonna do is use the human neurons  

43:18to validate so the step one is to use mouse  neurons because we can go high throughput awesome  

43:25and then and then what we’ll do is use the human  neurons the validate you know will prioritize the   candidates that we find in mice that also work in  yeah and I would point out you’ve been very humble  

43:35in this talk about how little you know I mean you  are the same guy a nice guy so having you use your  

43:40mice which is you know when other researchers call  us and say they want to get involved we’re like   we’ll call Gavin get as mice that’s what everyone  does so it’s it’s it’s what you’re doing there  

43:49is pretty awesome and you and you mentioned the  patient advocacy groups so I would be remiss if   I didn’t do some advertising sync our research  run does have an s RF fellow in your lab right  

43:59we’ve been we’ve been funding someone for two  years and we’re on board to keep that up for at   least another year so the idea is that hopefully  we we’ve beefed up your team and you guys can  

44:08move even faster in spite of kovat so I have my  question stream is filling up fast Heather I’m  

44:16unmuted you if you want to ask your question and  then I’ll go to Hans next Heather are you there  

44:24oh you’ve even renewed it yourself this mutant  game is tricky can you hear me yes sorry all  

44:35right great thanks so much so it’s so Gavin you  know the the from what I’m intuitive right you’re  

44:42you’re saying there’s no critical  window exactly with this concept of SynGAP and  

44:50and brain function right. So and I know  drug development because I’m involved   in it myself, takes a really long time. So just  as a clarification, is there an expectation if  

45:02we have kids who are, you know, seven, eight, nine,  ten, somewhere around there and we’re talking  

45:07about it ten years out there being a potential  solution that helps with that regulation of the  

45:12SynGAP protein, that even those older patients  would be helped and I’m sure there are other   parents who have, you know, children who are 20  years old right now or etc and I just from a  

45:23simplistic perspective like mine is that a correct  interpretation? I… yes and no. So you know these  

45:35are not easy questions  to answer especially when you talking to families  

45:41so you know I have to be careful exactly what  I say. I mean I’m telling you what I think but   I have to be careful how you phrase things. So my  original paper this really this big splash paper I  

45:50had in 2012 the first SynGAP modeling paper  explicitly states a SYNGAP1 critical period   okay and what that means that there are functions  of SynGAP that are tied to developmental periods that  

46:01we think are in mice and we think that those  periods are in humans and no one knows exactly   when they are in humans and when they end but  they’re probably present and so that made a lot  

46:11of parents sad, frankly, right. So what I had done  and I thought a lot about it and talked to  

46:19people, other scientists and many of us  came up with the kind of idea at the same time  

46:24is that these proteins, these genes, are disease  genes for a reason. They’re very few protein genes   like Syngap. Just a handful of them okay like it’s  there’s a famous paper by the Buxbaum group they  

46:34came out this year and Cell the satyrs from paper  and that and that paper they outline the the genes  

46:39there pretty much cause of form of autism right  and Syngap is the top on the list top three  

46:44and there’s maybe only a dozen the two dozen  proteins that have that kind of power on brain   development okay and so why why out of the 20,000  genes why is Syngap special? And so the  

46:55way that I reason why Syngap is so special is  because it encodes a protein it’s very unique that  

47:01does lots of different jobs. You know there isn’t  just one SynGAP protein, there are actually a dozen  

47:06SynGAP proteins that are called isoforms that are  made from the same gene but they have different   structures within them and so the idea is is that  this is the emphasis I have from the first slide  

47:16so if you just stay with me you’ll see where I’m  going with this this is that there’s more than   one function of the SYNGAP1 gene. Some of  those functions direct developmental processes  

47:25that probably do have critical periods and that  there probably is a window you know that could  

47:32close I mean that that’s that’s what we that may  be what’s happening I can’t say that for sure but   the really important thing is that there are very  clearly functions of SynGAP that are not linked  

47:43explicitly to development meaning that at least  in a mouse the functions of there are functions  

47:50of the SYNGAP1 protein that the mouse needs  for its whole life to be able to change its brain  

47:56with experience you know. The most fundamental  thing the brain does after it develops is to  

48:02change with experience so you can you can keep  it running you know you have a running chart  

48:08recorder of experiences right and you learn and  you remember right that’s who we are right is our   brain records our experiences and it does that by  physically changing and SynGAP is instrumental  

48:17in that process and and a lot of that function  can be put back into the mouse brain when we  

