Read more about ENDD: https://curesyngap1.org/endd/


0:00it automatically oh great

0:07so we’ll wait a couple minutes

0:13hi everyone Welcome to our webinar we’re going to wait a couple minutes while we

0:18see the attendees joining

0:25so now’s our time

0:31yeah well while people join you and come say hi

0:37and come say hi Lucy say hi while we’re waiting yes

0:44hi Lucy buddy

0:51Lucy just woke up so this is this is her I just woke up please

0:56are you ready for this interview this is gonna be so fun Lucy

1:02right right yeah we’re interviewing your dad and Ingo

1:08yeah you can help me out lose it because your dad thinks I didn’t look at the questions

1:15yes Ingo needs some Ingo needs some help some hints yeah give him a pep talk she’ll pull on

1:22your ears yeah all right okay well um we we seem to

1:30have um our our numbers are um are not going up exponentially

1:35anymore in terms of attendees so why don’t we go ahead and get started uh

1:41thanks everyone for joining today I’m Charlene sunrigby president and co-founder of the stxbp1 foundation and

1:48I’m here today with Dr Ben Prosser and Dr Ingo Helbig so Dr Prosser is

1:54associate professor of physiology at the perimen school of medicine at University of Pennsylvania and Dr Helbig is

2:02assistant professor of Neurology also at Paramount school um so congratulations to both of you uh

2:11um some pretty big news everybody was buzzing about it right after the news

2:16dropped so 25 million dollar new center called end at University of Pennsylvania

2:23um where Ben you’re going to be the new director of the center and Ingo you’re going to be the co-director and so we’re

2:30really eager to learn about you know what this means and um so I thought to

2:36start things off it would be great to um for you guys to talk a little bit about your background so you know the you

2:42you’ve been um you know very very visible in our community but we also have a lot of

2:48families who are new so then you started in heart research and expanded to

2:53neurology so maybe we can start there can you share a little bit about your story yeah

2:59um absolutely so um yeah I started my lab at Penn I think 2014 or so and for the first four years

3:06or so we studied first four years or so we studied exclusively the heart and then in 2018

3:12um my amazing daughter Lucy who was attempting to walk on over here actually right now okay I think her mom said that

3:19this was her time to show up um Lucy was born and

3:24um after uh I think about day four of live started having seizures and pretty

3:29quickly after that was diagnosed at Children’s Hospital of Philadelphia with stxbp1

3:36and I think the the first two weeks after Lucy was diagnosed were probably the

3:42hardest um maybe of my life I think is reasonable to say um and that that sort of feeling of of

3:49helplessness as a parent I think was probably the hardest thing that that I have experienced

3:55um but I was fortunate to be um where I was at Penn and right next to chop and quickly got connected with with

4:02guys like Ingo who who saw Lucy when uh shortly after she was diagnosed and with

4:08other experts um outside of the heart and specifically in the brain including Dr Beverly

4:14Davidson who is our our close collaborator and the other co-director of The Institute who’s not joining us

4:19here today but playing a pivotal role and um we quickly started brainstorming on

4:25how we could potentially I could potentially try to make a difference in this space

4:31um we came up with some some new ideas to try um uh to work on some therapeutic

4:37development for stxbp1 and um started a new arm in my lab going down that path

4:44and with other collaborators across pen and shop and and uh in in a few short

4:50years it’s really transformed into sort of a full-blown full-blown program and center and that’s kind of what got us to

4:56where we are now that’s cool yeah it was really great to meet some of your lab last week at the

5:02uplifting athletes event and see how there was the heart cohort and then there was the neuro cohort oh yeah and

5:08they’ve started to cross-pollinate really well the people in the heart cohort that you know because cell biology molecular biology the brain and

5:15heart are very different but there’s a lot of shared underlying fundamental principles and so in terms of the genetic therapies we’re trying to to

5:22develop we utilize what we learned from the heart we take it to the brain and vice versa and so there’s some nice Synergy there now

5:28for Ingo so you’ve really been you know in

5:34um working with the stxp1 community for a long time and in fact you were the

5:39first person who had any expertise from a clinical perspective that we were able

5:45to connect with when we got um Juno’s diagnosis um so I wanted to

5:50um but of course there’s a lot of folks who probably maybe haven’t even heard of you so um can you tell us a little bit about

5:57what you do and your connection to stxbp1 yeah so I’m a neurologist at

6:02Children’s Hospital of Philadelphia and I actually kind of transferred from Germany Europe to um Philadelphia in

6:102014 and um I kind of almost like stumbled across the xpp1 so I was aware of this

6:16condition after an epilepsy genetics research for the last probably 20 years and when I kind of started at shop

6:23Children’s Hospital of Philadelphia um one of my first patients was actually a young boy with Immortal spasms and

6:29test takes bp1 I think it kind of yeah snowballed from there to get more

6:35patients coming to us that we actually realized there’s quite a bit of an unmet need and also kind of a lack of

6:41expertise so we kind of try to build this systematically we have now seen yeah quite a number of patients I think

6:47we’ve seen more than 120 individuals with sdxp1 and yeah this allowed us to

6:52kind of look at the entire range of um presentations is studying in their young

6:58kids to adults that’s great so

7:03um let’s talk about this Center can y’all tell us a little bit more about the news and frankly why is this a big

7:10deal yeah um absolutely so I mean one thing I want to clarify right off the bat is you know this Center it and this is critical

7:17to its success it’s really spanning both pen and chop so it’s very much a collaborative Center across these two

7:23institutes many people think of these institutes as interchangeable sometimes the investigators do as well because we all collaborate with one another and we

7:29even share physical space but they are two separate institutions and so part of this go ahead Charlie I’m going to

7:35interrupt you because some people may not understand what the difference is can you say what pen is and what chop is

7:42well sure so so Penn is part of the University of Pennsylvania which also

7:47has an undergraduate campus I’m part of the Perlman School of Medicine sort of medical school component of pen pen also

7:53has a hospital system there but it’s typically more focused on sort of adult

7:59um uh well patients where chop the Children’s Hospital of Philadelphia actually I’ll let Ingo describe better

