45 – 3rd Annual Synapse Roundtable (Full Presentation)

Event Time

December 3, 2021 at 4:00 pm

Dr. Bichell – COMBINEDbrain – Cures happen faster when unique disorders find strength in collaboration
Dr. Dallman – Miami – Sensorimotor integration in gut and brain of zebrafish Syngap1 and Shank3 models
Dr. Kolevzon – Mt. Sinai – Clinical Trail Readiness Endpoints and Outcomes
Dr. Smith-Hicks – Hopkins – Sleep & other potential biomarkers for SHANK3 & SYNGAP1
Dr. Chung – Simons – Simons Searchlight Registry Insights
Dr. Brimble – Ciitizen – Ciitizen Registry Updates on SYNGAP1 & STXBP1
Dr. Prosser – UPenn – Antisense olligonucleotide therapies for #STXBP1 & #SYNGAP1 disorders

THIS IS FOR TRANSCRIPT ONLY:

0:20good morning everybody thank you for  coming to the third annual synapse   roundtable my name is Michael Graglia i  am the managing director of the Syngap  

0:27Research Fund and it is such a thrill to  welcome our incredible speaker here today  

0:33in the interest of time i’m going to hand this  over to my colleague carlene song rigsby and  

0:38let her introduce yourself and then our  first speaker dr terry yourself great thanks  

0:44mike good morning i am charlene sun rigby and  i’m the president and co-founder of the STXBP1  

0:51foundation and thrilled that we are having this  roundtable this morning i would like to introduce  

0:57our first speaker terry jo bichelle she is the  executive director of combined brain and she is  

1:03going to be speaking on cures happen faster when  unique disorders find strength and collaboration  

1:10thank you terry jo thank you so much for having  me i really appreciate this this is great and  

1:18i’d like to share my screen all right it worked so  far so good and now um can you see my slides okay  

1:28yes so okay so um as charlene said i’m  the founder director of combined brain  

1:37combined brain is a consortium made up of at this  moment 26 separate patient advocacy foundation  

1:48organizations which you can see represented  here behind my head and also on this slide  

1:57we i founded this because uh i’d been working  in the Angelman field for quite some time for  

2:06about 20 years i have a son with Angelman syndrome  and what i found out in the past that things have  

2:14been changing in the past 20 years quite a bit  so 20 years ago when he was originally diagnosed  

2:23it was uh really rare to get a single gene  diagnosis for a neurodevelopmental disorder  

2:31we didn’t really know how to collect  natural history we didn’t really know how to  

2:39we didn’t have an icd-10 code for our disorder  we didn’t know the morbidity and mortality rates  

2:47for Angelman syndrome we really had to dive in  deep and find out everything we possibly could  

2:54about Angelman syndrome and in doing this  um what we found and and there are a few  

3:03other neurodevelopmental disorders that were  also early diagnosed Prada willie syndrome  

3:09also on the same 15th chromosome area  dupe 15 also the same 15th chromosome  

3:17a few other disorders that were diagnosed really  in the early days in the 90s and we at that point  

3:29really were working hard to show how unique  we were to show that we weren’t actually  

3:37we shouldn’t be lumped in with autism or  lumped in with intellectual disability that  

3:44Angelman syndrome was really special because  in fact it had all these unique characteristics  

3:54and so now that 20 years have gone by and  whole genome sequencing is happening and  

4:01we are finding more and more and more disorders  that we can identify with the genetic mutation  

4:08every single day now things have changed a little  bit and so now what we found out is we’ve got to  

4:16do this fine line we’ve got to work really hard  to find out what is unique about each disorder  

4:25but we’ve also got to figure out what we can  share what can overlap what can we possibly do  

4:33that we’ve that somebody else has already done so  we don’t have to reinvent the wheel and what i’ve  

4:39been telling people lately is you’re special  but you’re not that special and what we really  

4:47need to do is work hard together and make sure  that we can help each other get to our cures  

4:53faster so that’s why i found a combined brain let  me see if this will advance yes it will and it’s a  

5:02consortium led by patient advocacy foundations  because face it even now even with amazing  

5:11clinicians researchers in the field really what we  all need to acknowledge is that parents more than  

5:20anybody else are the leaders for rare disease  research parents are the people who care the  

5:27most about a disorder parents are the ones who can  actually get the big picture of what life is like  

5:34to live with a child with a disorder or a family  member with the disorder and so in fact these days  

5:41it’s parents and patient advocates who are really  leading the research for rare diseases of course  

5:50working tightly with the clinicians the industry  members and researchers who are working on these  

6:00disorders but i mean patient advocates are are are  really key so we are a patient advocacy foundation  

6:09and our mission is to fast-track cures for all of  these disorders that are part of combined brain  

6:17and we have three represented on the round table  today uh Phelan mcdermott syndrome which is um  

6:25represented by cure shank and STXBP1 disorder  and SYNGAP1 mutation those three are uh  

6:35three of the neurodevelopmental disorders that are  part of combined brain and what combined brain our  

6:43focus is on severe rare genetic neurodevelopmental  disorders the reason why we focus on that there  

6:54was a lot of work being done in autism there  was a lot of work being done in epilepsy  

7:00there wasn’t very much work being done in  cognition and our disorders are all disorders  

7:07that have severe cognitive disability  so this is why we are working together  

7:16on uh looking for biomarkers and outcome measures  for um neurodevelopmental disorders so when  

7:25you think about and i’m not going to read this  slide you all have had plenty of time to read it  

7:30while i’ve been talking um so if you think about  cognitive disorders and treatments for cognitive  

7:40cognitive disorders i haven’t  had enough coffee yet evidently  

7:45these are our members current members we do have  a long waiting list that’s building every day and  

7:51part of the reason for that is because there are  new neurodevelopmental disorders diagnosed every   day so i do think that our membership is going to  expand in 2022 but this is a current membership  

8:05um anyway when you think about how um oh forgot to  tell you these are the three disorders that are um  

8:15here represented today so um when you think about  a neurodevelopmental disorder and um what how are  

8:26you going to uh measure how are you going to do  a clinical trial how are you going to cure it  

8:32how are you going to figure out if a treatment  is working what you uh what we did in the past  

8:40and we did an Angelman syndrome uh we made  a mistake which was we put the rodent models  

8:49in the center of the picture so we  did a lot of great research in the lab  

8:56and when my son was diagnosed there were no  clinical trials whatsoever for human beings  

9:05but there were clinical trials going on in the  lab for rodent models and we were all focused on  

9:13those rodents it focused on those rodent models  and what we could do to improve their lives  

9:21and so uh what happened was that we we did  find some great treatments for rodents with  

9:29Angelman syndrome we reversed the phenotype  in rodents with Angelman syndrome many times  

9:37and when we did this and then moved  those compounds or those repurposed drugs  

9:42into clinical trials with human beings our  trials all failed so what we realized is that uh  

9:51we need to put human beings in the center of this  picture and when i say we i don’t mean just the  

10:00people i’m friends with or the even the angelman  community or even the rare disease community  

10:07the FDA realized that trials were failing and not  just for neurodevelopmental disorders all kinds of  

10:15trials were failing because patients were not put  in the center of the equation and um so the FDA in  

10:252017 and 2018 introduced the some guidances which  really try to explain to industry and researchers  

10:39that you need to put patients in the process from  the beginning you have to find out what is it like  

10:49to live with the disorder what what is what is  your day-to-day life like what what would matter  

10:57to you as a patient or to a family to change  if you found a treatment so we have all these  

11:07amazing genetically related treatments  now coming down the pike so many kinds  

11:15uh you know obviously gene therapy uh but  also antisense oligos uh s i rna mi rna  

11:25CRISPR we have uh so many possibilities for  genetically related treatments that could actually  

11:35really correct the underlying disorder beneath  any of these severe neurodevelopmental disorders  

11:44and if it worked if one of these therapies  worked and it changed something it improved  

11:52something what what would matter to  patients to improve what what could we  

11:59measure that would show that quality of life  is better for that patient and that family  

12:06so now what we do is we’ve got to actually  find out what matters to patients first it’s  

12:13one of these things that’s so obvious it just  drives you nuts that people didn’t do it before  

12:19and then we have to collect the natural history  on that so we have to ask questions about uh life  

12:27that matters to patients on an on a regular basis  over time not just once right before study but  

12:35over the length of a person’s lifetime then we  have to figure out which of those things can be  

12:42measured in the models the rodent models even the  cell models and then we have to figure out what  

12:48endpoints can we develop for trials based on what  we can measure and the humans and the rodents and  

12:54what matters and then we do the clinical trials  that’s how we get clinical trials to succeed  

13:01so this is what combined brain was built to do and  uh by working with all the member organizations  

13:10we really help all these patient advocacy  organizations identify that they themselves  

13:19have the most responsibility and the most access  to all of these parts of drug development that are  

13:27represented above this timeline from you know the  gene id to a cure before the fda so it’s really at  

13:37this point up to patient advocacy foundations to  lead the charge for natural history and really and  

13:45this i’m gonna might be a little controversial  i hope not but the patient advocacy foundations  

13:52really need to own the data for natural history  trials because researchers come and go y’all you  

14:00all get new jobs you retire you decide to move  to another institution researchers come and go  

14:07industry comes and goes uh clinicians come and  go but the patient advocacy foundation they are  

14:13going to care about this disorder for that until  it’s cured and then after it’s cured probably to  

14:20help find patients and get them to the treatment  they need so natural history data it’s got to be  

14:28spearheaded or coordinated or at least owned  uh accessed by the patient advocacy foundation  

14:36plus they’re the ones who have the list of  patients they’re the ones who are going to   recruit all the patients to get in the natural  history and then to get in the clinical trials  

14:48and actually if we do natural history  right natural history can be a control  

14:55this is the holy grail of natural  history we all got to work hard on that   and then disease concept studies  and disease burden studies  

15:04these are really and really really important  in drug development you have to understand  

15:11what is the burden of a disease on uh on a family  or a patient how you know if if if a patient has  

15:20a severe neurodevelopmental disorder what has to  happen in the whole family does somebody have to  

15:26give up work how many medical appointments are  there how much money does it cost that’s disease  

15:31burden and then disease concept i’m going to talk  about in a minute is what the disease is like in  

15:38daily life and then it’s really up to um patients  to give input to patient-centered outcomes how  

15:46are you going to measure if a treatment’s working  without asking a patient so all those things are  

15:52on the top of the timeline and then everything  below the timeline that’s got to be done  

15:59really spearheaded by researchers by industry by  clinicians but they’re going to need stuff from  

16:05up on top of the timeline so to get biomarkers  you’re going to need bio samples so you’ve got  

16:12to talk coordinate for those and same thing with  all everything else on the bottom of the timeline  

16:21so as part of our 2021 initiatives we worked  hard to get the foundational work done for all  

16:30of these various components of drug development  and uh because time is short i’m not going to go  

16:38into details on any of these but i hope that  you can get a hold of me through the website  

16:44combinedbrain.org or you can email me and i’m  just going to talk about a couple things right now  

16:51um that we’ve been working on that are really  pertinent one is a biorepository how are you going  

16:58to get all those biosamples i mean how are you  going to get those biomarkers without biosamples  

17:04and this is where i tell people you’re special  but you’re not that special because it’s a lot  

17:10easier to work across disorders to figure out  biomarkers what proteomics can we do what uh are  

17:20there possibly um byproducts uh that could go up  in that are in blood that could go across a whole  

17:29bunch of different disorders could you measure  not just what’s specific for the disorder like  

17:36gene expression but also what might go across  disorders like neurodegenerative products so  

17:43we need biosamples so we’ve opened a biorepository  that goes is open to any neurodevelopmental  

17:51disorder and researchers can access these samples  at really the lowest cost you could possibly  

17:59get by with in this field we also do  these conceptual models of disease  

18:06we do the draft of the of the conceptual model and  today we have on this call two disorders that have  

18:15gone forward to to do the uh fully um the the the  final disease concept study so in a nutshell what  

18:27a disease concept study is is a literature review  looking at every symptom ever reported and um then  

18:36uh oh i see mike popping up so i better hurry  up and we ask every question uh that you can

18:44think of about what your daily  life is like and we add all of   those symptoms to a big disease concept  map and from that we draw all of our

18:57goals and objectives so one of them showed  that of our original 20 disorders communication  

19:05especially expressive communication was one of  the number one issues for every single disorder  

19:12and so we have a new initiative working with  duke to expand a communication measure called  

19:19the orca the observer reported communication  measure to 12 different combined brain disorders  

19:25amongst those the very first three are uh syngap1  stxbp1 and well phelan mcdermott is is the fourth  

19:35and the reason why those are our first few  disorders to be looked at is because when  

19:42we did our disease concept models we could  compare the disorders to each other to see  

19:49who was similar and who is different and as  the orca was actually invented for develop  

19:55for angelman syndrome we wanted to start out with  the disorders that were closest to angelman at the  

20:02beginning syngap1 and stxbp1 and then philly  mcdermott and so now i’m going to conclude my  

20:09talk with uh asking if you have any questions  um and did i leave time for a single question