48:22put the protein back in so we’re very excited  by that and we’ve seen it time and time again   we have papers that are gonna be coming out that  look in different ways and we see this over and  

48:31over again and so I guess the best way to think  about this is is that there are windows and they  

48:37may close but there are other and maybe those  will be restored maybe they won’t but there are   probably other functions of SynGAP that relate  to particular phenotypes in the kids that that  

48:48can be restored maybe even I should say there  are other genetic disorders they’re related to  

48:53Syngap. So Phelan-mcdermid syndrome driven by  SHANK3 and well pink thing has seen essentially  

48:59the exact same principle with SHANK3 where SHANK3  will cause developmental insults  

49:05but there are functions of SHANK3 that are very  clearly associated that are not associated with   development and and our what are called retained  throughout life meaning that if you put SHANK3  

49:15protein back in you also would improve brain  function. So this isn’t a SYNGAP1 special  

49:21principle I think this is generally generally  the case for genes that cause neurodevelopmental  

49:26disorders hey does that answer your question? Yeah  it does. Just to add color not to take too much  

49:33time I happen to my Syngap kid happens to be a  twin and you know what I find fascinating about  

49:40him is that you know at birth I wouldn’t have  noticed there was necessarily a difference and   that you know as my children have grown and now of  course there are very different people their  

49:50paths have been so different but my Syngap  kid can remember certain things I mean it’s it’s  

49:57years earlier when he was little he’ll remember  when we go back to a location he gets things but  

50:03yet I can hammer through you know a you know a  math lesson or you know discipline lesson and he  

50:10just does not get it no matter how many times you  do so it’s it’s interesting when you were talking   about the concept of memory and critical periods  and development as they go forward you know what  

50:21is sticking with them versus what is not and  so I was curious so it does and as best as we  

50:27know science right exactly hey Gavin there’s a  the questions are piling in so I’m gonna give  

50:33you like 30 seconds to read through the chat you  can read the past 5 questions quickly and I just   want to make two points I’m you alluded in the  different developmental path different druggable  

50:44targets and the different stages of which we can  attack the problem papal insufficiency – you’ve  

50:50been encouraging us to fund or to look at other  researchers who help us better understand that   and I want to just tease the audience a little  bit because we have 50 parents on srf is going  

51:01to be doing a fundraiser soonish to for a new  grant to look at exactly that so we have been  

51:09in in conversation with Gavin and others and we’re  grateful for his time and his guidance and we are  

51:15looking to better understand Syngap and and I  want to make one more point Gavin and I’m hoping   you’ll agree with me but you might not um after  spending two years in the rare disease space my  

51:25observation is as you said we have a lot to learn  but compared to a lot of other genes quite frankly  

51:32and I’m not trying to be flattering to you here  you know that I’m not like that we’re really lucky  

51:39to have you and Rick and Jimmy and I could go on  down the list like relative to other genes we have  

51:45a good base and while there’s a ton we don’t know  parents true or false parents should be hopeful  

51:51that we will make some progress in our kids  lives because time is brain based on the stable  

51:58of strong scientists we have would you agree with  that or yeah and I can so I read through the chat  

52:04really quickly and there’s something in there  that I should address there very good questions  

52:09in there several there’s one topic we should  address the back to your point Mike I agree   with you and so it it isn’t I wouldn’t say it’s  luck it’s it is reality that there are fantastic  

52:21researchers in the sing up one space and I can  tell you that more and more being recruited every  

52:26day I mean I’ve personally recruited four or five  different people in the same gap one space just  

52:32by scientific conversations and interactions and  it’s not because I’m some master manipulator right  

52:37it’s because the reason why they’re the reason  why Syngap has great researchers associated  

52:43with is because it’s an interesting gene right  it does things it’s a special so you know it’s  

52:51a famous synapse protein you know dendritic spine  protein post synaptic you know there’s hundreds   and hundreds of those proteins right and most of  them actually have you know duplicated copies of  

53:01them right so there’s you know you sure you’ve  heard of PS 295 and all these other you know   there’s four proteins like PSC 95 and in the  synapse right there’s you know there’s PSC  

53:1295 in SAP 102 and PSC 93 right in chaps in 110  they’re very similar to each other there’s no  

53:17protein like Zynga in in in in the synapse so it’s  kind of unique in its function and because of that  

53:23uniqueness and because of the the clear effects  that you have when you regulate it in cells in  

53:29neurons or in the mouse you know the mouse is a  pretty amazing mouse there’s lots of phenotypes  

53:34to study that are unlike other mouse models you  pull people in you know and you publish good work  

53:40that it’s interesting and inspires people and  other people want to work in that space and so   historically genetic disorders of the brain have  been funneled into a couple of different genes  

53:51Fragile X and you know the recipes for good  reason those were discovered years ago and  

53:58they developed robust research enterprises around  them but the era of genome sequencing has led us  

54:06to genes like Syngap that can only be discovered  by sequencing and that was just ten years ago.  