8:05What chop specifically is yeah um so shop is like is it Children’s

8:12Hospital we have our own research institute we have our own research Enterprise and um this is kind of the

8:19connections are yeah many so we I’m I’m also an assistant professor at the

8:24permanent school but my lab and my clinic is a chop and I think this is um

8:30I think the reason why I mentioned this then is because we’ve been through almost like a week of kind of coordinating this yeah it’s kind of

8:36wears heavier on our shoulders right now and which one is which um but it’s basically those are the kind of two major institutions in a

8:42university city and um Philadelphia that drive biomedical research and there’s a lot of can we

8:49bring this up because this is unusual it is unusual yeah that’s that’s right even even there’s a lot of

8:55collaborations across pen and chop and and there are other centers of excellence as well that have

9:02investigators that that that work and reside at Penn and investigators that work in reside at shop the reason it’s

9:08so critical for for our Center and our Enterprise is because again we need sort

9:15of both the the gene therapy expertise the basic science expertise the the translational expertise translational

9:21science which there is bits at both pen and shop and then we really need the clinical component the the

9:27patient-oriented component and much more of that infrastructure is built throughout chop and so it’s only by

9:33leveraging the expertise at both that we think we’re able to do something special and that’s why we created this somewhat

9:40um unconventional Center that really is sort of spanning both of these institutions

9:46great and so you mentioned Bev Davidson um who are some of the people who is Bev

9:53Davidson who’s now also the co-director of the center with Ingo and who is who

10:00are some of the other researchers or um research uh research clinicians clinician researchers who are involved

10:07yeah absolutely so um you know maybe I’ll just back up a

10:12second I mean part of what actually got me really excited in thinking about this Center idea was actually last year at

10:18the stxbp1 um uh it was the summit meeting so both the family and the researcher meeting

10:24and I saw ingo’s group presenting on the sort of disease concept model for stxbp1

10:31and a lot of the sort of phenotypic mapping of the disorder in patients we had folks from from Bev’s group who are

10:38Bev is really a specialist in gene therapy in using viral vectors to

10:45actually deliver genetic material for example to the brain and breath is focused on the brain for a long time

10:50she’s really a world expert in this domain and it was clear at that conference as well that gene therapy for

10:56stxbp1 is getting closer and more tangible and then there’s whatever crazy

11:01I sort of bring as a parent scientist and trying to keep everybody motivated and with an eye on the prize and it just

11:08felt like this very sort of rare their Confluence of of expertise across

11:14different critical domains that are necessary to actually bring something from a discovery phase to get it into

11:20patients and so we wanted to leverage that to try to build this center now what the center also lets us do is go

11:27outside of just those three clinicians researchers for example and we have for

11:32example Liz Heller who is a professor in actually focuses on

11:39epigenetics but is really using crispr-based tools at Penn to work on

11:44certain Gene editing or Gene activation strategies we’re hoping to bring in other researchers taking advantage of

11:50some of Penn’s recent successes in mRNA technology so Penn played an instrumental role in developing the MRNA

11:56technology for example for the covet vaccine and we want to leverage some of that expertise to help with our RNA

12:03Therapeutics approaches that we’re trying for stxbp1 and for syngap1 the

12:08other disorder that we’re working on um I should mention Dr Heller Liz Heller is also an aunt to a to a child with

12:15syngap1 Disorder so adding in more of this sort of parent scientist energy that I think can really make a lot of

12:21change in this kind of space and then I know Ingo is bringing in a lot of additional folks from the chop side that

12:27can help us tackle all of that so much that goes into that clinical trial Readiness category that I know a

12:34lot of this audience have heard about and so if you can go you want to speak to that yeah and I think it’s really I think a unique construct or a unique

12:41Center that we can um get tackle this from you know all different sides so usually when we have

12:47um the research funding when we have a initiative typically only affects one issue so it’s either gene therapy or

12:54clinical studies and here we actually really the unique chance of pushing this from from all different sites make sure

13:00that this really kind of comes to together so on our end we have engine which is a jobs epilepsy

13:05neurogenetics initiative which is probably the largest epilepsy genetics clinic in the country and this has built

13:12our kind of clinical and um operations for the last three years and this gives

13:18us like the background to now move our clinical care into Natural History studies

13:25clinical trial Readiness studies and eventual clinical trials and I think you can almost imagine this kind of

13:31narrowing this down from both sides until this eventually happens okay and I think this is really a very unique

13:37mechanism and um as you can see from my I’m stalking myself at the camera I’m super excited and I think this is really

13:43a unique possibility in yeah the what’s like the history of synapse research

13:49that we can really approach this from so many different angles yeah really from a very very multi-disciplinary approach um

13:58I haven’t actually specific not 19 because I’m really at the risk of forgetting someone yeah and I think we

14:04just have a very broad range of genetic counselors which only attendings um researchers working with us and um I

14:10think we’ll kind of introduce our team out like a different time but I think we really approached this from the clinical

14:15part in in a very broad range and have a very big footing there or very wide base

14:21to push this forward yeah that’s um that’s really great can you you mentioned natural history study

14:29and can you explain what that is

14:34because yes okay so let me let me as our Clinic how much how much I think it convicted

14:41processor yeah how much time do we have so um let me take one step back so um

14:48treating sdxp1 is not trivial and I think this is what probably many um

14:53listeners and and attendees of this webinar realize um no child and no doubt

14:59with s takes probably one is um yeah the same and I think there’s a

15:04very required range for for sdx pp1 in Hollywood CS symptoms and this actually

15:10creates quite a big problem when we would try to kind of treat this and this has to do with um if there’s a clinical trial

15:16what are we actually looking for so we know that CJs can be very Dynamic and Estates but we want we know for example

15:21infantile spasms which is the most common stereotype in s takes but P1 um which happens in roughly 40 of all in

15:28individuals can be very easily treatable or they can be very resistant sometimes

15:33even in individuals with the same genetic change so what we need as a first step and this

15:39is what I think our team has been working on for the last few years is some sort of like a new understanding of what s takes pp1 really is