20:19oh you’re silent not really but  thank you so much i think one of   the reasons we asked you to kick this off  is because we’re so proud of being a part  

20:26of combined brain and the whole theme  of this round table is collaboration so   this is a great opportunity for us to show  our communities and our colleagues that  

20:36that we are working with you and all these great  organizations on the screen to do anything we can  

20:42um to help our kids in the most efficient manner  possible because our kids are sick as you rightly   said and we care deeply um in the interest of time  and out of respect for all the other speakers i’m  

20:50going to plow right through thank you so much dr  michelle i will see you soon at the fast meeting  

20:56um i think and over to dr dahman who is a  neurologist a neuroscientist i should say  

21:01at the university of miami and like every all  of our speakers today dr dahlman is working on a  

21:07couple of our genes so um in the interest of time  i will let you take it away thank you so much for   being here thank you so much for inviting me to  participate in this round table and i was really  

21:20i’m i’m glad i’m following terry jo i i  use animal models um but we’re trying to  

21:27do this work um in the context of also being  cognizant of natural history and and so i hope to  

21:38tell you a little bit about  our integrated approach   looking we’ve started with syngap one and  shank three models of of um zebrafish models  

21:50okay so here’s a a quick rundown of what i’m gonna  go through i’m gonna give you a brief introduction  

21:58talk about zebrafish models talk about  integrating the clinical and basic studies  

22:03and then give a little summary  in future directions snapshot   so when as someone who works in an animal model  and not even a rodent model a zebrafish model  

22:15we focus on symptoms that we feel like we can make  mechanistic insights on and where the mechanistic  

22:24insights might inform treatment strategies and so  the two that we’ve focused on are altered sensory  

22:31processing and gastrointestinal distress both i’d  say symptoms that that we know a little less about  

22:41and then one of the things that that i’ve learned  in my foray into this field is that the gut itself  

22:51is an organ that functions through sensing  information nutrients in the lumen and producing  

23:00a behavior peristaltic movements to aid in  digestion so this this idea of sensory processing  

23:08being an important symptom that has big  impact on quality of life this altered  

23:15sensory processing could play out in the gut  as well and as all of you know the speed of

23:25identification of genetic forms of  neurodevelopmental disorders has been  

23:30very rapid um and so this is just a slide  from saturday stream at all 2020 that shows  

23:38some of the single genes of large effect that  have been linked to neurodevelopmental symptoms  

23:46and i’m circling shank 3 and syngap i think  i’ve i’ve put in the the year in which um  

23:57variants in those genes were linked to neurological conditions in humans and you  can see that syngap was linked much more  

24:08recently than shank three and as such  um the natural history that’s known  

24:14for different conditions is very different just  in part based on when that linkage occurred  

24:22okay so my lab focuses on on the sensory  motor symptoms and in particular we’ve  

24:31we’ve taken a deep dive into gi symptoms  in part because so little is known about  

24:37how those symptoms arise and actually um in  attending felon mcdermott family foundation  

24:43meeting and talking to families these gi  symptoms were symptoms of a big concern and so  

24:52so that’s how we got into looking at these um and  so this this circle here are molecularly defined  

25:01forms of asd with documented gi distress and um  this is an incomplete list uh i before um agreeing  

25:11or not before the meeting this morning i looked at  stx bp1 and and they’re also gi symptoms described

25:20in in that condition even though it’s  not listed on this this set of these  

25:28um genetic forms of neurodevelopmental um  disorders six have in animal models um of six  

25:38of these forms have shown that there’s reduced  motility reduced movement in the gi tract and  

25:45that movement is critical to digestion and gut  function because it’s part of a reflex that when  

25:55the gut senses nutrients um it induces these  contractions it induces mucus secretion and and  

26:02um and hormone secretion that aids in digestion  coordinates with the brain coordinates behavior  

26:10so the one of the hypotheses that we’re interested  in testing is that this reduced motility is a  

26:16common aspect of asd-linked gi distress and  then you can see that three of these animal  

26:23models are zebrafish models i’ll show you why  zebrafish are useful for looking at gi movement  

26:32but there are a lot of genetic models in zebrafish  that haven’t been examined for gi motility  

26:40so zebrafish are a good model for this  because by six days after fertilization  

26:48they have these relatively translucent larvae  that are eating on their own um and you can  

26:57actually watch this is a movie of a larva that’s  been fed and the food includes six micron beads so  

27:05you can actually watch these peristaltic the  part of the reflex that i was talking about

27:12in vivo and that makes it quite straightforward to  quantify what’s going on different from us right  

27:21where digestion is happening inside and it’s  not visible in addition we’ve been looking at  

27:29the response of the nervous system to external  stimuli like light and and as i said we’re  

27:37starting to think about this sensory motor  integration both at levels of gut and brain  

27:44okay so what have we found um what so this is  again these peristaltic movements uh um that  

27:53our response to feeding in wild type this is our  shank three model and believe it or not the movie  

28:00is going so there’s a little twitch that happens  here every now and then um and this is a fed  

28:06syngap model larva you can see that there’s  actually quite a bit of motility in the gut  

28:13but it’s not coordinated from a  roth’s anterior to posterior direction  

28:20um and so we can quantify this this behavior  and we can show that so for instance in um  

28:30in wild type there’s a particular rhythm that is  also seen in syngap but is slower in shank three  

28:38and so this echoes this need  to kind of understand um

28:48these studies suggest that so yes both are showing  um gi symptoms uh both genes seem linked to these  

28:56gi symptoms but manifest in slightly different  ways that that that are important to understand  

29:05so the other test that we do in the zebrafish  is whole gut transit and what happens when you  

29:12in in both shank 3 and um syngap larvae so what’s  happening here is we fed them beads in wild type  

29:18and in wild type what happens is the beads are  consumed and then make their anterior posterior

29:26journey through the gi tract to be expelled  and this usually happens within 12 hours of  

29:33consumption the first expulsion whereas in shank 3  at this intermediate time the beads all accumulate  

29:41at this junction between the upper the the  intestinal bulb which is like the stomach  

29:46and the upper intestine and only by 24 hours do  you get expulsion this is true in syngap as well  

29:54and this is quantified here um so what are the  cells that mediate this gi reflex well it turns  

30:02out that your gut is lined it’s sprinkled with  these um endocrine sensory endocrine cells called  

30:08enteroendocrine cells in light blue and those  actually make most of the serotonin in your body  

30:16in response to either mechanical or chemical  stimulation in the lumen of the gi tract those  

30:22are activated and talk to enteric neurons  that activate the smooth muscle cells  

30:28so um this circuit is really important for  taking food in the lumen and inducing the  

30:35reflex that is mucus secretion and contractility  in the gut and um to go deeper into this circuit  

30:43um we’ve been collaborating with liu  and john rawls at duke university  

30:50the other thing that points us to these enter  endocrine cells as being important is that if  

30:56when we quantify enteric neurons and anterior  endocrine cells which are important for motility  

31:03both syngap and shank iii mutants have reduced and  numbers of enteroendocrine cells which could mean  

31:10that they’re less sensitive to luminal stimuli  and therefore don’t produce the normal response  

31:18and i think these um you know both from  the therapeutic perspective and from um um  

31:27animal model studies most of the attention  um with these genes that are linked to  

31:34neurodevelopmental disorders has been  focused on the central nervous system   but the gut also has a a significant nervous  system through the enteric neurons and um  

31:47you know in the collaboration with with john  rawls he does this single cell sequencing of the  

31:54intestine and here is so what they do is  they take the intestinal cells um and do rna  

32:03sequencing on the single cells and what’s shown  here are the different types of intestinal cells  

32:11and then on the this this axis are genes that have  been linked to these severe neurodevelopmental  

32:18disorders um and and where these  genes are expressed in the intestine  

32:23and these first five rows are the entire endocrine  cells so you can see that shank 3 catnap norexin  

32:31cdkl5 scn are all enriched in these sensory  endocrine cells indicating that they could  

32:38be really functionally important to the gi  distress that’s impacting these individuals  

32:46you can see that other genes linked to asd are  more generally expressed throughout the intestine   and syngap is not expressed in the intestine  of the zebrafish but is in expressed in the  

32:57enteric neurons and so this this raises the  possibility that that therapies will have to  

33:10be cognizant of those cells in the gut  that are also that will also need um  

33:17to address the genetic the genetics of those  those cells okay in in addition to um gut  

33:28uh sensory motor integration we also  look have looked conducted studies of um  

33:34responses to visual stimuli in the shank  in this in our shank model and what we find  

33:42uh so this is an assay that is done in zebrafish  where you have light to dark transitions and  

33:48anytime you turn off the lights there’s a lot more  swimming and that response is dampened in um in  

33:57both in two different models of shank three  with where the mutations fall either in the  

34:03n-terminus or the c-terminus and what you can see  if you do if you map the responses in the brain  

34:12the responses to that that turning off  the lights are that the pineal gland  

34:17turns on and the hind brain and spinal cord  turn on corresponding to this increased movement  

34:22whereas in the shank models the pineal turns on  but it fails to activate this hind brain region  

34:32which is associated with the movement so this  this suggests that the sensory processing deficit  

34:39is in the hind brain so to test that possibility we transplanted  cells from a wild type animal into a shank  

34:503 mutant animal here you can see at one day post  fertilization these cells have populated the hind  

34:57brain and this is at five days or actually  six days when we do the behavioral assays  

35:02now these these shank three model has a wild-type  hind brain and that actually rescues their  

35:10response to the light stimuli so that this shows  that um behind brain is actually shank three in  

35:19the hind brain is really crucial at least in  the zebrafish for responses to light stimuli  

35:25okay um i know i’m i’m losing time so i  wanted to tell you that we’re also trying to  

35:33contribute to better understanding gi symptoms  in um in neurodevelopmental disorders um and

35:45one way is as mentioned by the previous by terry  it’s really important to have objective measures  

35:53and so it turns out that you can measure whole  gut transit time by eating a muffin with a   blue dye in it and this was actually done on a  epidemiological scale in england but not with with

36:08kids with neurodevelopmental disorders and we  also have um in collaboration with bahraik moshiri  

36:15who’s at atrium health we developed a blue muffin  that that copies the the tests that are used um  

36:24that involve x-ray and um to to measure  whole gut transit with the idea that if we  

36:31could use the blue dye and look for arrival  of a blue poop um that would provide whole  

36:36gut transit that could be done at home  and without intervention and this is um  

36:43uh ready we have seen whether  this is a child with a syngap um  

36:51mutation and she’s willing michael  and she wants some more styles

37:02yeah it’s edible huh okay so we’ve also developed  an app to try to do in a prospective manner gather  

37:11these symptoms related to gi distress and um  what we’re hoping to do is use these measures um  

37:21in patient populations at the same time  as we’re looking for mechanisms of gi  

37:28phenotypes and zebrafish models to develop  strategies for these gi symptoms more generally  

37:35and this is the wonderful group that has supported  this research it’s been a huge team effort  

37:42and so i think i have a teeny amount of  time for questions if anyone has them

37:59um dr dalman do you see the question in the  q a panel yeah i do um and i think um it is  

38:06possible that increasing so there are you can  yes this is something that we’re planning to test  

38:14it’s likely that it um that it  would work in in the model that  

38:20has problems with the entire endocrine  cells but we have to test that

38:27hi everybody i’m sorry i’ve lost my voice  i’m geraldine bliss um i’m the president  

38:33and co-founder of cure shank and the mom of a 23  year old son with family mcdermott syndrome and  

38:39i’m delighted to introduce you guys to dr kolovzan  he’s a professor of pediatrics and psychiatry at  

38:46mount sinai school of medicine he is the clinical  director of the siever autism center and the pi  

38:54of the phalen mcdermott syndrome natural history  study in the developmental synaptopathy’s   consortium alex has a tremendous amount of  experience in characterizing kind of the  

39:04natural history of fellow mcdarmod syndrome and  also in conducting clinical trials and family   mcdermott syndrome and other neurodevelopmental  disorders so alex thank you for joining us today  

39:16thank you caroline it’s very nice to be here  i’m so sorry that you don’t feel well that   looks and sounds painful maybe you  need a blue muffin those looked awesome  

39:28i was really glad i got to see that  all right i’m going to share my slides

39:48all right can you guys see now  my full screen yes okay cool

39:58all right i’m sorry that i missed the previous  whole talk but it sounded like we were talking   about sort of translational work from  animal models to clinical trials and kids  

40:07that’s also where our work started i want to  focus today mostly on the kids um and just  

40:14talk a little bit about what we’ve learned in  terms of the natural history and the phenotype   of filmmaker syndrome some of the challenges  we face and then a few of the ways that we’re  

40:22trying to address those challenges so this may  have this may be redundant at this point but  

40:27film the german syndromes due to shank three apple  insufficiency these are these are small deletions   or mutations on the terminal end of chromosome 22.  we know shang three acts as a master scaffolding  

40:38protein and glutamatergic synapses we know  it induces neuronal formation it represents a  

40:44potential target for treatment these kids all  have you know profound global developmental  