54:11So these other genetic disorders had two decades  headstart and so in ten years, in seven years  

54:18we’ve gone from essentially zero disease-related  research in Syngap to tons of papers and it’s  

54:24it’s growing exponentially. So I think if one  of the points of this talk is hope, then I think  

54:30you should all be very hopeful because what  we know now is a fraction of what we’ll know   in a few years and in a decade I can’t even  imagine. We may have solved most of the major  

54:40problems of Syngap and then it just comes down  to finding the therapeutics. That’s how I   view it. Awesome. I’ll let you take those questions  now if you want to plow through the chat yeah so  

54:50there’s been there’s some there’s this discussion  questions about SynGAP toxicity. So it’s paramount  

54:58question. So it’s so much effort it’s just logic  right so if so much effort is put into strategies  

55:05to raise SynGAP protein because the accepted cause  of this disease from eighty percent of patients is  

55:13low SynGAP protein, what happens if you make, what  happens if your therapy works too good and raises  

55:19SynGAP protein beyond what the cell normal exceeds  right and so that worries people like me and in  

55:27other people and other scientists and it should  worry you because, you know, every drug  

55:37that works in a disease is a poison if it  works too well, right. So it’s anytime you develop  

55:45any type of therapy you want to understand what’s  called a therapeutic index and so you want to   understand how much is needed to give you relief  and how much of that drug then leads to toxicity  

55:56and why and so we don’t understand if SynGAP  proteins can be toxic. Those experiments haven’t  

56:05been done and so we are creating tools to study  that question and so I can’t… I can tell you that  

56:13in cellular systems, in in vitro systems where  you grow real neurons and you express too much  

56:20SynGAP, the neurons don’t like it and neurons  will die. That does not mean that, that does not  

56:26mean that expressing too much SynGAP in a  brain will cause brain dysfunction but it makes  

56:32us wonder and worry and so the only way to really  test this is to engineer systems, tools in  

56:41animal models first that can allow you  to tune levels of SynGAP ideally in a SYNGAP1  

56:50model where you have too little SynGAP half  SynGAP and then what you want to be able to do   is the tune up SynGAP to where you get back to  a hundred percent which is the therapeutic which  

56:59you would which is a wild type situation or a  normal SynGAP level but then you want to push   it beyond that right and you want to go beyond  to say what happens if I make two times as much  

57:09SynGAP as I wanted? Does the brain like that? Does  the brain like that more? Maybe if too little SynGAP  

57:15causes poor brain function maybe more SynGAP  increases brain function. Maybe it’s a cognitive   enhancer right. Maybe we want our military and our  pilots and and our college students to take this  

57:25drug I don’t know. Maybe it’s poison. Maybe  it’s horrible for the brain and so we have to  

57:31ask these questions and we have to do  it and so it sounds easy and it sounds easy and  

57:37it is easy to talk about but it’s not so easy to  do this in practice and so we’re creating these  

57:44tools and we’re putting the effort into  doing it and we have our first revision one   tool Mouse being delivered we hope this month and  so we’re gonna start testing it out and hopefully  

57:58revision one is enough to answer these questions  but more often than not you need revision two or   revision three. So we’ll see. So this is one of  the answers that I’ll be able to hopefully give  

58:06the community you know in a year you know in a  year or two is is that we understand how much   what happens when you make more SynGAP  than you want and hopefully the answer is  

58:16it makes brains better you know but we’ll  see. Hopefully that answered that was Hans his  

58:22question and a few other people so hopefully that  answered answered your question other the other  

58:29one a few questions Marta and Pavel both sort of  alluded to this is there hey we when we rescued  

58:35the mouse what what phenotypes will be affected  behavior sleep etc I realize that’s almost I  

58:44think that’s pretty hard to answer but you want  to take a shot at your thought on that well we   looked at some and so we’re discovering new new  phenotypes all the time and a lot of that work  