15:47so we um what is kind of yeah those under the term of Natural History studies or or um clinical trial

15:54Readiness is really a concept to Define and narrow down what a disease actually

16:00does and trying to really measure this in very clear yeah facts or availability

16:06of measurements that we can then use for clinical trials it’s basically answering the question if if there was a

16:12medication now what are we actually looking for how can we yeah find a difference that makes

16:19things 30 better yeah and I think these kind of studies they take a little bit of sophistication especially in the nor

16:26developmental space and this is where it’s actually very nice that over the last few years there have been no Concepts there have been new kind of

16:32strategies on how we can assess this and now basically we have the possibility to really kind of move this forward very

16:38very quickly that’s great so I wanted to go

16:43um to talking about therapy development and you know Ben you had outlined that

16:48you know really this is bringing together a lot of you know kind of broader approaches you know you’ve been

16:53focused on anti-sense oligonucleotide Therapeutics or ASO therapies you know

17:00since um you know now I think for four years and so

17:05um it seems uh it’s a it’s amazing to me to think about you know the first time that we met in 2019 at the the Summit

17:14where you were presenting some of your work and and you know pretty shortly after that we were able the foundation

17:20was able to give a 75 000 gift to help to accelerate the um this work how do

17:27you see you know in the in the next couple of years the therapy development

17:33efforts kind of changing and expanding maybe in a little bit more of a uh like

17:39a concrete way or you know specific way than what you talked about in terms of

17:44kind of modalities previously um sure so do you mean specifically how

17:51do we see our ASO program being accelerated by the center or do you mean how will this allow us to add additional

17:58modalities or perhaps you want me to comment on both actually on both yeah both okay so so maybe I’ll start with

18:05the ASO side of things so so indeed that was sort of the first approach that we started working on and we did receive a

18:12um an excellent seed Grant from the foundation that helped us kind of accelerate that and since then we’re able to generate a good amount of data

18:19using these Asos to try to up regulate STX bp1 which we think would be

18:24therapeutic and that’s led to a partnership with a pharmaceutical company who is helping us to move these

18:30programs forward what this end Center really allows us to do is

18:37is accelerate past the point where we currently are on our ASO program so in other words we’ve identified compounds

18:44Asos that are capable of affecting stxbp1 levels in cells or in healthy

18:51mice but to move that from here it’s actually getting it into a kid

18:56requires a lot of additional expertise part of this requires generating new

19:02specialized Mouse models that can actually be used to test those Asos and then not just to look at how that

19:08affects the levels of stxbp1 but how it affects the behavior and the cognition of these mice and there are Specialists

19:15across pen and chop who can do these kinds of assays to show not just is our are we restoring the levels of STX but

19:22are we actually seeing a functional difference in these specialized mice that actually contain a fully human copy

19:29of the stxbp1 gene which makes them a very good model for being able to take those results and try to translate them

19:35to humans as the next step so that’s really one of the key pieces on the ASO side the other piece that I should

19:42mention is Asos are are simplistically to think about them are small pieces of

19:47RNA and again I mentioned earlier in the conversation about sort of this expertise in RNA biology across pen

19:53which is actually see at a tremendous investment just in the last couple of years and so we’re hoping to leverage some of

19:59those Technologies particularly in RNA delivery to hard to Target cell types so

20:05neurons the brain cells that we need to get into for an STX pp1 therapeutic are hard to Target and there are folks

20:11within our community that are working specifically on that challenge how do we get RNA DNA into neurons and there’s

20:17multiple different ways we can do this and so one of the ways is through working with Folks at Penn with expertise in RNA biology the other

20:24brings in this additional modality and Bev Davidson’s real expertise which is using viruses to deliver I should say

20:32harmless viruses because that word is always a bit of a red flag but viruses to deliver genetic material to the brain

20:37this is something that I really wasn’t very enthusiastic about until the last couple of years when there’s been some

20:43real breakthroughs both in showing proof of concept that this could be effective for stxp1 and that’s really work that’s

20:50been led by Ming Shan shoes group down at Baylor but then also by others who are making breakthroughs in getting these this

20:57virally encoded genetic material into the brain and Bev’s group has had a recent breakthrough in this domain that

21:03gets me excited about that possibility so this is a program that will really be accelerated by this Center that hasn’t

21:09been a major Focus until more recently for us yeah and I think I’ve been one of the

21:15largest skeptic threat yeah absolutely that I think it’s really interesting how this has changed over the last three

21:22years because typically I look at these things and kind of sometimes ask what is actually coming out of the basic

21:27research or translational research that is really eventually be able to result in treatments and especially when it

21:34comes to viral Gene therapies this has been dramatically changed over the last few years there were a few viral Gene

21:39Therapies in clinical practice now for for blindness or for adrenal liquidystrophy which is similar

21:44degenerative disc disorder so this is possible and um I think I’m very optimistic that the

21:50way that this kind of moves forward that this um is very very promising

21:55so Ingo we um the stxbp1 foundation has just launched a three-year strategic

22:02plan so our second three-year plan and it’s called stxbp1 fast forward and just

22:07a little advertisement I released our first podcast this week and so folks haven’t seen it check it out on YouTube

22:14watching it the other day I came by and I saw your face on her phone I was like oh hi Charlene and then he was like it’s it’s a recording

22:22getting the word out um so the our uh the plan’s goal is to

22:28accelerate and enable the development of therapies um with a big focus on clinical trial

22:34Readiness um you know and of course supporting our community today with care and so I

22:40wanted to ask you do you how do you see the end and stxbp1 fast forward align or

22:48work together you want to start or should I yeah why don’t you start okay I’ll just I’ll just

22:54jump in and probably say that the code is something different so I I actually think it’s only by

23:01really working together across these entities that that either one will actually be maximally effective

23:07um and so you know I think it’s important to note and and you know this

23:12is a this is a we’re extremely fortunate this is a massive donation to us that we think could really be a transformational

23:19gift but it’s not like this buys are secured for stxp1 there’s still so much