40:49delays a whole range of dysmorphic  features none of which are specific   um they all have language impairment they also  need to be of intellectual disability about  

40:58eighty percent probably have or 86 percent of  the states have low muscle tone a lot of that is  

41:03also related to gi dysfunction as you heard about  probably the most common of which is constipation  

41:09sleep disturbance is a really pronounced problem  that affects kids profoundly and also of course  

41:15parents and i guess this is a an epilepsy group  so about 25 of these kids will have epilepsy  

41:23there’s probably no specific kind  of epilepsy or seizure phenotype   it’s really all over the map and probably up  to 40 percent of kids if not more will have  

41:33underlying eg abnormalities without specific  clinical correlates um and and many will also just  

41:39have non-specific histories of febrile seizures so  that’s that’s feeling determined syndrome in 2013  

41:48dean approached me and said you need to put in a  grant to study the natural history i said no way   we’re not ready um she kept at it and paired us  up as a filament dermot syndrome consortium with  

42:01tuberous sclerosis and p10 or calvin syndrome and  so we formed this developmental synaptopathies  

42:07consortium all around these these synaptic  genes and our goal was really to comprehensibly  

42:14characterize the phenotype in children  adolescents and now adults we’ve included   using a whole array of medical genetic behavioral  and cognitive measures we really set out to add to  

42:25the literature by doing prospective assessments to  following kids over time and to to really sort of  

42:31ensuring that what we understood about the  phenotype at least today was was correct   um we were very interested in tracking the  natural history obviously that’s critical  

42:39for developing clinical trials we don’t want to be  picking symptom targets that are highly variable  

42:45and we want to be thinking about what are  potentially tractable in the context of treatment   we were very interested in developing biomarkers  first using neuroimaging and now focusing more on  

42:55electrophysiology and i’ll talk about that  today also and then the real you know main   drivers here is to to develop a new treatment  so we want to eventually start to assess  

43:05safety tolerability and the feasibility of  experimental therapeutics we’ve done that   in four or five different clinical trials  relatively small scale all at a single site um  

43:15and we’re really looking now to kind of expand to  leverage our whole network so the network exists  

43:20across now five sites focused on film and dermit  syndrome there’s probably ten sites in the in the  

43:26dsc overall but mount sinai rush with lothasory  and elizabeth barry kravis boston children’s with  

43:32mustafa sahin and sid street vastava the nih the  intramural program with audrey therm and stanford  

43:38john bernstein we have collected data for about  140 150 patients at this point uh 90 in our first  

43:46round and we’ve now been funded for a second  round and we’re doing baseline assessments and   we’re following people out after one two three  and now four years as well so it’s a really  

43:56robust um longitudinal study at this point um the  second iteration which was just funded i think  

44:02two years ago is now including kids that are  younger than 18 months uh rather younger than  

44:08three and older than 21 so we’re really  trying to capture the entire lifespan here

44:13well you know one of the first things we we’ve  done and we continue to add to it and refine it   is develop a kind of a standardized assessment  battery and we’re really interested in a whole  

44:22range of features from from cognitive ability to  adaptive behavior language motor functioning um  

44:28you know one of the things that kind of unifies us  is this autism phenotype even if um only about 60  

44:34percent of kids will feel the government syndrome  actually meet criteria so we do a lot of digging   into the autism phenotype especially now around  sensory symptoms and then and then other kinds  

44:44of behaviors sleep regression has become  a very very important area now to focus on   quality of life of course and any kind of  longer term cognitive changes that might occur  

44:54so this is our battery we recently published a  study looking at the relationship between the  

45:00phenotype and the genotype probably the largest  least prospectively collected study to date um  

45:06and i thought i just put some of the features up  that we now kind of established the prevalence   where as i said hypotonia is probably the most  common feature gastrointestinal dysfunction mostly  

45:16most commonly constipation apraxia uh ataxia  spine abnormality so there’s a whole kind of  

45:23you know broad and highly variable phenotype that  affect people from you know 80s oh sorry you know  

45:31from 86 90 percent of people you know all the way  down to four or five percent i think dysmorphic  

45:36features gets a lot of attention um because it  certainly alerts people to the to the concern  

45:41and it triggers the need for genetic testing  um but there’s really no specific i would say  

45:48this is more of a feature you know probably one  of the more common ones and more unique ones to   film the german are just plastic nails but again  nothing would be considered in any way path and  

45:56mnemonic i guess i’ll make a point also um i  haven’t seen it in the chat yet but i’m sure  

46:01carol dean will pay me to do this um as it  turns out you know a lot of the epilepsy panels   when you when you have a kind of a seizure  phenotype and you order genetic testing  

46:10and you um and you there are a number of different  sequencing panels that don’t include shank three  

46:16so while chromosomal microarrays will pick up  a large number of kids because of copy number   variants affecting uh terminal 22q um you really  need to do sequencing to pick up obviously smaller  

46:28you know point mutations and sequence variants so  it’s just important to be thoughtful about which  

46:34panels you’re ordering because you know shank 3  is obviously one of the most common causes now of  

46:40autism and neurodevelopment disorders even  if not um specific to epilepsy so it’s just  

46:46it’s critical to think about exactly  which genes are included in your panels  

46:51other features include things like disrupted  sleep as i mentioned anxiety more and more  

46:56we’re understanding now that kids that around  puberty are really vulnerable to developing pretty  

47:02pronounced neuropsychiatric decompensations with  the emergence of symptoms that are consistent with  

47:08bipolar disorder and even catatonia it doesn’t  happen in all the kids but the prevalence seems   to be becoming you know greater and greater as we  learn more we’ve been becoming more attuned to it  

47:18and then this issue of regression  although progression is characteristic of   you know neurodevelopmental disorders and autism  broadly you know up to about a third of kids  

47:26it’s certainly very characteristic also of a  subset of people who feel the turmeric syndrome  

47:32and some of the things that i started  here which i wasn’t going to cover very   specifically but there seems to be a relationship  between the size of the deletion where smaller  

47:42deletions and point mutations are actually people  that are at higher risk of regression it may very  

47:47well be because even at baseline they’re probably  they have higher levels of language and higher  

47:52levels of adaptive functioning perhaps but um  they’re more prone of course to also progressions  

47:59um in terms of cognition and adaptive behavior  you know these are kids that are severely to   profoundly affected for the most part obviously  there are people on sort of both ends of the  

48:07spectrum but for the most part we definitely see  this as a pretty severe intellectual disability

48:14um and we have a bunch of different language  tests including more objective tests like the   ebt and the tbvt um again all of which just show  pretty pronounced uh impairment where only about  

48:25half these kids are really verbal in a meaningful  way you know more than half are considered to be  

48:30minimally verbal and since some of the importance  of these measures that they all represent possible  

48:36tools to be using the context of clinical trials  so to sum up some of the natural history and i  

48:42didn’t present what the phenotype looks like  over time although when we’ve looked at it it   does seem to be stable to a large extent with  the exception of some standardized measures  

48:50where we’re seeing some growth into deficit  just based on the comparison to typical peers  

48:55but in general we’re seeing that most of  these measures seem to be relatively stable   and many of the tools that we’re using are  potential uh tools that we can be using in  

49:05clinical trials because of this stability  and just the the test three tests over time  

49:10um so the the natural history will clarify the  phenotype for us and i think we’ve done a lot   to really better understand that and establish the  prevalence of various features i think we’ve done  

49:20a lot to try to identify targets for therapeutic  interventions and i’ll talk about some of the   tools that we’re using um eventually we hope to be  able to identify demographic genetic environmental  

49:29variables that actually correlate with  disease outcomes the ability to try to predict   who’s at higher risk of regression the ability to  try to predict who’s a higher who is sort of more  

49:41likely to develop a meaningful language all  these things are really critical in terms of   just helping families and helping understand what  the course of illness will be and then we’re also  

49:50focused now on developing better consensus  guidelines to establish both assessments  

49:56monitoring schedules and then of course treatment  at least to the extent that we know about   what works and so we have a big working group now  that’s been developed across many many different  

50:07specialty areas and hope to put out a consensus  guideline um sometime the next six months

50:14okay so that’s the phenotype and then in terms of  the the clinical trial readiness um you know this  

50:19is really where we’re all kind of so challenged  right because i think if we had the best medicine   in the world or even the gene therapy perhaps  we wouldn’t necessarily feel convinced that the  

50:28tools that we have to measure change over  time are especially sensitive or relevant   specifically to film the tournament syndrome  so generally speaking you know you think about  

50:36clinical outcome assessments as either patient  reported caregiver reported clinician reported  

50:41you can combine instruments to create compositive  instruments and then the ideal of course are like   more objective tests so in film with german  syndrome um we don’t have patient reported  

50:50outcomes but we’re still really kind of committed  to trying to figure out um you know how to assess  

50:57treatment benefit right and according to the fda  treatment benefit is really determined by how a   patient survives feels or functions as a result of  treatment and there are so many different symptom  

51:06domains that really profoundly affects these kids  and um and affect their quality of life and so  

51:12we’re really thinking a lot about across virtually  all these these domains whether it’s caregiver   clinician or objective tests to try to target  specific domains and develop but much better  

51:22refined tools that are that are actually  valid specifically to film the german syndrome  

51:28so one of the first things that we did was  actually just took existing tools right so again   this idea of an autism phenotype is important  to us it’s one of the things that unifies  

51:36the um the developmental center top  of these consortium across different   genetic conditions and the srs is a very common  tool it’s used in autism and neurodevelopment  

51:46disorders you know it’s one of the most commonly  used ones it’s also used in some clinical trials   as an outcome measure so we were interested in how  it performed in film and german syndrome because  

51:55we had a suspicion that it was not going to be  especially relevant and in fact it really seems   to have limited utility in general in populations  with severe intellectual disability including phil  

52:05mcdermott syndrome one of the challenges that we  saw was that the majority of respondents endorsed   really the greatest severity of autism  so there was a really pronounced sealing  

52:14effect um this is despite the fact that you know  less than 60 of the kids met criteria for autism  

52:20we found that there was no significant difference  between the srs scores whether you had autism or   didn’t have autism so that was obviously a problem  in terms of this measure um in about i think in  

52:302017 uh sturm developed a 16 item questionnaire  that was a sort of a briefer version of the  

52:35srs but it was supposed to be for people with  individuals with with intellectual disability  

52:40but but still has kind of limited performance in  our in our film german syndrome population so this  

52:47this was kind of what we predicted um it was a  good sort of first pass in terms of assessing  

52:53existing tools um and it was disappointing  although we learned a lot and i think i’ve since  

52:59kind of abandoned this particular measure in in  field major syndrome another domain in addition  

53:05to autism and sort of part part of autism really  is sensory sensitivity and more and more just   based on our clinical experience it seems that  there’s a relatively unique sensory profile  

53:16within feeling of german syndrome at least in  comparison to idiopathic autism so one of the   other things that we did is just took the existing  short sensory profile and did a comparison between  

53:25film and german syndrome and idiopathic autism um  and overall we found that feeling film and german   syndrome kids actually showed less overall sensory  sensitivity and here higher scores are actually  

53:36more typical performance on this measure as  opposed to most measures where higher scores are   worse um but in particular we saw that there was a  kind of a specific subset of the kids who had more  

53:48sort of low energy or weak symptoms or  more kind of in general hypo reactive   and that seems to be pretty specific to film the  german syndrome well not specific necessarily but  

53:57at least compared to autism more broadly um these  kids have a lot more hypo sensitivity in general  

54:04so some of this also led uh our group and paige  cypre in particular was our chief psychologist  

54:10develop a specific sensory assessment for  neurodevelopmental disorders so this is   really the first assessment that’s combining a  clinician administer administered observation with  

54:19a caregiver interview and it’s capturing sensory  sensitivity so if you think about the [ __ ] in  

54:24many ways this is mimicking the [ __ ] play but  but tapping specifically into visual tactile and   auditory sensitivities it’s appropriate for sure  for use in severely affected and minimally verbal  

54:35populations kids with autism show significantly  more sensory reactivity symptoms on the sand  

54:40compared to typically developing kids so we  know that and then again when you look at female   german syndrome in comparison to idiopathic  autism we see that these kids are much more  

54:50prone to hyporeactivity symptoms um compared to  idiopathic autism so this is thought to be now  

54:57a beneficial tool for both research and  potentially for clinical use um it’s now been   licensed and there’s going to be ways to kind of  get trained up on it and use it clinically as well  

55:07um we have a method of trying to test  all of our measures and you know both  

55:15existing measures and measures  that we’re trying to develop   in the context of clinical trials so we  will always be doing sort of pre and post  

55:21um assessments in the context of treatments  one of the things that we did with our our  

55:27igf-1 trials was we did the sand before and after  treatment and we found that actually kids with  

55:32filament german syndrome showed both significant  improvement um in sensory symptoms following 12  

55:38weeks of treatment but but in particular that that  improvement overall was driven by improvement in   the hyper reactivity domain so that was kind of  an important finding for us and has now led to  

55:47a number of brands that have really embedded  this tool in a much more um consistent way

55:54i’m just looking at the time oh i have  five minutes okay maybe i’ll skip this one  

