45.e – 3rd Annual Synapse Roundtable, Cures happen faster when unique disorders find strength in collaboration

Event Time

December 3, 2021


0:10good morning everybody thank you for

0:12coming to the third annual synapse

0:13roundtable my name is michael gralia i

0:15am the managing director of the singap

0:17research fund and it is such a thrill to

0:20welcome our incredible speaker here


0:23in the interest of time i’m going to

0:24hand this over to my colleague charlene


0:28and let her introduce yourself and then

0:30our first speaker dr terry ufcel

0:33great thanks mike

0:35good morning i am charlene sun rigby and

0:38i’m the president and co-founder of the

0:40stxpp1 foundation and thrilled that we

0:43are having this round table this morning

0:46i would like to introduce our first

0:47speaker terry jo bichelle she is the

0:50executive director of combined brain and

0:53she is going to be speaking on cures

0:55happen faster when unique disorders find

0:58strength and collaboration thank you

1:00terry jo

1:02thank you so much for having me i um i

1:05really appreciate this this is great

1:08and i’d like to share my screen all

1:11right it worked so far so good

1:14and now um can you see my slides okay

1:18yes so okay so um as charlene said i’m

1:23the founder director of combined brain

1:27combined brain

1:28is a consortium

1:31made up of at this moment 26 separate

1:36uh patient advocacy foundation


1:40which you can see represented here

1:42behind my head and also on this slide

1:47we i founded this because

1:50uh i’d been working in the angelman

1:53field for quite some time

1:55for about 20 years i have a son with

1:58angelman syndrome

2:00and what i found out in the past that

2:03things have been changing in the past 20

2:06years quite a bit so 20 years ago when

2:10he was originally diagnosed

2:13it was

2:14really rare to get a single gene

2:17diagnosis for a neurodevelopmental


2:21we didn’t really know how to collect

2:24natural history we didn’t really

2:27know how to

2:29we didn’t have an icd-10 code for our


2:33we didn’t

2:34know the morbidity and mortality rates

2:37for angelman syndrome we really

2:39had to dive in deep and find out

2:42everything we possibly could about

2:45angelman syndrome

2:47and in doing this um what we found and

2:51and there are a few other

2:53neurodevelopmental disorders that

2:55were also early diagnosed prodder willie

2:59syndrome also on the same 15th

3:01chromosome area dupe 15 also the same

3:0515th chromosome

3:07a few other

3:10disorders that were diagnosed

3:12really in the early days in the 90s

3:16and um

3:18we at that point really were working

3:21hard to show how unique we were

3:24to show that we weren’t actually

3:27we shouldn’t be lumped in with autism or

3:30lumped in with intellectual disability


3:34angelman syndrome was really special

3:37because in fact it had all these



3:44and so now that 20 years have gone by

3:47and whole genome sequencing is happening


3:51we are finding more and more and more

3:54disorders that we can identify with the

3:56genetic mutation

3:58every single day


4:01things have changed a little bit and so

4:04now what we found out is we’ve got to do

4:06this fine line we’ve got to work really


4:10to find out what is unique about each


4:15but we’ve also got to figure out what we

4:17can share what can overlap

4:20what can we possibly do

4:23that we’ve that somebody else has

4:25already done

4:26so we don’t have to reinvent the wheel

4:29and what i’ve been telling people lately

4:31is you’re special

4:33but you’re not that special

4:36and what we really need to do is work

4:39hard together and make sure that we can

4:41help each other get to our cures faster

4:44so that’s why i found a combined brain

4:47let me see if this will advance yes it


4:51and it’s a consortium led by patient

4:54advocacy foundations because face it

4:56even now even with amazing


5:01clinicians researchers in the field

5:05really what we all need to acknowledge

5:07is that parents

5:09more than anybody else are the leaders

5:12for rare disease research parents

5:15are the people who care the most about a

5:18disorder parents

5:20are the ones who can actually get the

5:22big picture of what life is like to live

5:25with a child with a disorder or a family

5:28member with the disorder and so in fact

5:31these days it’s parents and patient

5:33advocates who are really leading the

5:36research for rare diseases

5:39of course

5:40working tightly with the clinicians the

5:44industry uh members and researchers who

5:48are working on these disorders but

5:51i mean patient advocates are are

5:54are really key

5:55so we are a patient advocacy foundation

5:59and uh our mission is to fast track


6:03for all of these disorders that are part

6:06of combined brain and we have three

6:09represented on the round table today

6:11phil mcdermott syndrome which is

6:15represented by cure shank and sdx vp1

6:19disorder and syngp1 mutation

6:23those three are uh three of the

6:27neurodevelopmental disorders that are

6:30part of combined brain and what combined

6:32brain our focus is on


6:37rare genetic neurodevelopmental

6:40disorders the reason why

6:42we focus on that there was a lot of work

6:45being done in autism

6:46there was a lot of work being done in


6:50there wasn’t very much work being done

6:52in cognition


6:55our disorders are all disorders that

6:58have severe cognitive disability


7:02this is why we are working together

7:06on uh looking for biomarkers and outcome



7:12neurodevelopmental disorders so when you