23:24work that has to be done and there’s more work that can even than can even be done at pen and chop and all of our

23:29Collective brain power combined there so we still need to work effectively with

23:35the foundation to identify okay what is it that this Center can achieve what is it that we can’t achieve what outside

23:41Partners do we need to to bring in what additional efforts do we need to motivate elsewhere with people that have

23:48expertise that we don’t um have in-house um to really fill all those gaps the

23:55thing that’s been so um the the the biggest knowledge gain for

24:00me over the last couple years I came from a sort of a basic science fundamental Science Background I thought if you discovered a new therapy and you

24:07could show you know this works in a mouse or something like that that meant you were good you were done it’s so clear to me how much more has to be done

24:13across how so many different domains to really effectively bring a therapeutic to clinic and so it’s only by working

24:20with patient foundations like the sdx pp1 foundation and centers of excellence like this where we can combine clinical

24:27basic translational expertise including with other researchers from around the world

24:32um to really have a Global impact on this disorder to reach

24:39as many kids as possible to reach as many age groups as possible um we cannot do that alone and so that’s

24:46where I think the Synergy comes in now I would say this is exactly kind of reaching as many um individuals as

24:51possible this is where the foundation is really helpful and I would say um we would be nothing without the S6

24:57would be one Foundation because I think this is something where we really kind of um yeah I’m extremely thankful and

25:02and kind of really um yeah almost dependent on on the fact

25:08that we have a very good family advocacy Organization for our secret one Chinese is a big thank you to you here live on

25:14your podcast yeah well and um the

25:20um I think we can kind of the way that you can think about this is that um when it comes to

25:26um enrolling as many you know children and adults as possible um we don’t just want to do this at one

25:32side we just don’t want to do this at in Philadelphia but we would like to kind of do this in in other places in in

25:38Texas we’d like to do this in Colorado and this is where we basically yeah launch it as a multi-site natural

25:44history study with with different sites yeah I think we’re going to start with four sites and it’s going to be

25:49Philadelphia Colorado um um um Houston and New York I hope we can

25:55get this up to seven or eight sites eventually I haven’t told this to you yet Charlene but I believe it and

26:02um I think this is important because it’s something that we cannot do and I think the other thing we’re really kind of um we’re really looking forward to

26:08synergizing with the foundation is patient Outreach it’s something that has a much different kind of emphasis that

26:14is much broader when it comes to um preaching families and communities and I

26:19think this is a very kind of perfect combination we can go kind of in a very

26:25detailed you know fashion into the understanding S6 people when we’re going to do specific EG studies and we’re

26:30going to look at biomarkers and those are things that might be difficult for other sites but once we have something

26:36we can easily Translate to get this to a larger study yeah that’s great and you know I want to

26:42say that we are just really so thankful you know in terms of the collaboration the close collaboration and

26:49um you know joint work we’ve been able to do and you know just to comment on what your point was Ingo also is is that

26:57we can really collaborate in that in this natural history study that I guess we haven’t officially announced but we

27:03are I guess announcing it now um that we’re working on um the foundation is going to you know fund the

27:11work you know at the um at the different centers obviously this uh this new um

27:18sorry at the different hospitals sites um with this new funding that’s coming

27:23through and it really um you know changes what can happen within you know chop and you pen and so

27:30we’re just very very excited about it um so um I want to leave some time and make

27:36sure because there’s some questions that are starting to come in um on the on the chat but I wanted to go

27:42back to a point that you both made around older kids so

27:49um you know in working with um you know in and engaging with

27:54um some of the you know biotech and Pharma partners that we have there’s been an interest in you know starting

28:00with the youngest kids and you know I think that I was excited to hear both of

28:06you say older you know children um I am curious about what you think

28:11we’ll need to do um with those populations in order to understand them well enough so that they

28:18can be also included in therapeutic you know development pipelines or programs

28:24yeah so maybe benefit let me just started I think this is when we when I

28:30think people in the epilepsy genetics field start talking about natural history studies and clinical trial Readiness studies maybe five years ago

28:37we actually realized quite soon there’s actually quite a difference what people meant by this so I think that there is

28:43the natural history study that is kind of really meant to move yeah a certain

28:49compound or a certain therapy into practice as soon as possible and and

28:54then there there’s kind of the idea that we would also like to understand the disease at large I think it’s a very big

29:00need in the aspect that people and feel to understand what happens beyond the age of six or seven we understand s

29:05takes people one extremely well until the age of five but our information afterwards what happens during puberty

29:10or how do children with ethics would be one become adults with their sticks could be one this is largely unanswered

29:16and I think this is a different type of natural history that is not necessarily something that will have immediate

29:21impact for a clinical trial but it’s very important down down down the road

29:27to understand what is the outcome when we look at a at the lifespan of an

29:32individual with with sdxdp1 so I think this is where I think we the foundation and we as As and we’re kind of in the

29:39center of this and we can basically kind of yeah do both understanding that those are different

29:45needs and um that we can yeah move the important pieces for trial Readiness towards um drug development and trials

29:53and kind of understand the natural history although over time to complete the picture

29:59that’s great thank you so the announcement talked and I I see a

30:04question in the Q a hi Sunita thanks for joining um I see that the announcement it said

30:11that the initial focus of the center is going to be on therapeutic development for stxp1 and syngap and then later

30:18expand to other neurodevelopmental disorders and so what are you when are

30:24you planning to expand and and maybe I can frame that also by asking are there

30:29Milestones that you’re thinking about in terms of getting to with sdxbp1

30:35um you know and syngap before you would expand yeah I think to start this off I mean there’s sort of going to be when we

30:41think about the center right there’s really two two parallel arms that have to eventually converge to actually get something into kids and that’s sort of

30:47the translational research arm and then the clinical development arm and the answer to this question might be different on both of those tracks

30:55um and for example I know that ingo’s team is already working of course on a number of other genes in the neurodevelopmental space

31:02so I’ll speak from some sort of more the translational research arm which is really more the the arm that that my

31:08group is involved with and so um we have been spending a lot of our

31:13time the last couple of years on stxbp1 and syngap one to advance what we call