55:59so the other types of measures that we’re  trying to develop use electrophysiology both  

56:05auditory event related potentials but also  visual evoke potential so vps in particular   are a non-invasive technique to evaluate  the functional integrity of visual pathways  

56:14they’re recorded from the occipital scalp in  response to a contrast reversing checkerboard   the major and let’s see if you can see  my oh sorry you can see my my mouse right  

56:26so the major peaks um this n75 peak  reflects glutamatergic activity  

56:31and the p100 reflects the kind of  um subsequent inhibitory response   um so the balance between excitation and  inhibition is reflected in these in this  

56:41waveform this is a very typical waveform of you  know virtually anybody that was that’s typically  

56:47developing and it could be an infant or an adult  but in film and german syndrome what you see is   sort of a massive attenuation of this n75 peak and  then of course also an attenuation of reflexive  

56:58inhibitory peak that’s exactly what you’d predict  based on knowing that the shanks three gene is an   anchoring protein for uh glutamatergic synapses  right and so when you compare people with

57:12typically developing folks to people with  idiopathic autism to film a german syndrome   and even the film determines syndrome siblings  what you see is it is a dramatically reduced um  

57:22n75 peak and so we think about that as a potential  marker to um hopefully predict treatment response  

57:30and then the the the goal is to kind of match that  up with with clinical outcomes specifically around  

57:37the sensory domain um you can do vp’s pre and  post treatment with with drugs that we know act  

57:43as kind of growth factors like igf-1 and here in  particular the results show that improvement in   the active treatment group this is a very small  subset so this is very preliminary data but  

57:53improvements are seen in um the the  beta and the low gamma frequency bands  

57:58um so the thought is that this is potentially an  important measure and it definitely reflects the  

58:04fact that there’s increased excitation  as a result of treatment with igf-1  

58:10i think biomarkers are you know everyone talks  about biomarkers and and they’re ideal because  

58:15they’re objective but they’re only really going  to be i think extremely useful if they’re tied   tightly to sensory or or or clinical symptoms  in general and so here this this shows that  

58:26the kids with film german mcdermott syndrome  show more visual hypo reactivity compared to  

58:32idiopathic autism typically developing kids and  that the extent to which that hyperactivity occurs  

58:38is actually pretty tightly correlated with the  magnitude or the amplitude rather of the of the   excitatory peaks so we do think there’s a nice  relationship between sensory activity the vps  

58:50and we’re showing also relationships between  the um sand here which is our sensory measure  

58:56and the uh the vp response particularly  around the the glutamatergic peaks  

59:02so this just gives you kind of a a little bit  of a sampling of the kind of work that we’re   doing the way that we’re thinking about clinical  trial readiness um there’s you know many other  

59:11groups and and we have a lot of other tools that  we’re testing um but the hope is that you know  

59:18once uh really viable treatments are are available  to test we’ll we’ll be ready with with the  

59:25right kinds of measures and we’ll certainly know  enough about the phenotype in the natural history  

59:30um so the the just to summarize so we obviously  want to be carefully phenotyping these kids and  

59:35that’s i think what we’ve been doing um we’ve  got a number of target symptoms of interest   that we think have really important impacts  on quality of life and clearly reflect the  

59:44phenotype um establish the natural history  which is an ongoing project and and we’re   starting to learn more and more um we want to  refine existing clinical outcome assessments  

59:54and we want to develop some new new tools and of  course we have to develop and validate biomarkers   both as sort of a stratification tool but also  hopefully as a way to predict treatment response  

1:00:05and this is our team this is this is  way back when we were able to actually  

1:00:10meet together in real life i guess i’m happy to  take any questions i got it exactly in 20 minutes  

1:00:19nailed it i don’t know if we have a ton of time  for questions unfortunately but i’m so grateful   for daryl dean for inviting you to this because i  know charlene and i are looking at this salivating  

1:00:30and you know thinking about when we’ll be able  to see such rich data and even you know dreaming  

1:00:35about being a part of the dsc for stx bb1 and  zynga thank you so much i have i have questions  

1:00:42but i an interest time and out of respect for the  next speaker who’ll be talking about uh tank three  

1:00:47and singapore i’m going to keep this going so much  doctor focus on um our next speaker is dr connie  

1:00:52smith picks from johns hopkins the kennedy krieger  institute um i can’t say enough nice things about  

1:00:58her but in the interest of time i will just let  her wow you herself dr smith hicks take it away  

1:01:05and thank you for being here and i will brag that  she is on our sab you get the privilege of her

1:01:12where are you connie okay hi everyone  can you see my slides yep okay wonderful  

1:01:20all right so thanks mike and the organizers  for inviting me so i’m going to talk about  

1:01:27sleep and synaptopathies um and  i’m gonna briefly just talk about  

1:01:34uh an overview of syneptopathies and then  why we chose to study study sleep with some  

1:01:42focus on some of our work looking  at sleep in philadelphia and SYNGAP1

1:01:52then i’ll end with a little summary and some next  steps and perhaps some thoughts about limitations  

1:01:58of the work that we have done so far so um  you know when we think of synaptopathies we’re  

1:02:05thinking about disorders of the  nervous system in general but it can  

1:02:10certainly be a consequence of uh dysfunction  at the synapse both peripherally or centrally  

1:02:17but for the purposes of this talk i’m really going  to be thinking about what occurs centrally meaning  

1:02:23in the central nervous system so there’s there’s  been a significant increase in the number of genes  

1:02:30that have been linked to NDD and currently they’re  thought to be over 2000 genes that have been  

1:02:37associated with neurodevelopmental disabilities  many of them function at the level of the synapse  

1:02:46both pre-synaptic and postsynaptic um but the the  schematic uh here features uh three genes that  

1:02:55are being discussed today so STXBP1 uh shank and  uh SYNGAP1 and what you’ll notice is that STXBP1  

1:03:06primarily functions in the presynaptic compartment  whereas shank and Syngap primarily function  

1:03:13in the postsynaptic compartment and schengen  syngap are involved in synaptic plasticity  

1:03:21mechanisms whereas STXBP1 is primarily  involved in release of neurotransmitters

1:03:32so we know a lot about the clinical features um  of all three disorders just in in general we know  

1:03:40that they are certainly associated with a complex  clinical phenotype that will include global  

1:03:48developmental delay intellectual disability autism  and epilepsy um and we know that sleep is a common  

1:03:57feature in many neurodevelopmental disabilities  in individuals with SYNGAP1 it’s reported to  

1:04:06occur in about 62 percent of individuals and then  in individuals with feeling my dermot in anywhere  

1:04:13between 25 and 50 percent of individuals and i  think from the previous speaker slide i think  

1:04:20we had probably 62 percent if if i recall or 56  if i recall now although sleep difficulties are  

1:04:29reported in patients with intractable epilepsy and  we see uh significant epilepsy in individuals with  

1:04:38sdx bp1 the prevalence of sleep disturbance  in that population is not entirely clear

1:04:46so the the focus of our conversation is really  going to be related to shank and SYNGAP1 so why  

1:04:56steady sleep well you know it’s it certainly is an  area of on that need and uh we know that sleep is  

1:05:06critical and good quality sleep is critical  for many physiologic functions it supports  

1:05:13neurogenesis plasticity brain development and  behavioral function and any parent of a child  

1:05:21will tell you that poor sleep negatively  impacts behavior and there’s this bidirectional  

1:05:28association between sleep and mood  and certainly sleep and cognition

1:05:35thus uh poor sleep not only impacts the  child but also impacts the caregiver  

1:05:44sleep is not just a common problem in  neurodevelopmental disabilities but it is pretty  

1:05:51prevalent in the general pediatric population  and approximately 25 percent so one in four  

1:05:57children who are otherwise typically developed  have sleep problems and depending on the  

1:06:05the nature of the neurodevelopmental  disabilities the prevalence of sleep   can be anywhere between 50 and 95 percent  uh sleep difficulties may manifest either  

1:06:16with difficult difficulty with  sleep onset sleep maintenance  

1:06:23problems with having increased daytime sleepiness  or breathing challenges occurring during sleep

1:06:33so work from several groups in preclinical models  of shank shows that the shank protein is involved  

1:06:45a circadian rhythm of and these  studies are actually done in rodents  

1:06:53um but the synaptic level of shank protein  varies over the course of the day and  

1:07:02the the changes uh correlate with changes in  serum melatonin now mice lacking exon 21 in  

1:07:12shank 3 are shown to have less sleep during  the dark period dark period and this disruption  

1:07:23in shank 3 expression is also correlated with  um disruption in expression of many of the genes  

1:07:32that regulate the circadian rhythm so based  on this we know that shank 3 is important  

1:07:40for the regulation of sleep and um just a note i  want to make the exon 21 in shank 3 is actually  

1:07:50one of the hot spots for many of the pathogenic  variants that are seen in individuals with pmd

1:07:59like shank 3 syngap1 is also an important  regulator of sleep and syngap1 is expressed  

1:08:08in the suprachiasmatic nucleus which is the brain  circadian clock its levels vary over the course  

1:08:17of a day um and the indiv in rodent models  that are haploid insufficient force in gabon  

1:08:25have increased activity during the dark  phase relative to wild type mice so  

1:08:36why why did we compare sleep in singapore  and philly mcdermott well we opted  

1:08:43to look at these two disorders because one  they have a shared clinical features and their  

1:08:50genes converge on shared molecular pathways and  share and have shared physiologic consequences

1:08:58we studied sleep in this population and  the the patients were recruited from three  

1:09:05sites two in the u.s and one in the uk we  recruited patients with singapoand felimit dermot  

1:09:15and typical developed siblings we took all comers  from as young as uh three years old uh up on up  

1:09:27what we noted was that there was no  significant difference in the number   of males versus females for either of the  three groups that were included in this study

1:09:39i shared earlier that sleep is a common  problem in both singaporean and filament  

1:09:45derma then so it’s not surprising  that many of the patients were

1:09:52taking at least one medication that is routinely  used to treat sleep you can see that melatonin is  

1:09:59by far the most common medication  that’s used in both groups of patients  

1:10:08we used the child the children’s sleep habit  questionnaire to evaluate the sleep profile this  

1:10:16is a parent reported a screening measure and it  evaluates um uh behavior or sleep um difficulties  

1:10:27that are both behaviorally mediated as well as  medically mediated the cshq has been validated  

1:10:37in kids between age 4 and 10 but it’s been  used in children younger and children older  

1:10:46and a total score total score that  is greater than or equal to 41  

1:10:53suggests um clinical significance of uh  disrupted sleep not only do we look at the  

1:11:00total score but we are also able to parse  um sleep features along eight uh subscales  

1:11:09looking at certainly uh resistance to going to  sleep delayed sleep onset how long the child  

1:11:15remains asleep anxiety parasomnias and breathing  related difficulties as well as daytime sleepiness

1:11:27so using the cshq we first asked  is there a difference in the total  

1:11:34score and then the sub sales scores between  all three groups and we show that individuals  

1:11:42with SYNGAP1 and individuals with filimide dermoth  both had more severe sleep problems when compared  

1:11:52to their typical developed siblings however  individuals with singapoand had more sleep  

1:11:59difficulties than those with filament derma and  that’s indicated by the higher total mean score

1:12:10this difference between philly mcdermott  and singapoand seems to be driven primarily  

1:12:18by differences both in bedtime  resistance and a difference in daytime  

1:12:25sleepiness where you see that SYNGAP1  individuals had higher scores on both  

1:12:33we also noted that nighttime awakenings  parasomnias sleep disordered breathing and  

1:12:42sleep duration were common problems in both  singaporean and philo mcdermott individuals

1:12:53because there is in general thought to be  an age difference in the manifestation of  

1:13:00sleep difficulties we divided our our  cohorts in those who were younger than  

1:13:07age 11 and those who were older than  age 11 and another motivation for   doing that is again because the cshq was  validated in those younger than age 11. so  

1:13:22we asked you know is is uh sleep difficulties  in uh these disorders age dependent and so um we  

1:13:31looked at this pattern and we can see again that  uh individuals with uh SYNGAP1 had a higher total  

1:13:40sleep score so i’m a worse sleep profile than  individuals with uh feeling like dermot and we  

1:13:47we saw that pattern um in those who were younger  um than than 11 years of age so those who were  

1:13:54prepubescent and that’s consistent with what  we saw when we looked at the larger group

1:14:03we also see that the the difference in is the the  difference between these two groups is driven in  

1:14:14this case by sleep anxiety and also by daytime  sleepiness and the difference in parasomnias  

1:14:25between individuals with SYNGAP1 and siblings as  compared to philip mcdermott and siblings were

1:14:37there was no difference between those with uh  up syngap1 and those with PMD and both disorders  

1:14:44um had a more increased severity of parasomnias  as compared to typical developed siblings

1:14:54we um then ask well what is the profile of sleep  differences that we see in the the older groups um  

1:15:05we can appreciate immediately that um there  was a severity of uh sleep uh challenges  

1:15:15in both singaporean and filament derma  when compared to typical developed siblings  