58:53is driven by interactions with your children right  so we are inspired to understand brain dysfunction  

59:00in particular aspects of brain dysfunction by  talking to you about your children all right  

59:05because you know SYNGAP1 sounds like it  has a lot of similarities to other disorders but  

59:12the end of the day if you really look into it you  know it’s unique and so your kids have unique problems associated with SYNGAP1  haploinsufficiency and some of them share many  

59:26of these problems right and so the ones that where  everybody shares we want to look into and see if   we can model that in an animal to understand are  those the kind of phenotypes that can be  

59:35fixed and when can they be not fixed can they  be improved and when can they may improve and   so memory and learning is obviously something that  people talk about a lot as a problem in SYNGAP1  

59:47disorders and so we we had a paper in e life  a couple years ago where we show that you know  

59:53important parts of learning you know where you are  and where you’ve been and am i there those types  

1:00:00of learning and memory seems to come back in adult  right so markers of epilepsy so seizures that  

1:00:09we that are happened in mice because they have  too little SynGAP that those behaviors those  

1:00:16convulsions go away when we put SynGAP back in  the adult animal and that’s interesting  

1:00:23because that suggests that the epilepsy or the  mechanisms that lead the convulsion or epilepsy  

1:00:29aren’t necessarily locked in from an alter from  an abnormally developed brain. It may be that those  

1:00:36mechanisms are there all the time and they’re  waiting to receive SynGAP protein to then correct  

1:00:42themselves that’s that’s one experiment that  worked it doesn’t mean that epilepsy will be cured  

1:00:49if we can put SynGAP back in an adult but it’s  certainly suggested and that’s exciting so memory  

1:00:54learning and memory and and measures of seizure  and animal models appear to be fixable to some  

1:01:03extent after development I think that’s promising  can I have one more question and then if anyone  

1:01:10else has something else please please message  me so you know I always have to throw in an   advertisement the next speaker in two weeks is dr.  Shipla Kadam from KKI she studies EEGs and sleep  

1:01:20so for people who have questions around sleep I  I loved Gavin of course I also loved Shilpa she’s  

1:01:25just they’re both a pleasure to talk to and don’t  don’t miss that one but the question Gavin and  

1:01:31I’ve put this to both you and Rick when is there  gonna be something I can put in my kid is the   question I ask everybody every day and the answer  from the ASO people is I don’t know before kovat  

1:01:42optimistically I would have said a few years now  maybe it’s a few years plus one or two and then   when and then the million-dollar question that was  part two of Hans this question is Gavin you have  

1:01:51this amazing drug library you’re doing all this  amazing work when are you gonna have an answer   and because of the volume and the scale and scope  of what you’re doing and the speed of science like  

1:02:00that answer is is can you help I mean we’ve talked  about this privately but can you share whatever  

1:02:05you want to say publicly around how parents should  frame their hopes assuming we continue to support   and encourage science around when there might  be actual therapeutics we can dose our children  

1:02:16with yeah you know and you know me I try to stay  grounded and I try to give… I’m not  

1:02:22an egomaniac I’m you know I’m you know I try  the best I can I think I’m a good scientist and  

1:02:28I think I can make a difference but at the same  time I’m grounded and I try to keep a reasonable   outlook. ASOs, if they work, yeah, it’s gonna be  exactly what industry says because you know  

1:02:39there’s been there the development timeline for  Nusinersen is they know how long it took the  

1:02:46successes that have been publicly demonstrated for  ASOS related to Gervais models that went really  

1:02:54fast right so that’s one of the banette benefits  of ASOS is that if that mechanism works in a gene  

1:03:01it can be fast you know the question is what if it  doesn’t work what is Plan B and so that you know  

1:03:11there really is no plan B I mean there’s another  type of ASO that might work for a type of SYNGAP1  

1:03:18transcript that might be inhibitory but that’s  you know that’s that’s a very defined biology if  

1:03:25it works it’s exciting if it doesn’t there’s  no plan B and so what I try to and this is and  

1:03:31this is where I try to stay grounded is that the  screening that we’re doing is to uncover really  

1:03:36it’s a way to uncover other way like what are all  the ways we can regulate Singha protein because  

1:03:41this is what we got to do and so my um by a  screening system because of it Scripps I can throw  

1:03:46two hundred thousand compounds at this system and  I can and I can what’s called back translate the  