31:19our pre-clinical programs up to a sufficient degree where now the really

31:25the focus of this next upcoming year is to take those new therapeutic approaches

31:31that for example are working in cells or in healthy mice and to put these into Mouse models of stxp1 disorders to even

31:40put them into primates for example for some of these Therapeutics to start moving them forward in that pre-clinical

31:46pipeline and from from my standpoint this still needs to be refined and I have to say

31:52our milestones we are still uh more precisely defining and will over the next three to six months as we really

31:58start to better understand the capabilities of our Center but in my mind I want to get to a point where we

32:04have therapeutic leads on the gene therapy the ASO side that are showing some efficacy some proof of concept in

32:12Vivo in an animal model that is really directly translatable to humans then when we get to that stage right

32:19we’re past sort of the discovery stage we’re past the the idea conception stage coming up with a new therapeutic to

32:26modulate this Gene and then we’re more looking for safety and efficacy in Vivo and that frees up the folks that work on

32:33really the Discovery Science the fundamental science the thinking about how you could use an ASO to tweak a gene

32:39it’s sort of out of their domain now and their domain is freed up to then focus on other disorders that we would love to

32:46tackle and expand I know Lucy is sunshine and Lucy loves her friends and I know that I like to think that like

32:52Lucy would want to help as many in her community as possible so I love this idea of of getting to a certain level

32:58with STX and then being able to Branch out and do more in the community and that’s sort of the internal Milestone I

33:04have in my mind Charlene anyway about when we would start to do that from the translational research side but I’ll let

33:09dingo speak to it on the clinical development side of things yeah and I think um we sometimes get asked the

33:15question why don’t we call ourselves a sense of Excellence for Estes the people in our Center of Excellence for sync app

33:22one and and what I typically tell um uh people or advocacy organizations

33:27is that we purposefully do not do this because I think this will be unfair you know this would be kind of um this kind

33:33of adds some sort of like rivalry we can only be like centers in so many different conditions and

33:38um this is something that um this would have only pushed at Stakes 31 and syngap to the side a few years ago so I think

33:45we actually work um on many or developmental disorders I think the the

33:51push towards Estates we want an in syngap is really important because these conditions have been very neglected when

33:57it comes to trial Readiness and um therapeutic development and I totally

34:02agree with them that’s kind of we want to achieve some kind of yeah key milestones and then this kind of will free up things and we can move in

34:09parallel with other conditions but it’s um yeah there’s no kind of competition

34:15there’s no rivalry and between different disorders because um I would think of

34:20this more as like pilot conditions where we’re able to kind of really put our efforts and kind of translate this and

34:26then the other conditions will be next yeah and I think the one thing I’d just like to add for that is you know a lot

34:31of the work that we’re trying to do is of course work that is Paving the way right I mean this is this is Uncharted Territory in many ways and so anything

34:38that we chart for STX or for cinder both in terms of figuring out certain ASO strategies that can work again these

34:46genes are different but there’s a lot of similarities there’s a lot of overlapping mechanisms and the same thing with with the trial Readiness

34:52aspect the lessons we learn on these it hopefully makes it that much easier to translate yeah to to to to to to to the

34:59next Gene of interest um yeah and especially I mean we’ve already kind of learned lessons from from other conditions that exactly

35:05integrate success has been very kind of leading the the charge when it comes to really applying something that has

35:11outcome measures so if we know that much of the signs around quantitative EG comes out the the red and silica five

35:19field scaled development is is also in the cdkl5 field so I think we can

35:24already kind of integrating quite a few um yeah um strands there that other conditions

35:30have pioneered and we hope to kind of give this back to yeah I love this because you know um as

35:37you all know there are you know a couple hundred or more now um neurodevelopmental disorder genes and

35:44so if we can create a factory no that’s that’s the Hope right and I I wish we

35:50could do more immediately I really do because especially as we’ve gotten into the rare disease space and we’ve met so many of these amazing families and of

35:56course there’s lots of additional efforts going on outside Penn and Shop on different disorders as well but um I

36:02do hope we can do more I think we can well let me take a couple of

36:07um questions here from the the Q a so um one question do you have to build a

36:13physical Center you know so is this going to be a building and then also

36:18um and and I know you talked a bit about this during um uh during our discussion but you know is the money going to go

36:25entirely to research to clinical trials you know and and you know obviously it’s still unfolding but anything you can

36:31share yeah so I I can talk a little bit about the physical structures and this is actually one of the reasons why this Center was so attractive to me all the

36:37physical infrastructure is in place and this is one of the Beauties about one of the privileges we have at working across

36:43pen and Shop so for example to make the the adeno-associated viruses these viral

36:49vectors that would deliver a gene therapy for example it’s about a 45 million dollar facility that makes these

36:56clinical grade aavs that whole infrastructure is built and managed in

37:01chop already right the the first Gene therapies that went into humans that was done at pen and chop is what would

37:08produce that so that infrastructure is in place we don’t have to build that facility in terms of the the actual

37:14physical Labs of course there will be additional equipment purchases and things like that but but but Ingo has

37:20his his lab space his clinical space I have my laboratory space Bev does our other collaborators do we have the

37:27animal facilities we have the facilities for for mice for non-human primates as

37:32well and then within shop and Pen we have the clinical facilities as well so this is the beauty that that that 25

37:39million gets to go a lot farther because I don’t need to build a building and it can go a lot faster too because I don’t

37:44have to wait for a lab to be built right and these things take forever right so if we tried to move all of us into one

37:50new building then I’d be reporting on our first scientific results three years from now right and that’s not okay right

37:55so we get to hit the ground running because we have the infrastructure and the facilities in place yeah it’s pretty

38:02cool I didn’t actually think about it this way but we don’t have to spend a Time on buildings exactly so this money

38:07really does so and then to follow up your in terms of your question on you know where does the budget go to

38:13the budget’s going to go to where the science and and it takes us right and so

38:18we don’t know right now what’s going to be the most effective therapy is it going to be an ASO is it going to be a small molecule is it going to be a gene