7:15think about uh and i’m not going to read

7:17this slide you all have had plenty of

7:19time to read it while i’ve been talking


7:23so if you think about cognitive

7:25disorders and

7:27treatments for cognitive

7:30cognitive disorders haven’t had enough

7:33uh coffee yet evidently

7:35these are our members current members we

7:37do have a long waiting list

7:39that’s building every day and part of

7:42the reason for that is because there are


7:44neurodevelopmental disorders diagnosed

7:46every day

7:47so i do think that our

7:50membership is going to expand in 2022

7:53but this is a current membership


7:56anyway when you think about how um oh i

8:00forgot to tell you

8:02these are the three disorders that are

8:04um here represented today

8:08so um

8:09when you think about a

8:10neurodevelopmental disorder and

8:14what how are you going to

8:18measure how are you going to do a

8:20clinical trial how are you going to cure

8:21it how are you going to

8:24figure out if a treatment is working

8:27what you uh what we did in the past and

8:30we did an angelman syndrome

8:33uh we made a mistake

8:35which was we

8:36put the rodent models

8:39in the center of the picture

8:42so we did a lot of great research in the



8:47when my son was diagnosed

8:51there were no clinical trials whatsoever

8:53for human beings

8:55but there were clinical trials going on

8:58in the lab for rodent models

9:01and we were all focused on those rodents

9:04it focused on those rodent models and

9:06what we could do to improve

9:08their lives

9:11and so uh what happened was that we

9:15we did find some great treatments for

9:18rodents with angelman syndrome we

9:21reversed the phenotype in rodents with

9:24angelman syndrome many times

9:27and when we did this and then moved

9:29those compounds or those repurposed


9:32into clinical trials with human beings

9:35our trials all failed

9:37so what we realized is that uh

9:41we need to put human beings in the

9:44center of this picture

9:46and when i say we i don’t mean just the

9:50people i’m friends with or the even the

9:52angelman community or even

9:55the rare disease community the fda

9:59realized that trials were failing and

10:02not just for neurodevelopmental

10:04disorders all kinds of trials were

10:06failing because patients were not put in

10:09the center of the equation

10:11and um

10:13so the fda in 2017 in 2018

10:18introduce the

10:20some guidances

10:22which really try to explain to

10:26industry and researchers that you need

10:30to put patients in the process from the


10:35you have to find out what is it like

10:39to live with the disorder what what is

10:42what is your day-to-day life like

10:45what what would matter to you as a

10:48patient or to a family


10:53change if you found a treatment so we

10:56have all these amazing genetically

10:58related treatments now

11:01coming down the pike so many kinds

11:05uh you know obviously gene therapy

11:08uh but also antisense oligos

11:11sirna rna



11:16we have uh

11:18so many possibilities for genetically

11:21related treatments that could actually

11:25really correct the underlying

11:28disorder beneath any of these

11:31severe neurodevelopmental disorders

11:34and if it worked

11:36if one of these therapies worked

11:40and it changed something it improved



11:45what would matter to patients to improve

11:48what what could we measure that would

11:51show that quality of life is better for

11:53that patient and that family so


11:58what we do is we’ve got to actually find

12:01out what matters to patients first it’s

12:03one of these things that’s so obvious it

12:06just drives you nuts and people didn’t

12:07do it before

12:09and then we have to collect the natural

12:11history on that so we have to ask

12:14questions about

12:15uh life

12:17that matters to patients on an on a

12:20regular basis over time not just once

12:24right before study but over the length

12:26of a person’s lifetime

12:28then we have to figure out which of

12:30those things can be measured in the

12:32models the rodent models even the cell

12:35models and then we have to figure out

12:38what endpoints can we develop for trials

12:41based on what we can measure in the

12:42humans and the rodents and what matters

12:45and then we do the clinical trials

12:48that’s how we get clinical trials to


12:51so this is what combined brain was built

12:54to do

12:55and uh by working with all the member


13:00we really help

13:02all these patient advocacy organizations

13:05identify that they

13:07themselves have

13:10the most responsibility

13:12and the most access to all of these

13:15parts of drug development that are

13:17represented above this timeline from you

13:20know the gene id to a cure before the


13:25so it’s really at this point up to

13:28patient advocacy foundations to lead the

13:31charge for natural history

13:33and really

13:34and this i’m gonna might be a little

13:37controversial i hope not but the patient

13:40advocacy foundations really need to own

13:43the data

13:45for natural history trials because

13:47researchers come and go y’all y’all get

13:50new jobs you retire

13:53you decide to move to another

13:54institution researchers come and go

13:57industry comes and goes

13:59uh clinicians come and go but the

14:01patient advocacy foundation they are

14:03going to care about this disorder for

14:06that until it’s cured and then after

14:09it’s cured probably to help find

14:11patients and get them to the treatment

14:13they need

14:15so natural history data it’s got to be

14:18spearheaded or coordinated or at least