1:15:21in many of uh the sleep  subscales and that there was no  

1:15:29significant differences between um individuals  with older individuals with SYNGAP1 and a pmd  

1:15:39so um in in summary we see that sleep  is a common problem in NDDs in general  

1:15:47uh both the shank 3 and the SYNGAP1 protein  are important regulators of of sleep  

1:15:55we see from our data that there is uh  greater sleep difficulties in individuals  

1:16:01rising gap one when we compare them to  those with filament philadelphia then we  

1:16:07believe that this is dependent on age so the  younger Syngap kids have more sleep difficulties  

1:16:12compared to younger individuals with shank  three whereas the older individuals with  

1:16:19pmds seem to have more sleep difficulties  than their uh the the younger individuals  

1:16:28parasomnias nighttime awakening and  disordered breathing are common features   i think you know this uh data suggests that  both the total and subscale scores in the cshq  

1:16:40uh can be useful measure for evaluating sleep  i think that it’ll be important for us to look  

1:16:50at the the utility of this and natural  history study and what it tells us   about the sleep profile over time for populations  uh with SYNGAP1 or other synaptopathies  

1:17:06one of the questions we we often wonder about is  how does the chsq or any other measure that we use  

1:17:14how does that change over time when we think about  uh treatments um and that’s something that we  

1:17:22are looking into i mean we generally put  many of our patients on medications that  

1:17:29treat sleep and so this would be an easy thing  to do at least in the clinics so i want to  

1:17:37stop here and acknowledge certainly the families  and and children of SYNGAP1 uh and shank 3 the  

1:17:45parent advocacy foundations the work was done  in collaboration with jimmy’s group in texas  

1:17:51and Andy’s group in the university of  Edinburgh and certainly all our funding  

1:17:57organizations so i think i have um  probably two minutes for questions

1:18:12okay um and i see a question here in the q a that  says do you see a wearable tracker as being a way  

1:18:18to follow sleep habits over time um absolutely um  that’s actually one thing that we are embarking on  

1:18:26and we’re in the process of analyzing that data  i think um wearable tracker we may be able to  

1:18:32correlate um uh activity and uh uh delayed uh  sleep onset or latency just to falling asleep  

1:18:44with the cshq um some of the other measures i  think that might be challenging but yeah that  

1:18:49is something that we are we and others are are  doing and we just don’t have the data yet to share

1:19:03okay and um you think that sleep  could improve with treatments  

1:19:12um so absolutely uh oh genetic treatment so do  you think that sleep could improve with genetic  

1:19:19treatments um absolutely i think you know if  we are there there are many approaches that are  

1:19:29being proposed for um genetic treatments  whether it’s antisense olga nucleotides  

1:19:37or other modalities whether it’s read through or  many other approaches and if we are able to get  

1:19:49targets uh parts of the brain that uh certainly  are involved in in regulating sleep um then it  

1:19:57would be my expectation that uh sleep we should  be able to improve sleep and sleep generally in  

1:20:03my opinion at least is is a low hanging fruit  it’s one of the things that we are able to  

1:20:10um treat to some degree in many of our  patients i i wonder in in the data that  

1:20:20we showed you may might have noticed that uh  um the sleep onset delay was there was a lower  

1:20:31score subscale score although significant when  compared to typical developed peers but i wonder  

1:20:40if that lower subscale score and consequently  less impairment in the late sleep onset  

1:20:47is related to the fact that many of these kids are  on medications that um their their role is to um  

1:20:57uh to increase uh sleep so um targets uh  delayed sleep on sets and so i wonder if  

1:21:07we are being effective in in uh in shortening the  latency to falling asleep in many of the patients  

1:21:17with the with the current medications we use um  my expectation is that a targeting sleep will  

1:21:24improve um behaviors uh will it be a cure i i  don’t think so but it’ll be one of the the um  

1:21:35the treatment interventions that we would likely  employ in in as we think about how we uh treat  

1:21:45uh patients with synthetic one shank  three sdbx uh s txbp1 and other  

1:21:53similar disorders thank you so much dr smith hicks  um sleep i’m glad to hear you say low hanging  

1:22:00fruit i hope that will be the case it’s obviously  something that can really impact quality of life  

1:22:05i am delighted to introduce dr chung she is a  clinical and molecular genetics geneticist at  

1:22:12columbia university she’s one of the world’s  experts in the genetic basis of human diseases  

1:22:18she’s also the director of clinical  research at simon’s foundation   autism research initiative she’s the pi of  spark and simon searchlight which both aim to  

1:22:29understand genetic neurodevelopmental conditions  thank you so much for joining us dr chung thanks  

1:22:35geraldine i’m really thrilled to be here let  me see if i can share my screen the right way

1:22:45and hopefully you can see everything so i’m  very pleased to be here and i’m gonna show you  

1:22:51hopefully some data that i hope many people can  use and always looking for input on how we can do   better um this is part of the umbrella program  that i’m calling simon searchlight although as  

1:23:02geraldine said uh we also sponsor spark which  is a study that i think of as feeding into simon  

1:23:08searchlight so simon searchlight is predicated on  the fact that individuals with neurodevelopmental  

1:23:14disorders are clearly not the same and we  can start to understand better and we must   in terms of getting to treatment subdivide by  genetic basis and but also realize that as we  

1:23:24subdivide we can see synergies and obviously  the cenotaphies are a great example of that  

1:23:30this is just showing you the current genes and  copy number variants that we include within   simon searchlight to say that the knowledge  is still increasing in terms of the genes  

1:23:39that are involved and so we continue to expand our  genetic conditions that are concluded within that  

1:23:45and i’ll also point out we continue to iterate in  terms of inclusiveness and one of the things we’ve  

1:23:51been doing is increasing the number of languages  that we can collect and distribute data in both  

1:23:57in terms of just online writings as well as the  languages that our research team speaks with this  

1:24:03the goal in terms of simon searchlight is again  to be able to make for participants ie families  

1:24:10make it relatively easy to participate and make  it scalable in terms of the distribution of the  

1:24:15information so that we can all learn faster and  as we’re doing this i’ll show you some dimensions  

1:24:22we’ve been thinking especially about how to get  more resources than just data to researchers and  

1:24:28i’ll get into some of the specifics of that but  i can really feel a shift in terms of the impact  

1:24:33that’s having on the fields as we’re doing this  the the low hanging fruit so to speak or to be  

1:24:38able to get online data um the reason we’ve done  that some of you know that as we started this out   as something we called simon’s vip at the time it  was more burdensome on families we had them come  

1:24:48in person do a couple days in terms of evaluation  we still have those data freely available to   researchers but we realized that we couldn’t  include as many people due to travel restrictions  

1:24:58especially with covid the online community  afforded us much more flexibility to understand  

1:25:03in real time how covid was impacting our community  as well as being able to continue data collection  

1:25:10so as we’ve done that number one we collect the  data online as well as with genetic counselors who  

1:25:15review and uh be able to really i think help us  in terms of getting really clean robust valid data  

1:25:22having genetic test results from families  that we can validate their diagnosis sharing   that information back with families and community  groups as well as making that freely available to  

1:25:32researchers around the world and as we’re doing  this as i said we hope that this is partially  

1:25:37powering readiness for clinical trials as well as  being able to power the researchers who are going  

1:25:44to develop those understandings of basic mechanism  as well as some of those treatments this is just  

1:25:49an example of the online measures that we have  or in the medical history interviews that we do  

1:25:56the point or one point to this is that this is not  one and done but this is longitudinal appreciating  

1:26:01that things change over the life course challenges  changes people evolve and so we continue to  

1:26:07collect data as individuals are changing over that  life course both from a medical point of view as  

1:26:12well as a developmental point of view again i’ll  show it at the end but all of these data freely  

1:26:17available as we’re doing it we want to make sure  that this is as i said available to researchers  

1:26:24but also that this is more short-term affecting  clinical care in clinical guidelines and one  

1:26:31relatively easy way to do that we found is through  gene reviews being able to that’s for those of  

1:26:36you who don’t know it’s an online resource again  open access formatted in a consistent way where a  

1:26:42busy practitioner can be able to log in for the  gene of interest and find um sort of clinical  

1:26:48care what they should be doing in terms of health  surveillance or interventions and again something   that we as genetic professionals continue to  update we take that as a serious responsibility  

1:27:00so that’s something that we’ve powered many of  our searchlight genes to be able to enable gene   reviews i and my teams have done some of those  reviews but many others in the community have done  

1:27:09that as well and then also making sure the variant  level data is in clinvar so again it’s without any  

1:27:14identifiers in terms of participant identifiers  but making sure that diagnostic laboratories  

1:27:20have free access to the information so that more  individuals get correctly diagnosed as they’re  

1:27:26going through diagnostic testing i will say all of  this in the very careful curation of those genetic  

1:27:31test results we found to be incredibly valuable  although about 90 percent of the individuals who  

1:27:38come into the searchlight portal once we review  their genetic test results about 90 percent of  

1:27:44them in fact have the right diagnosis but they’re  a good 10 where that’s not definitive based on the  

1:27:49testing we’ve had so far one of the other things  searchlight does is to actually pay on our dime  

1:27:55for the genetic testing for instance of parents  if they have not been part of that genetic testing   process to make sure that we know whether this was  an inherited or de novo variant that also helps in  

1:28:05terms of interpretation of that variant as well  as getting additional information on additional   people that may be valuable and again that’s  value added in terms of what searchlight can do  

1:28:15all of these data available again the url is  right here in terms of safari base we have  

1:28:21incredible data navigators to also be able to  help researchers understand the data in addition  

1:28:26to data release notes and data dictionaries  but this is regarding specific clinical data  

1:28:32as i said genetic data but also importantly  biospecimens so whether they’re dna samples  

1:28:37induced blur potential lines other types of cell  lines making sure that’s available and importantly  

1:28:44an opportunity that we have called research match  so this is an opportunity for us to be able to  

1:28:50advertise to the community by gene or by groups  of genes research studies that are irb approved  

1:28:57through investigators around the world to invite  them to be part of their research whether it’s   online whether it’s in person but be able to match  those researchers with individuals in those gene  

1:29:07communities and that’s been i think is going  to continue to be a very effective way to allow  

1:29:12families to participate not just in searchlight  of course but much farther um this has been  

1:29:17an important resource that we’ve been creating  induced plural potential stem cells i’m listing  

1:29:22here and showing some of the conditions that  we’ve added recently in green the new cell lines  

1:29:29these are all done again at the expense of the  simons foundation and freely available both to  

1:29:34basic science researchers in universities as well  as in commercial settings within this in some  

1:29:41cases we have uh co-isogenic corrected lines  so that i think they have both good controls  

1:29:47as well as allelic spectrum so that we have many  different variants within the same gene so that if   there are any allele specific either differences  in mechanism or differences in severity those can  

1:29:58in fact be studied by researchers so again all  of these freely available we’ve had a call out  

1:30:03to the community to vote democratically on what  lines are necessary or helpful to the community   and always looking again for feedback if there are  lines that we don’t yet have established um within  

1:30:13this i started to describe but this research match  opportunity is something that’s always ongoing and  

1:30:18active and so this is something again that we can  take literally as studies are ready whether these  

1:30:25are clinical trials or survey-based studies or  looking for clinical readiness or a particular   measure whether it be sleep or something else to  help you with your studies and again to be able to  

1:30:34do it across conditions which might be helpful in  terms of looking across synaptopathies or synaptes  

1:30:41birthers other types of genes data sharing really  is something we believe very very strongly and  

1:30:47again we just be clear this is all de-identified  individuals we try and make sure that they are in  

1:30:54fact qualified researchers by requiring a research  distribution agreement which says that they agree  

1:30:59not to try and identify individuals within these  studies and as we do this organically it grows  

1:31:04so that data for instance from research  match studies organically comes back into   safari base so participants don’t have to keep  answering the same questions over and over again  

1:31:13but can be able to do something once and and have  many many people be able to benefit from that  

1:31:19as we’re doing this we do try and cooperate  with other groups that are also collecting data   in particular citizen for instance has been  focusing a lot on ehr data being able to work  

1:31:28together so that we can increase the power of all  of the different data sources that are available  

1:31:34um with this as i was saying one of the advantages  perhaps compared to some registries that might be  

1:31:41individually focused on a gene or a group of genes  is there are important differences that at least  

1:31:47i’ve noticed in comparing across our different  conditions individuals for instance who may be  

1:31:52wanting to explore a particular phenotype it’s  very easy to be able to look across genes and  

1:31:58be able to see what are the particular genetic  conditions that might be associated with either  

1:32:03very little of a particular symptom or a lot a  high frequency of that symptom and that might   be useful in terms of comparison across those  to understand that biology or behavior better  

1:32:14in particular for the synaptopathies as we’re  talking about we do have very very rich data   collections on some of these groups i give  a lot of credit to the family group leaders  

1:32:24it’s in large part because of their efforts to  rally the troops and to emphasize the importance   of research to their communities and i won’t go  through exactly all of the numbers of individuals  

1:32:35as of today but we do have large data sets for all  of the ones that i’ve boxed and shown and might be  