38:25replacement we don’t know but we’re gonna that we have the flexibility with this Center to redirect those assets to

38:31where the science takes us to to have our best chance of success in our in our sort of idealistic budget

38:39we do have funds for basic science for for Discovery Science for translational research in other words the studies in

38:45in animal models and we have we have quite a bit of funds for the the Natural

38:51History the clinical trial Readiness side of things and eventually we have a pot where we hope we would be able to

38:57support first and human trials um and and if we get to if we if we run

39:03out of all that money because we made it to First in human trials then then we were successful yeah I think this is

39:08actually a very unique mechanism that they can really allocate resources where they need to be and they’ll be actually

39:14kind of um have the flexibility um to kind of really go with the science and and with the clinical needs lead us

39:21and I think this is really kind of a unique and exciting mechanism and I just have to say I this is why I love working

39:27with Ingo and Bev as well and I like that we have another parent scientist as well as me within the center is that I I

39:35know the moral North for all these people and I know the difference that they want to make in the community and

39:42so to have the resources like that and with a like-minded group really trying

39:47to tackle a challenge and the flexibility then with it I I know that if if inco needs all the money to get us

39:53across the Finish Line like here man take it you know so and I and I really do trust the other investigators to be

39:59the same way like we are working towards a common goal and I love that about this Center and it’s not always the case in

40:05academic science I think and and that’s something that I feel is really special about our opportunity yeah and it’s like likewise if you need all the kind of

40:11money for like the yeah I I actually I’d rather talk about like resources and I think this is in a way

40:18you know useful that they can really yeah Define this along the way where the

40:24needs are and I think this is often when we I think that you mentioned earlier that sometimes seems so easy to come in with basic research to say he’s like a

40:31good basic science solution why isn’t this in humans yes and and that this never been only one straight story this

40:38there can be hold ups at many different parts of the way and we have the flexibility and the potential now to

40:44really kind of solve them whenever they come up that’s great so there’s a bunch of

40:50questions in the chat and about three or four of them have a really similar theme

40:55which is what can the community do what can parents and families do to help make

41:02this successful um do you want to talk about natural

41:07history yeah so what what um we’re gonna officially very lightly kind of started

41:13and launched in to July is our clinical trial Readiness program or how

41:18we call this um the synapse Clinic yeah so this is going to be a kind of attempt to really Define these conditions and

41:24make them ready for whatever Ben and Bev are going to give us in a few years from now yeah and

41:30I think this is something we’ll be kind of it’ll be built up on the community to kind of um yeah come to us and then

41:36engage with us here this doesn’t need to happen just right now I mean we all know that there’s a tremendous sense of

41:42urgency you know but right now we’re kind of deep in the planning stages and this is going to start in July

41:48and I guess the only thing I would add to that is I want to encourage all the parents and the communities to to not in

41:56any way take their foot off the gas right so so we can do a lot with this Center and with this gift but as we

42:02mentioned earlier we cannot do everything and it requires the uh again the the international collaboration

42:09across many different domains to take not just this disorder across the finish line but then also to allow us to to

42:16have a bigger impact and so um please please don’t um

42:22uh become complacent in any way right it is the activation of this community that

42:28has gotten us to this degree and and which will take us the next the next step but there’s a lot of work left

42:35yeah um and uh this is making it uh making me I have five or six six things

42:41that I want to say but uh maybe just say one and then I’ll go to a question um which is just in terms of activation

42:47and so for folks who are on the um you know on the Web Conference

42:53um please join our contact list you know that way you can keep getting updates on

42:58what’s happening there was a question in the chat around you know do we have an

43:04idea of what percentage of diagnosed patients are enrolled in Natural History

43:11you know studies and so um you know Ingo I don’t know if you want to comment on on that or can you

43:18know kind of come up with a uh a percentage but maybe you can start out maybe you can talk about how what um

43:25number of patients you think are diagnosed right now yeah so maybe I would start by saying

43:31that I think one ripple effect I’d like to have from kind of the center is that we kind of get more diagnosis and more

43:39awareness I think we’ve seen this with many other genetic epilepsies that they’re actually um yeah that they become well known so I

43:47always think of this what happens to a child when parents need to bring their child to an emergency room is is the

43:52kind of physician is the nurse practitioner familiar with this condition and we know that we’ve actually made quite some

43:58progress there for um patients with trophy syndrome and I think part of this is really kind of getting these

44:03conditions on the map and saying we actually can increase the overall awareness I think that the discussion we

44:09have going on that that um S31 needs its own ICD code is one of these important

44:14things um and when it comes to the kind of um diagnosis we often see that there’s

44:20quite a yeah it depends on which angle you actually use and you see that the

44:26patient said we’re aware of are just a fraction of patients we can actually find but when we do you know when we

44:31look at official statistics um and this is even less than the foundation has on their contact page so

44:38I think trying to kind of synchronize this and trying to really um get patients and get children and adults to

44:44where they need to be and and where they can be helped is important when it comes

44:50to Natural History studies it doesn’t actually these these studies are not um large in a sense that we need every

44:56individual around the country to to to to be enrolled so often studies where we

45:01would like to yeah get in our cash flow conservation probably um do specific measurements on 100

45:07individuals who have some representation and then Natural History studies typically kind of continue with maybe 25

45:14to 30 individuals if we kind of look at very very closely and this is not meant

45:19to kind of exclude anyone that’s just kind of trying to really find a representative Patient Group that that

45:26we can really kind of study very very closely to get them up to the point where we Define outcome measures yeah

45:32and actually you mentioned International I know that we have some parents who are

45:38um you know from uh from outside the U.S on the call and I just wanted to mention

45:44that the natural history study that Ingo mentioned earlier that we’re launching

45:49in the U.S across multiple centers is going to be aligned with the natural

45:55history study that’s getting launched in Europe under Esco and so you know we

46:00don’t we really are you know very committed to this idea that it’s a true you know research ecosystem globally

46:08um for stxp1 okay all right so I have the questions just

46:13keep coming in I uh this is just uh so that people are so excited about this um so question