1:03:53mechanisms that regulate Singha protein okay  and so that’s gonna lead to a whole bunch of  

1:04:00biology projects and that’s gonna lead to a better  understanding of how can we raise single protein   that’s gonna lead we think to plan B Plan C plan  B plan E like I’m not gonna develop those drugs  

1:04:10I’m gonna tell drug companies and pharmaceutical  companies these are what you should be looking at   you should be making drugs for these right so I’m  trying to elucidate ways to do this okay if I had  

1:04:20twenty million dollars if someone dropped twenty  million dollars on my door on scripts you know  

1:04:25my office the it would be accelerated because  it’s a manpower issue I’ve been lucky to get NIH  

1:04:32funding for this is because this platform that I  developed you can use for any single gene disorder   right it’s a discovery tool for a regulation of  any gene that causes disease through too little  

1:04:42expression so the NIH likes that because they’re  like if it works for saying that they might work   for you know their single gene disorders so I’ve  been lucky in that way but because of that I have  

1:04:50to kind of always keep one eye on how flexible  is this for other systems so I can’t go full  

1:04:56blast on just SYNGAP1 because it’s more of  a general tool which is where you know if you know  

1:05:03if I was lucky enough to get you know some large  gift from somebody I could put people on it and  

1:05:09they would be able to work just on the single one  stuff and I’m not asking for money from anyone   I’m just saying at the end of the day there are  some projects that are just we don’t know enough  

1:05:18we need time we need to do research and there are  some projects like screening where it’s a manpower   problem the bottleneck is manpower well I mean let  me do that for you I am asking for money like we  

1:05:27that’s why we have imposed tucking in your lab  and if we as parents gonna raise more we would   have more postdocs in your lab so if anyone  wants to give money 1% goes to the labs but  

1:05:36um I was trying to push you to a to the hard part  Gavin which was if we hope for ASO is in three to  

1:05:43five years which is the number people are shared  with me the scale and scope of your work you’re  

1:05:50not because parents say what when’s Gavin gonna be  done and I don’t think they understand that this   is if we’re talking years right so you’re this  is a biology project this isn’t a drug so it’s  

1:05:58it’s it’s Pro okay so I hear what you’re saying  so there are ways so Scripps has unique libraries  

1:06:06other people don’t have okay and so there’s we  have the world’s largest repurposing library   right we have this Sol thousand compound library  of every single drug like compound that is safe in  

1:06:16people right it contains all of these compounds  that failed in clinical trials that are safe in   people and so we’re screening that stuff  now and if we find compounds that get validated  

1:06:25and racing that protein those can be tried soon  you know right that’s that’s why we purposing  

1:06:31is so exciting is because you can the avenue to  trying them and the kids as fast you know but the  

1:06:36chances of that working or low but it might work  and so if that doesn’t work then we have to go the  

1:06:42the longer route which is to try to find probes  that basically those probes will tell us about   what our druggable pathways that race Inga and  it could pay I mean it could take 10 years right  

1:06:52I mean you know I you know I just I can’t put a  timeline on it I can say the repurposing screen  

1:06:58that we’re doing we were doing it and encoded it  I’m not I’m not exaggerating we we got that we   got the libraries from from La Jolla in February  and I ordered $15,000 worth of reagent to screen  

1:07:09that and it would have been done that it would  have been done by now but koban weava shut down   for three months so now you know we’re hoping to  start that screening in September that’s how bad  

1:07:17Cove it screws everything up because you have to  shut everything down and then restart the Machine   and it takes a lot of time I’m not complaining  I’m just saying it’s it’s not as simple as just  

1:07:26taking some meat out of the freezer and font  and cooking a steak you got a like you know mice   need to breed you know reagents have to be ordered  like infrastructure has to be rebuilt that kind of  

1:07:36thing none of us think what you’re doing is easy  and we’re grateful you’re doing overtime but we  

1:07:42still have 40 parents hanging on I there were two  questions that came in I don’t know if you want to   jump into these because they’re big one of them  is any insights into gee no fee no correlation  

1:07:51good to million dollar question and then sort  of a second-order question about penetration of  

1:07:58brain with ASO which i think is gets us into the  complicated complexities of delivery for eso’s on  

1:08:07those yeah the first one I’ll take first because  it’s easy is that I can’t remember what’s publicly  

1:08:12available and what’s secrets that I’ve been told  so I can’t comment all’s I can say is is that it’s  