1:32:40of interest to the group here in particular and  not surprisingly uh these are all of them are  

1:32:46associated with neurodevelopmental conditions but  in particular if we look at some of the major uh  

1:32:52sort of conditions that we see everyone has  some degree of cognitive neurodevelopmental   issues most have issues with epilepsy or seizures  and autism or asd on the left is seen in a large  

1:33:05number but certainly not everyone and i want to  be clear that although safari i think is known  

1:33:10for being an autism uh sort of umbrella in terms  of the research this is really a genetics first  

1:33:16approach in which clearly not everyone within  these genetic groups has autism nor are we solely  

1:33:22interested in autism as a manifestation so in  fact we fund many researchers who study these  

1:33:27conditions not solely for the purpose of autism  but for epilepsy or other behavioral issues  

1:33:33the types of things we give back to family or  these research snapshots that i’m showing you here  

1:33:38we try and do this as regularly as we can  and especially as we have no data releases  

1:33:43so you can see for instance with STXBP1  in the last data release we had of 68   individuals or SYNGAP1 with 31 individuals  being able to see the types of things  

1:33:53the types of distributions of frequency of  manifestations that we see and again we hope   that this information is valuable to families  and we’ll continue to enrich it as we think  

1:34:02about the numbers increasing responses to certain  medications or problems with certain medications  

1:34:08but deeper detail that we often hear families  wanting to have answers to um within this we see  

1:34:13many different manifestations beyond what i just  said um some that are more observable directly by  

1:34:19a clinical observation and so getting increasingly  deep in terms of some of those assessments  

1:34:25but again being able to see some things  that are common features across many of   the synaptopathies and in fact across many of  the neurodevelopmental conditions that we study  

1:34:34um so with that the other thing that i’ll say is  that this last year some of the investigators know  

1:34:39we had an a request for applications or an rfa  at safari that was specifically giving funding  

1:34:47opportunities to investigators not solely to  use simon searchlight data but to be able to go  

1:34:52deep in particular it was genetically focused so  to go deep in terms of understanding mechanism  

1:34:58but importantly driving us closer to therapeutics  and so i think we’ve just been able to finish the  

1:35:04review of those uh rfa or those grant submissions  and in fact awarded those applications out and  

1:35:10i’m very excited to see um that we are i think  going to be able to give significant amounts of  

1:35:16dollars at the simons foundation i think based  on the success this last year we’re thinking   this is going to be something to continue doing  to be able to catalyze on the therapeutic side  

1:35:26but specifically for the conditions that we have  under searchlight so i hope as a brief summary um  

1:35:32this again is something in terms of what might be  a resource available from the simons foundation  

1:35:37again the url to be able to get any of the cell  lines or any of the data that we have here we have  

1:35:44scientists on the safari team that can help you  in terms of again any taking requests for anything  

1:35:50else that you’d like to see that we don’t already  have as well as rfas that we have throughout the  

1:35:55year for funding for any of these programs so i’ll  stop there but uh thanks again for including me

1:36:05thank you so much dr chung it’s it’s a real  honor to have you in this event um we have a  

1:36:11couple minutes for questions like dr smith hicks  you’ve actually left some time which is amazing   um if until questions roll in i just want to  say that srf i’m sure my colleagues at stx pp1  

1:36:25and shank3 we do encourage our patients to take  part in simon’s searchlight and i’m particularly   thrilled to know that through partnership  with your incredible team jennifer and others  

1:36:35we have also been working on getting a  connection with citizen who’s going to talk next   so hopefully we’ll be able to get our community  taking advantage of both of citizens medical  

1:36:45records and of all the incredible investment that  simon’s does it just i just can’t say enough i’m   so grateful and honored to have you here um if  there are no questions about wait here they come

1:36:57so the first question in terms of a significant  reason why singapore has half the pool of patients   in safari base is the other genetic difficulty  it’s uh we support everyone so we’re not filtering  

1:37:09anyone it’s simply who volunteers so if anyone  would like to get the word out certainly we   encourage you to and we continue to expand in  terms of capacity based on how many families we  

1:37:18have so you keep them coming and i promise we’ll  keep up with you so i’ll give you that challenge  

1:37:24um and then do we have resources for families  as far as understanding their disorder genetics  

1:37:30biology the answer is yes absolutely so we support  uh family meetings both online uh has been during  

1:37:37covet times but also in person oftentimes  we’ll have sessions like genetics 101 or  

1:37:42we’ve had sessions that i’ve done about gene and  cell therapy and how to be able to understand that   so there are lots of resources and we’ve  recorded all of these so they’re enduring  

1:37:51resources that can be available to families  asynchronously anytime and especially i did   that because i know families are newly diagnosed  every day and we want them to get that information  

1:38:00right away when they’re in that state of panic  and trying to learn as much as they can so we   can certainly follow up but they’re scattered  in a few different places but youtube is an easy  

1:38:10way to find a lot of the information content and  we’re happy to share that as a resource afterwards

1:38:17and i will also say fat breeland because you’re  one of ours um we are working to correct that  

1:38:22there are incredible opportunities for the  simon’s foundation like the cell lines and i   will also mention that simon’s foundation supports  autism brain net who srf is a proud partner of i  

1:38:32know it’s a horrible thing to think about but  we encourage our families to consider donating   their loved ones brains after they pass hopefully  we don’t have to face that for a while but it’s  

1:38:40important for research so simon’s just does so  much and we want to see our patients in that and   hopefully by building this bridge of citizens  who will hear from next and simon searchlight  

1:38:48will be able to up those numbers and really take  advantage of the generosity of that foundation  

1:38:54mike just one more since you mentioned  autism brain net an unabashed advertisement   if any of you can get the word out to scientists  we will be having uh or actually just released a  

1:39:03request for applications for scientists to  use the resource from autism brain net so  

1:39:08again we’re not just creating those resources  but we’re giving funds to scientists to do   the science so please encourage them to apply  we’d love to have them use it for your groups  

1:39:18absolutely thank you um with that i  will go from one of the giants in uh  

1:39:26genetics and registries to somebody i humbly think  is one of the future giants one of my favorite sav  

1:39:33members ellie brimble from citizen is just one of  my favorite people and i will let her talk about  

1:39:40citizen and thank her in advance for all of her  good work for all of our kids go ahead ellie oh  

1:39:45well thank you for that very kind introduction um  let me get set up can everyone see the slides okay  

1:39:57yep perfect um so thank you very kindly for  the introduction and for inviting me to speak  

1:40:04with you today i’m going to be sharing some  information on behalf of citizen which is  

1:40:10now part of the larger in vitae family and so  to start off with an introduction to citizen  

1:40:19this is a patient-mediated platform  so patient-centric patient-focused  

1:40:24and it really allows participants to  collect and store their medical records  

1:40:29and then what we do with those medical records  once they’ve been collected is transform those  

1:40:34into research-ready data sets so the goal is to  make these computable digital and relevant so  

1:40:41that they can be shared at the user’s discretion  in order to support research and clinical programs

1:40:50the fda has recently come out with guidance  around the collection of real world data and   so we’ve worked to ensure that the way we approach  data collection is consistent and of high quality  

1:41:02and one of the ways that we’ve sought to  approach this is by taking a framework that  

1:41:07includes two different levels so our topmost  level we refer to as the disease model which  

1:41:14essentially serves as the conceptual foundation  for the data products on the citizen platform  

1:41:20and so what the model is doing is it’s defining  in advance what types of data is extracted  

1:41:26ensuring that information is relevant and  important to the conditions on the platform  

1:41:32and then it also establishes relationships between  those different types of data so rather than just  

1:41:38having kind of a linear outline of various  symptoms and procedures and interventions  

1:41:45we’re able to create a network of information  describing how things are connected to one another  

1:41:51within the disease model we have also built out  a manually curated ontology and the intention  

1:41:59of the ontology is to be able to harmonize and  normalize the information that’s collected so we  

1:42:04can essentially think of this as a really large  data dictionary ensuring that each term or each  

1:42:11piece of data that we collect from medical records  is assigned a standard way to talk about it  

1:42:18so we all know that many of the many individuals  who have a rare diagnosis are followed by many  

1:42:24different providers and so what this allows is  even if providers and doctors are talking about  

1:42:30the same types of symptoms in different ways  we’re able to normalize across that variation

1:42:38we’ve been incredibly lucky to work with some   fantastic organizations including  two that are represented here today  

1:42:46and so what i wanted to take an opportunity to do  was share some of the data that we’ve collected  

1:42:52in order to encourage collaboration and further  use of this data so by the end of the year we  

1:42:58expect to have complete data for 70 individuals  with stx bp1 and 105 individuals with syngap1

1:43:10in order to illustrate the range of data  that we collect from longitudinal medical  

1:43:16records um we’ve randomly selected  50 individuals from each cohort  

1:43:21and i’m going to be sharing some  data with you for those individuals

1:43:28to start with here are some characteristics of  the 100 participants and spread across stx bp1  

1:43:36and on the left hand side here we’re looking  at the distribution of males and females  

1:43:42and so we can see that it’s a roughly equal  distribution for both populations and then these  

1:43:48um two graphs here are showing the distribution of  age whether that’s age today or age at diagnosis  

1:43:57and so we did not see any significant difference  between the two cohorts in terms of age today  

1:44:02or at age of diagnosis and we can see the  averages here are relatively close to each other

1:44:11one of the things we pride ourselves on at citizen  is our somewhat ruthless approach to collecting  

1:44:17medical records we do our best to ensure that  we are fully capturing the patient’s interaction  

1:44:25with the health care system whether that’s at  one institution or at multiple institutions  

1:44:30and so i wanted to share some information  around the medical records that we collect   to give you a sense of the breadth and scope of  data so comparing stx bp1 to syngap when we look  

1:44:43at the number of institutions that we’ve  collected medical records from for syngap  

1:44:49this is about six institutions oh my apologies  for stx bp1 this is about six institutions  

1:44:55and for sin gap it’s about five but you can  see that it ranges all the way up to 17 or 18.  

1:45:03in terms of the number of individual documents so  these represent individual clinic notes imaging  

1:45:10reports labs lab reports for stx bp1 we were  looking at an average of 212 documents per patient  

1:45:19corresponding with about 750 pages and for  syngap it was slightly less about 175 documents  

1:45:29corresponding with approximately 650 pages of  information but again you can see that there  

1:45:35is a wide range of volume of data in many cases  dependent on the presentation of the individual

1:45:46so as i mentioned in our introduction slides  we have a disease model which defines different  

1:45:53types of information that we collect and one  of the broader categories of data we refer  

1:45:59to as clinical diagnosis but it’s really meant to  capture any diagnoses phenotypes signs or symptoms  

1:46:06that a patient may experience and so one of the  exercises that we did to get a sense more broadly  

1:46:15for the diagnoses of individuals with either stx  bp1 or syngap is we took those unique diagnoses  

1:46:24and mapped those back to a broader organ  system and this is one of the benefits of   using a standard terminology which allows that  propagation um in a somewhat automated fashion  

1:46:36and so what i’m showing you in the graph  here in the light green color we see stxpp1  

1:46:43and then in this tealy bluey greeny color we see  syngap and we’re showing the number of unique  

1:46:50diagnoses mapped to each organ system across  those cohorts so for example looking at the  

1:46:57neurology bars at the very top of the graph  we see that there were 408 unique diagnoses  

1:47:03spread across the or counted across the population  compared to 327 in syngap and so unsurprisingly  

1:47:14we see that some of the more commonly affected  organ systems or broader categories of systems are  

1:47:22neurology neuropsych which we’ve included some  behavioral diagnoses as well musculoskeletal  

1:47:29gi and eye and so this is certainly consistent  with what’s been presented here today as well  

1:47:37we can also dive in so you know first we talked  about diagnoses more broadly but we can also  

1:47:43narrow in to focus on more specific diagnoses  and so here i’ve pulled some diagnoses that  

1:47:49are relevant to either one or the other or both  of the conditions presented here today and so  

1:47:56we can look here at the frequency of epilepsy  any developmental and epileptic encephalopathy  

1:48:03any movement disorder phenotype and autism  diagnosis or behavioral challenges and so  

1:48:09already here we can start to see some differences  in the phenotypic spectrum of these two conditions  

1:48:16so when stxbp1 we see that we’re observing  a higher frequency of developmental and  

1:48:22epileptic encephalopathies as well as  movement disorder whereas looking at  

1:48:27syngap there appears to be a higher frequency  of autism diagnoses and behavioral challenges  

1:48:34so we can certainly do this across the full  spectrum of diagnoses that are extracted   to start to tease apart some unique  differences between various conditions

1:48:46one of the important um approaches to data  extraction that we take is every unique data  

1:48:52point is assigned a date and so this allows us to  characterize the phenotype across an individual’s  

1:48:59lifespan and so one way i wanted to highlight that  today was to talk about the presenting diagnosis  

1:49:05or symptom in both stxbp1 and syngap1 and so when  we look at stxbp1 we can see that there is um  

1:49:17kind of a very striking presentation  where epilepsy is certainly the most  