46:20um from Allison how can my local neurologist and team stay connected or

46:25what should they know I feel like that’s for you yeah and

46:30there’s actually quite a complex question that I think I cannot really answer in its entirety right now so I

46:37would say when kind of um when it comes to local positions and local

46:44neurologists and we often have a wide spectrum of knowledge when it comes to to S takes pp1 I would actually directly

46:52refer them to the foundation web page whereas where we have actually content that we have co-written and I think this is an information that we and our

46:59generic counselors have kind of put together on on sdx pp1 on what the conditions are and what we kind of think

47:05as um as like the clinical Spectrum but I often maybe would kind of say as a as

47:12a very kind of pointed comment is that um I would always encourage parents and

47:20Physicians not to yeah stop any treatment or kind of prevent

47:26any treatment just because we think a child has a um genetic epilepsy or S takes baby one I

47:32think we’ve seen this quite a few times but there’s this old kind of thinking that a child is meant to have seizures

47:38because they have a genetic epilepsy and therefore we don’t actually kind of treat this as intensively as we would in

47:44in anyone else I think this is the main thing that has takes really want is not a diagnosis

47:50um to become complacent but it’s it’s a call to action so a question about clinical care so

47:59um uh this is from Catherine so um will Dr Helbig be seeing patients

48:06through the center and you know you talked about the natural history study um her her son had been seen I think an

48:13engine previously and so there’s a question on how is engine actually

48:18related to the center and can you talk about clinical care versus research

48:24so we’re going to do both and this is in the planning stages right now so I don’t want to

48:30actually kind of talk yet go into too much detail at this point with our engine operations and and engine Clinic

48:38is going to be continued it’s it’s going to expand so this is not going to take away anything from it but ndd or end is

48:45really meant to kind of fill this gap between our clinical program and where we are on the research side

48:53um so I know we’re getting close to time but just a couple more questions uh one on multiple you know that there’s now a

49:01growing pipeline of therapies so there’s you know therapies that have been worked on and and are being worked on in Ben’s

49:08lab and then you know there’s also um you know nine therapies actually more

49:13than nine therapies now worldwide that are being developed for stxp1 and so

49:18um one um uh Bridget is asking is you know research going to

49:24um is the goal to run multiple trials so there’s a few questions here is the goal to run multiple trials with multiple

49:30types of potential treatments um or are you expecting that the research will narrow down to you know

49:37one one treatment and then one trial um and then also

49:43um just from a you know timeline standpoint do you think that a small molecule might be go to a clinical trial

49:49before a genetic therapy yeah so maybe I can speak to it I think that

49:54um the ideal goal is that we have multiple approaches going into multiple trials and part of that is because each

50:02of these different approaches has their own pros and cons they each have their different risk levels they each have

50:08their different potential efficacy efficacies and that is something that we

50:14want we want the the patient Community to have a choice a say in that at some

50:20stage because a number of these genetic therapies um it’s a big decision for any family or

50:26for any patient to to undergo and now of course the possibility is that we get to

50:31a point where something looks much more promising than another and that will be accelerated on its path towards the

50:37clinic but but that but we won’t stop there either this is an oversimplification and I’m

50:43making this too crude but but I like to view these in sort of different tiers and so indeed there’s there’s small

50:49molecules and some of these can include already FDA approved compounds for example that could have been repurposed

50:54to try to help stxbp1 that might have the quickest potential route to the

50:59clinic but it might not address really the underlying root of the disorder and

51:04so therefore it could be therapeutic perhaps the question could it be Curative that’s sort of that’s a dangerous area to get into but that has

51:11that has the the advantage of speed Asos are more specific right they’re actually

51:17targeting the STX pp1 or the syngap one RNA itself it does have a potential to

51:23really correct the underlying issue of the disorder um and it has a fairly quick potential

51:30route to the clinic because they’re already being used for administration to the um uh in the clinic for other

51:38disorders nervous system disorders such as spinal muscle atrophy and then you have the gene replacement therapy where

51:44we actually don’t have uh um a gene a replacement therapy targeting cortical

51:51neurons for example like would be needed for stxp1 that has advanced to an FDA approval and so that might be viewed as

51:58further along the timeline or a crisper based approach for example a gene editing approach and but that that that

52:04approach might have the highest for example Curative potential for example with with crispr you could come in and

52:10in this Ideal World you could correct the underlying mutation right where it starts um but that’s further down the Horizon

52:16so we want to motivate all of those three or four approaches in parallel so

52:21we hope we can get things into Quick kids quickly but then of course also so that we can ultimately get to the most

52:28effective therapy um in the long run that has the biggest transformational impact on the community

52:33yeah so I would love to come to a point where the availability of therapies and

52:39studies outrun our clinical capacities yeah so I think we have the we have the

52:45potential of scale and I think especially for s6pp1 um we’ll be able to kind of um translate

52:51everything that that comes down the therapeutic pipeline it’s great well let’s um uh I I there is

53:00one question that’s a technical question um that I think goes back a little bit

53:05to your point Ben around you know the different therapeutic modalities and and being able to reach certain types of

53:12neurons so um you know one at last year I think at the summit um one of the

53:17challenges that was discussed was distribution of therapies to the entire brain and not just to a fraction of it

53:22and um you know do you how do you think that this you know question can be

53:27answered or you know like what technologies are you thinking might be promising that and might be involved

53:33with in this area yeah so this is where I wish I had Bev on the call for this purpose because this is really one of

53:38the major focuses of her group so just as some background you know Bev Dr

53:44Beverly Davidson has been working on gene therapy and particularly with a neurological Focus for for really for

53:51decades at this stage and one of the major challenges for that field has been

53:56efficient neuronal transduction and there are ways that you there’s a

54:03there’s a variety of ways that you could try to deliver genetic material to neurons again one is through these adeno-associated viruses or aavs and one

54:11of the major focuses of Bev’s group is working on actually

54:16strategically evolving these viruses to make them better at getting into neurons

54:21and this is an area of of considerable emphasis for her group over the last

54:27couple of years and I don’t want to steal Bev’s thunder so I won’t say too much about it but I’ll just say that one