1:08:20a good question and I think largely it’s still  unknown I think there’s some data published in  

1:08:26human that says that they penetrate human brain  pretty well and I and and I know I can say this  

1:08:33because of my knowledge of sin gap is you know the  human brain is huge volumetric mass and so SynGAP  

1:08:38is expressed very heavily on the very outer part  right so your brain is floating in a sea of CSF in  

1:08:47those asos will be swimming on the outside and  they’re going to get in from the and from the   inside out and so sin gap is on that outside so  that’s promising but there needs to be more work  

1:08:57on that and that’s a big unknown the this.g no fee  no correlation it’s a great question so I the big  

1:09:05elephant of my talk is the people especially for  people that have missense kids is that there’s  

1:09:10been so much work done on on the what are called  the clearly pathogenic so the the nonsense and  

1:09:18the frame shifts and the deletions is because  we know we’re pretty ninety you know percent  

1:09:23confident that the mechanism is shared amongst all  those kids which is low seeing that and so one of  

1:09:30the things that we’re gonna start doing is we’re  gonna start doing a consortium with some other   people jimmy holder and some German scientists at  mocs Blanc to start doing genome phenome for the  

1:09:41missense and so some of you may be aware of that  and we are have a worldwide effort at trying to  

1:09:47collect genetic reports from kids and what we want  all we want all the reports we want the nonsense  

1:09:54we want the missense and we’re building maps of  all of these variants especially the unpublished   ones and so what we’re gonna do is then do  a systematic gino Fino of missense variants  

1:10:08especially we’re gonna look for areas in the gene  that cluster will make human cell lines human iPS  

1:10:14sees will make mouse models and we’re gonna try  to understand and we’re gonna try to answer this   question that I’m just going to pose if my my  child has a missense variant and they have this  

1:10:24phenotype do I think that my child would be a  candidate for sitting up raising therapies that’s  

1:10:32the question we want to answer because that answer  is difficult that’s hard we can’t give that answer  

1:10:37to parents now that have missense kids but we  think by doing these maps and comparing the effect  

1:10:44of Syngap the effect of variance in got mixed  with the clinical phenotype we think we’ll be able  

1:10:50to give that answer after this projects over and  this is a another kind of five year window project  

1:10:55we’re working on it so hopefully that that’s a  little bit of news yeah it’s exciting news we’re  

1:11:03excited to support it the questions are flying in  so I don’t know if you want to take a quick look  

1:11:09so that I can stay for I can stay for you know  while longer it’s it’s not a problem let’s go   through J let’s go through J J’s really quick  getting back to base biology what needs to be  

1:11:19done to get back to understanding the very basic  functions of how Syngap is transcribed translate   and regulated by the cell and getting back to the  range of phenotypes is it haploinsufficiency have  

1:11:27isoforms adjusting our protein and how do we alter  that so I wanted tile on if you just elaborate a  

1:11:33little bit for people who haven’t heard about  isoforms and just sum up like there’s a big  

1:11:40one there’s other ones and what we know and what  we’re still learning so I sephora’s are important  

1:11:46but they muddy the waters in terms of complexity  so isoforms are confusing for neurobiologists so  

1:11:55they’re going to be really confusing for everybody  else and so I’m gonna try can I share my screen  

1:12:00again yeah go for it because I have some stop  something on here it’s not data don’t worry

1:12:07can you see that sure there you go okay and so  it’s my very first slide I believe yeah so let  

1:12:21me do it okay so you can see this is the single  one gene okay and so there’s one single one gene  

1:12:30alright but there’s no one SynGAP protein okay  there are many we call them the sin gaps and so  

1:12:38and the reason why they’re multiple SynGAPs is  that there were a called alternatively spliced  

1:12:44exons and so you don’t need to know that other  than then when you make a sin gap one message   you mix and match different modules and you put  them in like building blocks and then they can  

1:12:54encode each one and you can see my cursor I assume  so like these are these are present in some but  

1:12:59not all SYNGAP1 messages so when this is  present here you end up with a single protein  

1:13:05that has either this protein end or this protein  end right if this isn’t included you end up with  

1:13:14this protein end or this protein end there’s  some research by my lab and also Rick’s lab   that shows that these these parts of the protein  that are mixed and matched within all of the cin  

1:13:24gaps in part different functions of the single  protein and so that’s one of the ways that we  