1:49:22common presenting feature whereas comparing that  to syngap we see a little bit more variability  

1:49:28in what might be the presenting symptom but  we do see a spectrum here with some overlap  

1:49:34where epilepsy and seizures delays and  hypotonia are common amongst the two conditions  

1:49:42whereas syngap we see reflux as one of the  more common presenting features as well as   feeding difficulty with plagiocephaly  and respiratory distress in the stxbp1

1:49:57we also looked to see whether there were  any differences between the age at onset  

1:50:02so how old were individuals when they were  first reported to have a diagnosis or symptom  

1:50:08and we do see that individuals with stxpp1 present  significantly earlier than those with syngap1  

1:50:16for an average of 5.2 months  compared to 11.1 months

1:50:23i also wanted to look to see whether  there were any differences in the time   to diagnosis so what this graph is showing us  is based on when the patient first presented  

1:50:34how many months did it then take  for them to achieve their diagnosis   of either stxvp1 or syngap1 and so we didn’t  see any significant differences between the two  

1:50:45with the average time to diagnosis for an  individual with syngap at 60 months and then  

1:50:51the average diet the average time to diagnosis for  an individual with stx bp1 was around 59 months

1:51:01i wanted to get a sense of whether the specific  presenting diagnosis impacted that duration and  

1:51:07so we broke the presenting features out into  epilepsy versus all other diagnoses and while  

1:51:15we do see that it appears those with epilepsy  did achieve diagnosis earlier than those  

1:51:22where the presenting symptom was not epilepsy  this didn’t achieve statistical significance

1:51:31we can also dig into specific phenotypes so  we know for both syngap1 and stxbpp1 that  

1:51:39epilepsy and seizures are an important  clinical endpoint to characterize   and so looking at the age of epilepsy onset  we do see a difference in age of onset  

1:51:51so looking at the graph here at the top we  broke out age of epilepsy or seizure onset  

1:51:58into neonatal so presenting within the first month  of life infantile onset presenting in the first  

1:52:05year of life and then childhood onset which would  be after the first year of life and we can see  

1:52:12that there is a striking difference between stxp  p1 and syngap where the majority of individuals  

1:52:18with stxpp1 have seizure onset within the first  year of life whereas this is really a minority  

1:52:23of patients with syngap1 and epilepsy where we see  that those individuals are presenting in childhood

1:52:34and we can also see that the age of  onset of epilepsy was statistically   different between stx bp1 and syngap  

1:52:42where again we’re seeing that individuals with  stx bp1 have seizure onset much earlier in life

1:52:51we also pull out information related to medication  use and the duration of medication use so here  

1:52:57i’m showing an example specific to anti-seizure  medications and so we’re looking here at the most  

1:53:02commonly tried anti-seizure medications in stx bp1  and syngap and so we can see that there are some  

1:53:12unsurprising names here we have kepra  phenobarbital on fee topo max and acth  

1:53:18and stxbp1 and then for syngap we see kepras  the most common followed by amphi lumityl  

1:53:26valproate and episoximide we also see that  in both cohorts people are trying a lot of  

1:53:34different anti-seizure medications so on  average in sdx bp1 we’re seeing people are  

1:53:40trying around five different anti-seizure  medications ranging from one to sixteen  

1:53:46um and in syngap this is about six different  anti-seizure medications ranging from one to 18.

1:53:56we can also take a look at how long medications  were used so even though some medications may  

1:54:01be tried more frequently we wanted to  try to get a sense of whether or not   some medications were felt to be more effective  than others and one of the ways we wanted to try  

1:54:11to approximate that was by looking at the  duration the patient was on that medication  

1:54:17so in these graphs we’re looking at the duration  of medication use normalized to the duration of  

1:54:22epilepsy and we see some differences here so  in sdx bp1 we see a couple new medications  

1:54:30that were not necessarily the most commonly  prescribed but they did appear to be used for a  

1:54:36longer duration compared to the the full number of  different seizure medications that were employed  

1:54:42and the same here with sigep1 and one thing that’s  interesting with syngap is if you’ll recall from  

1:54:48the previous slide kepra or levitharacetam  was the most commonly tried medication  

1:54:54but here we’re seeing that it’s not one of the  medications that was used for the longest duration  

1:55:00so this is an interesting approach that we could  take to try to understand whether or not certain   medications or combinations of medications  are felt to be effective by the treating team

1:55:13and then for the last couple of slides i wanted to  talk about data access one of the themes of this  

1:55:18meeting today is collaboration so we certainly  want to make sure that those interested in  

1:55:25these conditions know how to access the data we’re  collecting so all of the citizen data collected is  

1:55:32done so under a broad consent which has received  a determination of exemption through category 7.  

1:55:38and so in order to access citizen data to support  academic research we simply require the following  

1:55:45a study protocol outlining the  use of citizen data that has   achieved a determination of exemption through  category 8 which we are happy to assist with  

1:55:54as well as a signed research agreement and if  you have any further questions feel free to reach   out to research citizen.com and we’ll be happy to  support you and then i did also want to just make  

1:56:06a plug that we are working to connect patient data  across other platforms through common identifiers  

1:56:13with simon searchlight being one of the  examples where this has been very successful   and so really what we’re trying to do is to  prevent data from being siloed in different places  

1:56:23and so our goal is really to be able to connect  data that lives across various platforms to  

1:56:28create a really rich research data set that  can be used to accelerate clinical programs in  

1:56:35these conditions so you know one of the exciting  things about now being part of the embite family  

1:56:41is we’re hoping to be able to add genetic data  whether that’s the specific genetic variant  

1:56:48causative for a person’s diagnosis or  whole genome sequencing for example   we’re now going to be able to layer that  onto the longitudinal clinical data that  

1:56:57we extract x citizen whether that’s any  patient generated health data biospecimens  

1:57:03and we have also successfully connected  to individual patient registries as well  

1:57:08so this is part of a larger effort amongst  many groups to ensure that data can be   connected across various platforms where an  individual patient may be participating in

1:57:22and this is just a plug if you’re here at aes we  do have a poster with some more sungap data um so  

1:57:28feel free to come by to say hello i’ll be standing  by the poster tomorrow uh thank you very much

1:57:40and ellie i think we have one question in  the q a panel oh that’s a great question  

1:57:47and i may recruit dr chung  to help answer this as well   i can speak for the citizen data we are focusing  primarily on extraction of medical record data  

1:57:59so taking the information that lives in the  existing medical record from each time you visit a  

1:58:07physician or provider and transforming that into a  normalized data set and we are working to be able  

1:58:14to share data between um the simon searchlight  program as well and if you’d like to add to that  

1:58:21so as ellie said we’re very complementary  in terms of we’re really family facing   to be able to make sure we get that perspective  and uh get very granular data in terms of these  

1:58:31annual evaluations so the two are very much  complementary in terms of that and so we’ve   really striven to be able to make sure as  ellie said that we’re not siloed and that  

1:58:40you can put the pieces together to be able  to get the most out of the combined data sets

1:58:50great thank you well thank you so much ellie um uh i  think it’s just so exciting that we’re  

1:58:58really starting to build up data sets for  these rare neurodevelopmental disorders and  

1:59:04as ellie said bringing together  and integrating that data   is critical for us to be able to  extend our understanding and leverage  

1:59:14the work that’s happened to gather that data  so thank you um so i’ll move on to introduce  

1:59:21our last speaker for today um dr ben prosser  from university of pennsylvania he is um on the  

1:59:30stx bp1 foundation sab and he is also an sdx  bp1 dad and so i will hand things over to ben

1:59:40right thank you charlene thank you to  mike and charlene for inviting me to  

1:59:45talk today i’m thrilled to follow ellie  as well who sort of set up my talk nicely  

1:59:52in terms of presenting the the clinical  presentation and i’m going to talk about our   work trying to develop antisense algo nucleotide  based therapies for stx bp1 and syngap1 disorders  

2:00:05so these sort of um how it started how it’s going  memes are making their rounds on on social media  

2:00:11these days and so this is mine i started my lab  at penn about seven years ago and for almost the  

2:00:18first five years we studied exclusively the  mechanics the molecular biology of the heart  

2:00:25and and this was going well we thought um but then  we shook things up and these days about half of my  

2:00:31lab is studying uh the circuits of the brain and  genetic therapies for neurodevelopmental disorders  

2:00:38this is very different than the heart of course  um it’s not a great career move i think if you   can avoid it um but i couldn’t avoid it because  in 2018 my amazing and beautiful daughter lucy  

2:00:49was born and she started having seizures a  few days later and was diagnosed with sdx  

2:00:55bb1 encephalopathy um a few months after that  and so um it was a tough first year for lou  

2:01:03uh we couldn’t get her seizures under control but  eventually we did and now as you can see here lou  

2:01:09is a very happy kid as long as you were paying  full attention to her but lou is also three now  

2:01:17and she can’t crawl or walk or talk and that might  not change unless we change a standard of care and  

2:01:25so we started working on her disorder in the lab  and very early on in our efforts we also met and  

2:01:30connected with an amazing syngap family who helped  support our early work and since then we’ve been  

2:01:36pursuing parallel approaches to develop new  treatments for stx bp1 and syngap1 disorders  

2:01:44so the smartest thing of course that i did was was  realized i didn’t know what i was doing in this   space and to recruit folks wiser than i and so  this is the team that we’ve assembled called the  

2:01:55end team and and i think they’re they’re a bunch  of rock stars um with experts in in gene therapy  

2:02:02in crispr approaches in neurogenetics and  stem cell technologies and we really think  

2:02:07we need all this diverse expertise um to try  and move the field forward on these disorders  

2:02:15so i’m going to skip over the clinical  presentation of these disorders as it’s been   covered or is known um to this crowd and also the  role of these proteins i think was introduced a  

2:02:24bit by by dr smith hicks and others and so i’ll  get right into our approach so what’s our approach  

2:02:31to treat these disorders um here’s our two  copies of either the stx bp1 or the syngap1 gene  

2:02:38sort of a central dogma schematic and our kids  have a variant in one of these gene copies shown  

2:02:45here in red and depending on where that mutation  lies it can affect any or all downstream aspects  

2:02:51of this central dogma but regardless of the  mutation location a common downstream endpoint  

2:02:58is that you’re simply not making enough  functional stx bp1 or syngap protein and so  

2:03:04you have this haploid insufficiency condition  and so you can imagine a variety of different  

2:03:10therapeutic strategies to address this you  could try to correct the mutant allele directly  

2:03:16using gene editing you can try and add extra  copies of the gene with gene replacement therapy  

2:03:23or you can try and boost more out of this normal  allele you could bolster transcription splicing  

2:03:30translation protein folding and from our strategy  we’ve been focused primarily on manipulating  

2:03:37the processing of rna to try and boost more  expression from the wild type remaining allele  

2:03:46so there are a number of mechanisms that control  how much productive rna is made from a particular  

2:03:52gene of interest so in general our strategy  is to look for imperfections in this process  

2:03:58and then try to hijack or correct those mechanisms  to increase the amount of productive mrna and  

2:04:05so one strategy that we can employ is to try and  target alternative splicing where the same pre-rna  

2:04:13can be spliced into multiple different mrnas  and sometimes these alternatively spliced rnas  

2:04:20retain certain genomic elements that can target  that rna for degradation such as a retained  

2:04:30intron or a inclusion of a poison exon which would  trigger that rna for degradation through nonsense  

2:04:37mediated decay so if you can if you can redirect  or increase the efficiency of this splicing  

2:04:45you can potentially shuttle more rna into that  productive pool and make more protein the other  

2:04:52element that we’ve been targeting are micrornas  so micrornas are small non-coding rnas that can  

2:05:00bind to an mrna and target it for degradation  or repress its translation so if we can prevent  

2:05:08this micro rna mediated degradation we  could also make more functional protein  

2:05:15so how do we tune rna biology to our advantage  and this is where antisense oligonucleotides  

2:05:21or asos come in and these are small modified  nucleic acids that can bind to a target sequence  

2:05:29on rna through complementary base pairing and  manipulate its biology and there are multiple  

2:05:35ways that an aso can regulate rna the first is  to use a silencing aso or a gatmer this is where  

2:05:44asos with with certain chemistries can bind to  the mrna and and cause it to become degraded  

2:05:51and this is actually the classic way that asos  were used and it’s useful in in many disorders  

2:05:57doesn’t help us of course we’re trying to get more  expression the second common goal of asos is to  

2:06:02modulate splicing and where you can place an aso  on a specific element say a splicing enhancer or a  

2:06:11splicing silencer to redirect splicing for example  to prevent inclusion of one of these poison exons  

2:06:19and these splice switching oligos these have been  used successfully or are being used successfully  

2:06:25for the treatment of sma they’re also looking  promising for the treatment of gervais syndrome  

2:06:31the third way we could use an aso is to block  other rna binding proteins such as micrornas  

2:06:40so in this case you would put a steric blocking  aso right where that micro rna wants to bind  

2:06:46um and preventing that mirror from binding  and repressing your target protecting it  

2:06:52from degradation and so we’re pursuing multiple of  these splice switching steric blocking strategies  