54:32of the big things that got me excited about this Center was what’s happening in a Bev space regarding getting better

54:37at getting genetic cargo into neurons so that’s one way but again aavs and and

54:44there’s a lot of promise there but but but but but they haven’t been translated to the clinic yet right and so so we’re

54:50not putting all our eggs in that basket the other is one thing that I think is particularly promising and this is again

54:56something that we’ll take advantage of with the expertise in mRNA delivery Technologies so some folks may have

55:03heard of lipid nanoparticles for delivering mRNA vaccines for example lipid nanoparticles other systems can be

55:09used again to encapsulate genetic cargo and try to efficiently deliver it to the

55:14brain and there’s some colleagues who who who I hope that we can kind of more formally announce as part of the center

55:20in the not too distant future who are going to be focusing on those rna-based Technologies or I should say just those

55:26those delivery based Technologies to try to crack this major barrier which is efficient delivery of genetic material

55:33to neurons this is what I this is what I think is going to be sort of the game changing

55:39step over the next couple years this is where I feel like we’re on the horizon of overcoming this barrier but we’re not

55:44there yet yeah I think from the clinical side the way I think about this there are many

55:49kind of yeah it’s a it’s a race and whoever finishes this first it’s going to be the therapy that kind of feel

55:55eventually yeah in in clinic and I think it’s really important and as Ben said not not to put all your accent one one

56:01basketball we approach this from these kind of three layers the score molecules Asos and viruses

56:07so I’m going to let y’all have a last word but there is one question that just came in that I can’t resist asking which

56:13is a little bit related to this so you know ASO therapies are do they need

56:19to be you know are they going to cover every type of stxbp1 mutation and maybe

56:25and maybe not just Asos but genetic Therapies yeah this is a great question and one

56:31that we we shouldn’t start at the end of the hour because it’s really this is a big topic that requires a lot of time

56:36and it requires again more understanding of the disease presentation the genetics of the disease

56:42um but it’s it I guess what I’ll say this in a simplistic fashion it’s very true

56:47that there might not be a one-size-fits-all therapeutic and but there may be ASO strategies that can

56:53work for one particular type of mutation and another ASO strategy that could work for another that’s actually something that we’ve already been playing around

56:59with in in the lab for example but no it’s absolutely true that there may not be one size fits all and this is why

57:07we need to take while this while these therapies are coming online we need to better understand you know this this

57:12genotype phenotype relationship um with stxbp1 and and better understand

57:17the genetic spectrum of our kids so that we can if we need to be adding to those

57:23parallel approaches that we’re motivating you know parallel approaches for different types of mutations that

57:29may require a different Therapeutic Touch again I think this is where the advantage of literally sitting next to

57:35each other yeah and can really kind of solve these issues kind of very very clearly and that’s often a very kind of yeah complex way where

57:41Therapeutics developers have to kind of engage with um conditions and then we can do this all within the center

57:47because we have the expertise there can I add just one comment to this and this is just to satisfy my own sort of nerdy Obsession this is where where crispr

57:55Technologies hold their real promise right so if for example we could and they’re a long way away right but if we

58:01could get a crispr approach to correct the underlying mutation then it doesn’t really matter whether it’s a missense

58:06mutation a truncated mutate for example right so so that’s why those those Therapeutics even though they may

58:13be a couple years behind ASO or Gene replacement we need to motivate them as well because maybe ultimately that’s

58:18what becomes the broadest available technology to help the most amount of kids we don’t know that yet and that’s why we we don’t put our eggs in any one

58:25basket that’s great well I’ll ask y’all for any um closing remarks

58:31and then you want to go first sure I didn’t prepare any closing remarks and I’ve been talking so much I

58:38feel like I’ve gotten most of my points across um I guess I just what do I want to say I I

58:43I want to just convey my my I guess one thing I do want to say is I want to convey my thanks to the the the the

58:51donor as well for this incredibly generous gift and to do it in an

58:57anonymous fashion um it speaks to a humility and the

59:02generosity that I think is pretty remarkable and um and I know that

59:10for me I feel incredibly privileged right so I I know many of us search in

59:15life for the kind of what is our meeting in life what is our purpose what is our calling and for me I’ve felt for a few years now

59:21like I know where I can do the most amount of good in this world and now we

59:26have the resources to go after that with all that we have and that’s a pretty phenomenal feeling and so I think from

59:32my closing words I just want to express my thanks to that my thanks to the

59:38amazing collaborators that I have the opportunity to do this with it’s a it’s I’m not one who believes in fate and

59:45like every all things happen for a reason or whatnot but it is pretty remarkable I think that that that Lucy

59:50was born at chop and we have this opportunity across these and that we know these folks in the sdx bp1

59:55foundation this feels like a special Confluence to do some real good in the world and I’m remarkably thankful for it

1:00:02and I want to thank this community for everything that they can do for for

1:00:07helping those efforts and for continuing to stay activated and continuing to make a difference and continuing to keep us

1:00:13all motivated and energized this is a long slog and and it’s it’s a challenge

1:00:19um and uh we need the collective energy of this group to get it done and so I

1:00:24want to thank you all for that as well Ingo any last thoughts

1:00:30that’s a hard one to follow up on that I’m sorry oh sorry

1:00:36so maybe I should also say that that um yeah a very big thanks to the donor

1:00:42and I think of it also a very big thank you to the s61 community and I think what I would maybe be able to try to

1:00:48express as a clinician scientists is that I feel extremely honored I feel

1:00:53extremely humbled and I think this is going to change a lot of things

1:00:59congratulations and we are so thankful um for your long-term collaboration and

1:01:06partnership and yeah I think that you know to the community what I um what I

1:01:12would say and ask is you know stay activated this is you know

1:01:17um so amazing for us in terms of you know news to push things forward for

1:01:23stxp1 and you know let’s um let’s continue to um you know figure out how

1:01:29we can support this join our contact database and um now since we’ve launched a podcast

1:01:35series keep listening to the podcast all right thanks everyone

1:01:40thank you take care