1:13:30think that Syngap is a disease gene is because  it encodes proteins that actually have different   functions from the same gene now what does that  mean for therapy so that’s interesting that’s  

1:13:38one of the reasons why people think sand gap  school biologists think sand gap is cool but   what does that mean for you all and so what that  means is is that a therapeutic question is is do  

1:13:49I need to raise all the sing up on isoforms you  know yes well I guess you can ask it more basic  

1:13:56question is does my child have a disorder because  they lost one single isoform or all this thing  

1:14:02up one isoforms and so that’s important because  which ones do I need to put back ideally we don’t   know and so the ideal thing would be to put them  all back in like nature and pen and so hopefully  

1:14:13the ASO therapies can do that because that Quint  that questions answered now this there’s another  

1:14:19side question is is that there’s an a s those  don’t work a viable plan B or C that ones really  

1:14:26brought it up is could be gene therapy right so  you could put a functional copy of sing gap one   back in the brain that’s a little bit further off  because delivery of large messages like send gap  

1:14:37are tricky now and there are companies that are  working on that to try to solve that problem and   they’re also trying to take a functional copy of  a gene and be able to regulate its expression so  

1:14:47you don’t give too much or too little but that’s  gonna be some years on but that’s possible but   the question is is that when you do viral delivery  you have to pick one of these isoforms you can’t  

1:14:57you can’t put the whole sing up one gene back in  you have to pick one of these isoforms and you use  

1:15:02what’s called a cDNA so it’s very very important  to know which one of these is sufficient to bring  

1:15:08back function in the brain and that is related to  the phenotypes that we all care about right and  

1:15:14you and you all care about and so that Mouse that  I have that studying toxicity it also answered  

1:15:21it’s it’s a it’s a we think a clever Mouse because  it also answers the question that we’re getting   at now which is which isoform is sufficient in a  gene therapy setting to these isoforms and I can  

1:15:33tell you that it’s this ISO alpha one isoform that  we think is very very important and we’re testing   them yeah can you just said something that they  got that made my brain wake up a little bit you  

1:15:46said when you do viral delivery we have to choose  an isoform there to a OAS those are Amy’s no so  

1:15:52like and well Amy but any of these won’t work for  sing gap it’s too big but like but something like  

1:15:57an AV where you you package a syn got message  into a viral vector and then inject it into the  

1:16:03body and then it goes and it trans what’s called  transducing it enters the brain cells and then  

1:16:08inserts a copy of sing gap one in there that’s  some functional and then from that copy of saying   gap one it makes protein so that’s another way to  make more protein but then ASO will be taking with  

1:16:18a taking down an existing regulatory mechanism  right and they so would be would be an artificial   nucleic acid so like it’s something that looks  like a you know RNA or DNA right and what it  

1:16:31will do is you can see my screen still right  so what it’ll do is you know you have hapless   efficiency so you have half the mRNA what an ASO  will do is bind somewhere in this process to the  

1:16:42mRNA that’s still there and basically tricks it  into being more efficient yeah though right it’d  

1:16:49be like pumping up your tyre twice as much right  and you’re taking whatever’s there and making it   work twice as well whereas a gene therapy would  insert a new copy of sing f1 so now people are  

1:16:59now Hans is getting going and he’s asking about  prime base editing so can we can I just for the  

1:17:05sake of time tell you my my my high-level answer  when people start asking me about gene therapy  

1:17:11and base editing and you can correct it um it’s a  little selfish but I want to keep it simple when  

1:17:18I’m talking to parents I say look there are asos  in development right now there’s there’s depending   on how you count let’s just say a few plus and  those might be available in three to five years  

1:17:27Gavin is doing this massive drug repurposing that  might come around in about five years then there’s   this we’re not a good candidate for current gene  therapy av9 but next gen gene therapy maybe and  

1:17:37prime base editing maybe but the way I think about  the world that the next stop on this train is   ASOS on and then shortly after repurposed drugs  and then in the future as as the technique gets  

1:17:50better refined and generally tested out on travail  first for a variety of reasons we can look forward  

1:17:56to other viral vectors and or prime based editing  is that directionally correct yes my gut tells me  

1:18:03yes so I can’t add anything to what you said it’s  true that is that that is the time frame but my  

1:18:09knowledge of the science my gut will tell me and  at that rate at which everything is accelerating  

1:18:18you know I think the future credibly bright for  viral therapy so I think the future looks very  

1:18:28bright for viral therapies as long as there isn’t  some unfortunate road block along the way that  