14:22owned uh accessed by the patient

14:25advocacy foundation plus they’re the

14:27ones who have the list of patients

14:30they’re the ones who are going to

14:31recruit all the patients to get in the

14:33natural history and then to get in the

14:36clinical trials

14:38and actually if we do natural history

14:41right natural history can be a control


14:45this is the holy grail of natural

14:47history we all got to work hard on that

14:49um and then disease concept studies and

14:52disease burden studies these are really

14:55and really really important in drug

14:57development you have to understand

15:01what is the burden of a disease on uh on

15:05a family or a patient how you know if if

15:08if a patient has a severe

15:11neurodevelopmental disorder what has to

15:14happen in the whole family does somebody

15:16have to give up work how many medical

15:18appointments are there how much money

15:20does it cost that’s disease burden um

15:22and then disease concept i’m going to

15:24talk about in a minute is what the

15:26disease is like

15:28in daily life and then it’s really up to

15:32patients to give input to

15:34patient-centered outcomes how are you

15:36going to measure if a treatment is

15:38working without asking a patient so all

15:42those things are on the top of the

15:43timeline and then everything below the


15:47that’s got to be done really spearheaded

15:50by researchers by industry by clinicians

15:53but they’re going to need stuff from up

15:55on top of the timeline so to get

15:58biomarkers you’re going to need bio

16:00samples so you’ve got to talk coordinate

16:03for those and

16:06same thing with all everything else on

16:08the bottom of the timeline

16:11so as part of our

16:132021 initiatives

16:15um we worked hard to get the

16:18foundational work done for all of these

16:21various components of drug development

16:24and uh because time is short i’m not

16:28going to go into details on any of these

16:30but i hope that you can get a hold of me

16:33through the website

16:34combinedbrain.org or you can email me

16:37and i’m just going to talk about a

16:39couple things right now

16:41that we’ve been working on that are

16:43really pertinent

16:44one is a biorepository how are you going

16:48to get all those bio samples i mean how

16:50are you going to get those biomarkers

16:52without bio samples

16:54and this is where i tell people you’re

16:56special but you’re not that special

16:59because it’s a lot easier to work across

17:02disorders to figure out biomarkers

17:06what proteomics can we do

17:09what uh

17:10are there possibly um


17:14that could go up that are in blood that

17:17could go across a whole bunch of

17:20different disorders could you measure

17:23not just what’s specific for the

17:25disorder like gene expression but also

17:28what might go across disorders like

17:30neurodegenerative products


17:33we need biosamples so we’ve opened a


17:38that goes is open to any

17:40neurodevelopmental disorder and

17:42researchers can access these samples at


17:46the lowest cost you could possibly

17:49get by with in this field

17:52we also do these conceptual models of

17:55disease we do the draft of the of the

17:58conceptual model

18:00and today we have on this call

18:03um two disorders that have gone forward

18:06to to do the uh fully


18:10the the the final disease concept study

18:14so in a nutshell

18:16what a disease concept study is is a

18:19literature review looking at every


18:22ever reported


18:25then uh oh i see mike popping up so i

18:27better hurry up and we ask every

18:30question uh that you can


18:34uh think of um about what your daily

18:37life is like and we add all of those

18:39symptoms to a big disease concept map

18:42and from that we draw all of our um


18:47goals and objectives so one of them

18:50showed that of our original 20 disorders

18:53communication exp especially expressive

18:56communication was one of the number one

19:00issues for every single disorder and so

19:03we have a new initiative working with

19:06duke to expand a communication measure

19:08called the orca the observer reported

19:11communication measure

19:12to 12 different combined brain disorders

19:15amongst those the very first three

19:18are uh syngap1 stxbp1

19:22and well philly mcdermott is is the

19:24fourth and the reason why

19:27those are our

19:29first few disorders to be looked at

19:31is because when we did our disease

19:34concept models

19:35we could compare

19:37the disorders to each other to see who

19:39was similar and who is different and as

19:42the orca was actually invented for or

19:45developed for angelman syndrome we

19:47wanted to start out with the disorders

19:50that were closest to angelman at the

19:52beginning syngap1 and stxbp1 and then

19:55philly mcdermott and so now i’m going to

19:58conclude my talk


20:01asking if you have any questions

20:04and did i leave time for a single


20:09oh you’re silent

20:10not really but thank you so much i think

20:13one of the reasons we asked you to kick

20:14this off is because we’re so proud of

20:16being a part of combined brain and the

20:18whole theme of this round table is

20:19collaboration so

20:21this is a great opportunity for us to

20:23show our communities and our colleagues

20:25that that we are working with you and

20:28all these great organizations on the

20:29screen to do anything we can

20:32um to help our kids in the most

20:33efficient manner possible because our

20:34kids are sick as you rightly said and we

20:36care deeply

20:37thank you so much dr michelle i will see

20:40you soon