2:07:00for both stx vp1 and syngap1 i’m just going  to show you one example for each gene today

2:07:08so this was actually our first fairly simple  idea where if a certain amount of stx bp1 mrna  

2:07:14is normally being degraded due to micro rna  engagement then if we can remove that break  

2:07:21with an aso we’ll have more productive mrna  and more protein expression and there’s really  

2:07:26two key questions you have to answer to know  whether this could work one are there actually  

2:07:32any micrornas in human brains that are normally  actively silencing stxbp1 and if so where are  

2:07:40they binding stx vp1 which you need to know  to design your aso to sit there and block it

2:07:51and so we think this this general approach may be  broadly applicable to treating other forms of of  

2:07:56neurodevelopmental disorders as well as micrornas  silence many genes that are implicated in  

2:08:02ndd and so through transcriptome-wide mapping  of micro rna binding sites the davidson lab  

2:08:09found over about three thousand genes in in human  cortex that are actively being silenced by micro  

2:08:17rnas with high confidence and i cross reference  this list with the 155 best known genes that cause  

2:08:26neurodevelopmental disorders due to monogenic  haploin sufficiency and about half of those are  

2:08:32likely under active silencing by mirror in human  brains and that includes both stxpp1 and syngap1  

2:08:42and so that means for these 70 or so rare  diseases removing that microrna break could  

2:08:48potentially be a useful way to boost gene  and protein expression when it’s needed

2:08:55okay so can it work to make a long story short  we’ve honed in on a few different micro rnas that  

2:09:02may silence stx bp1 and this includes this mirror  218 and if we take a human neuronal cell line  

2:09:10and we treat it with an inhibitor of this micro  rna we can remove that break and we see an  

2:09:16increase in the amount of stxbp1 protein in those  cells which is quantified here on the right we can  

2:09:23also use crispr to just cut out that microrna 218  altogether and again we see a similar result with  

2:09:30upregulation of stx bp1 also upregulation of scn1a  which is the genetic basis for gervais syndrome  

2:09:38we think this is another target of mir-218 so  this is a potential opportunity but this also  

2:09:44highlights the problem of inhibiting the micro rna  broadly or directly micro rnas regulate hundreds  

2:09:52of different target genes and we don’t want to  upregulate hundreds of different target genes   which could have unforeseen consequences we just  want to increase stx bp1 so to do that we need to  

2:10:02put our aso in the right place on stxbp1 to block  that microrna and get specific rna upregulation

2:10:13so micron is they can actually bind all over a  gene but they bind most commonly in the three   prime untranslated region the utr this is  also where they tend to show their greatest  

2:10:23repressive activity so to determine if micrornas  were binding the three prime utr of stxpp1 we  

2:10:31generated a luciferase assay with just the three  prime utr of stxbp1 and we express it in these  

2:10:39human neuroblastoma cells what you see on the  right is that only when you transfect these  

2:10:44cells with both the utr of stxbp1 and your  antagomere to knock down mir-218 or mir-424  

2:10:53another microrna we think regulates sdx  bp1 you see up regulation of the stx bp1  

2:11:013 prime utr these others are all negative controls  so this gives us some amount of confidence  

2:11:06that these mirrors are normally binding and  suppressing stx bp1 through its three prime utr  

2:11:14and so if we just zoom in on that three prime utr  these arrows denote different potential micro rna  

2:11:21binding sites if we just zoom in further on  this last one we can look at the putative  

2:11:27nucleotide sequence for where microrna 218  is proposed to bind so we first generated  

2:11:34about nine different asos and we put them on  three of these different potential locations  

2:11:41these mere binding sites and asked which ones if  any increase stx bp1 protein expression so when  

2:11:47you look at the plot on the right here you see  that some of the asos targeting this mir 338 site  

2:11:52they did not work targeting mir-424 gave a  little bit of benefit and we get a better  

2:11:58expression increase with some asos targeting  mere 218. so this was exciting but this is  

2:12:04just nine asos we really need to screen  hundreds of asos to identify optimal leads  

2:12:10and so we’re working with ionis pharmaceuticals  an antisense company to try and find the best aso  

2:12:16leads that we are then testing now in ips neurons  that are generated from patients with stx bp1

2:12:26okay so what about syngap1 i’ll share some of  the different strategy that we’re pursuing on   on syngap so there is considerable alternative  splicing on syngamp and one element in particular  

2:12:38that i think we can take advantage of and so  this is rna sequencing of syngamp from adult  

2:12:44human cortex and so this is syngap mapped to its  genomic locus so these peaks correspond to exons 9  

2:12:5210 11 and 12 and these gaps are the introns  and you see a fairly normal splicing pattern  

2:12:59except for we noticed very early  on that there’s this little plateau   down here right before exon 11. that  corresponds to alternative splicing of exon 11  

2:13:11and within that alternatively spliced region  encodes a termination codon which will then  

2:13:17cause transcripts that contain this element to  be degraded through nonsense mediated decay and  

2:13:24we’ve confirmed that it indeed does as have  other groups shown that this leads to nmd  

2:13:31so if we could redirect splicing to the proper  start of exon 11 we could potentially get more  

2:13:37syngap and escape this nonsense mediated  decay so we looked for splicing modulators  

2:13:43that might be in that surrounding region and  we found that just upstream of that poison exon  

2:13:48are a number of highly predicted binding sites for  a particular splicing factor that’s a well-known  

2:13:54regulator of splicing in the brain called ptbp and  so we hypothesized that this this splice factor  

2:14:02could be promoting the inclusion of this  non-productive splicing event in syngap1  

2:14:11so to test that we designed a pcr assay to look  at that splicing event where we can detect bands  

2:14:18at the top here that correspond to the improperly  spliced transcript and at the bottom that  

2:14:24correspond to the properly spliced transcript  and if we knock down this splicing factor ptbp  

2:14:31we see that we switch the ratio  this isn’t that in hexels and   sushi cells and we can indeed get more of this  bottom productive band while reducing this top  

2:14:42non-productive band now importantly  corresponding to that correction of splicing  

2:14:48we get an increase in the amount of syngamp  productive mrna when we deplete this ptbp

2:14:57so just like with the microrna approach  though we don’t want to just inhibit ptb   broadly and we’ve done splicing analysis of what  happens when you do this and it’s regulating  

2:15:06over a thousand different genes in human neurons  so we want to specifically block its interaction  

2:15:12with ptbp and again this is where asos come in and  we put many different asos on several different  

2:15:20predicted or measured ptbp binding sites on  syngap sort of sparing the gory details we’ve  

2:15:27tried about 100 different asos to do this  and and these are some of our best results  

2:15:32so with a particular aso for example this is this  sso19 we see that when we treat cells with higher  

2:15:39and higher concentrations we increase the amount  of proper productive splicing and we increase  

2:15:45the amount of syngam gene expression this is our  current favorite sort of home run aso right now  

2:15:52um aso 85 where you see this really  robust induction of syngap mrna expression  

2:16:00um over five-fold and this does indeed translate  to a multi-fold increase in protein expression  

2:16:06in these cells as well so this this gets us very  excited um if we could increase protein expression  

2:16:13two fold in a patient’s brain cells that could  correct the underlying deficiency um but it’s  

2:16:19really important to note that these are not  patient brain cells right this is a screening cell   line and this is quite some distance away from a  child’s brain so how do we move this forward how  

2:16:31do we get a little closer um we can’t take brain  cells from our kids but we can take a blood draw  

2:16:37and we can use induced pluripotent stem  cell technology to turn those blood cells  

2:16:43into stem cells and differentiate those stem  cells into neurons that harbor the genetic  

2:16:49architecture of our patients this is what those  neurons look like these are neurons from a patient  

2:16:57with one of these two neurodevelopmental  disorders and we can measure the neuronal   activity their synaptic function and when  they don’t have enough stxbp1 or syngap1  

2:17:08these patterns are disrupted so this is sort  of where we are we’ve generated ipscs from  

2:17:14both stxbp1 and syngap1 patients here’s the  example from syngap where this patient had a  

2:17:22nonsense variant that led to the introduction of  a premature stop codon this r1240x mutation and  

2:17:31we’ve we’ve confirmed that indeed this leads to a  clean haploid insufficiency that’s reproduced in  

2:17:37these patient cells you see a reduction  in the syngap mrna levels by about 50 um  

2:17:43which corresponds to that mutant allele being  robustly silenced by nonsense mediated decay  

2:17:51and as you would expect then you see the similar  reduction in syngap protein expression and we  

2:17:57can use crispr tools to actually correct that  underlying mutation and we see that that restores  

2:18:04the levels of both the mrna and protein sort  of confirming both the causative nature of that  

2:18:10variant and giving us this nice isogenic pair of  cells for testing so this is where we are we have  

2:18:17another patient line also about ready for testing  and we’re treating these with our different asos  

2:18:23to try and find the one that restores the most  amount of protein and the most amount of function   in these neurons and that’s what we’ll try and  push forward into a first in human application

2:18:35so quick thanks to all the amazing folks who did  this work and really all of these individuals   contributed to the different aspects of the work  i shared today it’s a very collaborative team  

2:18:45and that’s lucy thanking you for your  attention as well and and to our funders   who are listed down here below i’m happy to  take any questions if there’s still some time

2:19:00thanks ben shameless plug one  of your collaborators liz heller   is a syngap ant and an srf grantee

2:19:11because i want to thank all of our families who  donate and point out how critical it is to support  

2:19:17scientists like yourself to do this work this  is an awesome colleague and we’re very excited  

2:19:23about her line of work as well which we didn’t  have time to talk about today but it all helps

2:19:31there is one question in the in the chat  is there an eta to getting to human trials  

2:19:39um the answer is is not a precise one um part  of the reason why we chose to pursue an aso  

2:19:48route early on when we were thinking about these  different strategies is that we thought it gave   us our most uh rapid chance of getting to the  clinic the fastest possible route um and the  

2:20:02um uh there is a demonstration of course a rather  famous demonstration of an aso being developed  

2:20:09and given to a child in need in dire need within  about a year and a half timeline and so given the  

2:20:18relatively good safety profile of asos  and their other approved clinical use  

2:20:24uh the drugs that you’re working with in your  in vitro studies are the same ones that can go   into the patient and so there is the possibility  of rapid translation without going over through  

2:20:36extensive testing perhaps in large animal models  for example which would still have to be done  

2:20:43for any sort of crispr or or or some of the  other genetic approaches that are pursued  

2:20:48so there’s a possibility of a quick timeline  but we can’t nail that down precisely   um today until we have a an  important meeting with the fda

2:21:02i see a separate question about who’s  funding doctor process work i’m not sure   if that’s something that i should i said  the nih and we have a sponsored research  

2:21:12agreement with ionis pharmaceuticals  who are both supporting our work i’ll leave it at that we’ve also  benefited from philanthropic donations

2:21:29thank you all very much thank you ben we’re all  we’re all rooting for you and  

2:21:37i’m sorry your child is sick like ours are  sick but we are so grateful that you’re um  

2:21:42you have the talent that you have and  you’re part of the team that you’re on and   so should i answer this last question that just  popped up or uh yeah go for it okay um what is  

2:21:52known about delivery of aso into cells in the  brain how similar is the set of cells each time   an aso is delivered that’s a really great question  there’s still a lot of mysteries about how asos  

2:22:02get into cells and their and their bio  distribution um there is some mechanisms that  

2:22:08are understood i think how those mechanisms vary  between different cell types in the brain um is  

2:22:14is not well understood um the delivery method  is is currently being done through interfecal  

2:22:19injection so into a spinal tap which is not  a really a pleasant experience of course  

2:22:25um and this has to be repeated say once every  three months six months depending on the lifetime  

2:22:30of that aso there are additional delivery routes  that are being pursued now in terms of implantable  

2:22:36devices that could have slow release technology  so it would be a one-time procedure for a child   but i don’t believe those have been clinically  approved yet um in terms of the efficacy though  

2:22:46however the the the work particularly with spinal  muscle atrophy and spin rasa or news and nursing  

2:22:51gives us a lot of confidence that this can be  an effective therapy to consistently regulate  

2:22:58alternative splicing in the brain  or in the central nervous system

2:23:06great and there’s is one more question in the chat  have you guys had a pre-ind meeting with the fda  

2:23:12and did dose finding come up um no we  are a little we’re we’re waiting for  

2:23:21some additional data in the  patient neurons to have that mean

2:23:27well thank you so much ben um it has been a  wonderful round table i’m truly appreciative  

2:23:33of all of our researcher collaborators  and geraldine i’ll let you close it out

2:23:40well a big thank you to all of our presenters  and all of the attendees just for taking the  

2:23:46time today to learn about synaptopathies and to  learn about the approaches that are being used in  

2:23:52the synaptopathies hope for those of you who are  epileptologists you work primarily with patients  

2:23:58who have epilepsy i hope you’ll remember to  think about synaptic causes of epilepsy when  

2:24:03you’re meeting new patients um thanks again and  mike thank you so much for organizing this event  

2:24:10we really appreciate all your work and efforts  yes thank you okay guys have a good one take care