1:18:34happened in the 90s you know you pen so I think  that the technologies are there and and I know  

1:18:40that there are very smart people in pharma that  have started venture funds and startup companies

1:18:48specifically for this problem so yeah so I think  I think it’s very promising but it’s gonna take  

1:18:59there’s some there’s some technical holders and  hurdles to overcome but when those are overcome   you know I think it’s gonna be very promising  awesome I’m gonna look can I throw one more  

1:19:09question at you and then we can live this crap  up it certain what they just asked and again  

1:19:15I’m gonna just opine for a second people come up  me when I talk about ASO is no like what about   G there and I say a we’re too big from the gene  therapy vector a benign but B gene therapy is one  

1:19:25and done whereas asosu can titrate so we should  we are and we should continue to be focusing on  

1:19:31asos could you help could use the lab of rate on  why Oh viral vector is you get a one time shot  

1:19:37versus ASOS are repetitive currently currently  viruses are one shot and that’s one of their  

1:19:44it’s a drawback for like a non-lethal disorder  right so like you know one shot is fine if the  

1:19:51alternative is is not nonsurvival right but so  that’s not the case for single most disorders so  

1:19:58you know it you could do more harm than good  with when you can’t when you can’t regulate   the expression of SynGAP if you put it in right  that’s that’s dangerous because we don’t know if  

1:20:06it’s toxic or not right so there’s no well there’s  no way you can do that for viruses that’s one of   the hurdles that people are trying to solve in  industry right now which is put kill switches  

1:20:16in so there’s an investigated scripts that has  had nice papers and Nature Biotechnology showing   you can put kill switches and viral vectors  so if it starts to become toxic use kill it  

1:20:25turn it off and then people are trying to take  the kill switches and turn them into you know  

1:20:33volume controls if you will right so you know you  want to be able to to turn up and down the volume  

1:20:44of how much protein you make off that artificial  gene right that’s what you want to do and that’s   what my mouse models can do in theory it would  be awesome to have a translational strategy that  

1:20:54you can do that because if you could and you  could put any gene you wanted in there you I   mean you’d have in theory cures for you know most  most of these disorders but that’s some time off  

1:21:04ASOS are different you have to inject it it’s a  small it’s a it’s a 20 base pair artificial RNA  

1:21:10DNA depends on how you look at it and so what it  does is it goes in and binds to sing up mRNAs pre  

1:21:15mRNAs and tricks them into doing things so it’s  like a drug like it’s just a drug that you can’t  

1:21:23take my pill you have to inject it into the inner  current ly into the intrathecal space because   it’s big and it doesn’t get across the blood-brain  barrier so you have to inject it kind of into the  

1:21:31brain that’s why they go into reports or through  the spinal cord awesome I’m very grateful Gavin  

1:21:43for how generous you’ve been with your time and I  think all the parents on this call will agree I’m   sure the questions will pour in and we might send  you a some of the burning issues but on behalf of  

1:21:55all the parents on this call thank you so very  much for for making yourself available it’s my  

1:22:00pleasure is good to see everyone and I hopefully  I’ll see some of you many of you in person soon   yeah I think the Floridians are gonna have a hard  time staying away from your lab I keep telling  

1:22:10Sydney and see you and you can see the chat is  blowing up with gratitude so really appreciate  

1:22:16it it’s my pleasure genuinely and like I said  I hope to see I hope to hope to meet all of   you in person someday yeah those two take care  everybody thank you Cheers just wanna remind  

1:22:26you in two weeks we’ll also have Shilpa talking on  July 2nd this is on this SRF Facebook page you can  

1:22:35register with that link at the bottom I’m sure we  talking about some of her specifically sing up one   epilepsy research and then also Helen bait up will  be two weeks after that and then a reminder that  

1:22:48we have five days left on this be kind campaign  so if you want to get shirts again the links on   our Facebook but srf kindness off bonfire srf  does a weekly parents meetup which is which is  

1:22:59always fun and generally useful I took the least  flattering picture possible of everybody in this  

1:23:05one but they’re good meetings and then just a  reminder we have the sing gap research fun board  

1:23:11is now up to twelve families and we’re always  looking for people who want to help so if you are   the time to do more and you want to be involved  reach out srf is pretty much everywhere we’re on  

1:23:23Facebook Instagram LinkedIn Twitter and sync every  search fund org is a good website to have handy