23 – Cognition, behavior & clinical trials in SYNGAP1

Event Time

January 14, 2021


Here are our introductory comments:

Dr. Andrew Stanfield Webinar Intro 1/14/2021

We are very excited to continue the SRF webinar series. The goals of the series are:

  • getting you closer to the science 
  • making you aware of the research that is been done and the opportunities to participate
  • and empowering your communications with clinicians 

We also want to give a plug for our next webinar which will take place on January 28th, 12 EST.  That will be with Dr. Karthik Rajasekaran on “”Cannabinoids: What do we know?”

Today’s speaker is Dr. Andrew Stanfield and his talk is titled ¨ Cognition, behaviour and clinical trials in SYNGAP1¨

Dr. StanfieldDr. Karthik is a Clinical Research Fellow, Honorary Consultant Psychiatrist at the University of Edinburgh.

Following the completion of his basic specialist training in psychiatry, Dr. Stanfield took up a position as a clinical lecturer at the University of Edinburgh. Within this post, he obtained a Wellcome Trust Clinical Research Training Fellowship to examine the relationship between the autism and schizophrenia spectrums.

Following this, he was appointed as a Senior Clinical Research Fellow in the Division of Psychiatry and Co-director of the Patrick Wild Centre.

He undertakes clinical work as an honorary consultant psychiatrist for NHS Lothian Learning Disability Services, including sessions for the Regional Autism Spectrum Disorders Consultancy Service.

He is also a founding board member of Tailor Ed Foundation, a lottery funded charity which provides behavioural interventions to children with autism.

After this brief introduction, I want to let you know a recorded version of this webinar will be available on the SRF website.

By the end of this presentation, you will have an opportunity to get your questions answered. We’d love to hear from you – please write your question in the chat.

For those of you just joining us, welcome to our talk today by Dr. Andrew Stanfield entitled ¨ Cognition, behaviour and clinical trials in SYNGAP1¨. It is now my pleasure to turn things over to Dr. Stanfield.

  • Older animal models to look at whether treatments are effective.
  • Trials across the age range. 

Webinar Overview:

Dr. Andrew Stanfield is the co-director of the Patrick Wild Centre, a research center for autism and intellectual disability, at the University of Edinburgh. In this webinar, he talks about the components of clinical trials, including the development stages, trial designs, outcome measures, and what is required to run a successful trial. However, even with all of the right moving pieces, there is only around a 13% chance of a clinical trial working, which Dr. Stanfield has learned from experience in his trials for Fragile X Syndrome. Dr. Stanfield explains the most critical parts of creating a successful clinical trial, including recruitment of participants, measuring the right outcomes, and taking the desired therapy from animal models in the lab to humans in the clinic, a process known as translation. He concludes the webinar by talking about his lab’s Neuro GD Study, a comparative study looking at the overlaps between Fragile X Syndrome and SYNGAP1, as well as the SYNGAP1 sleep study which will look at sleep difficulties in SYNGAP1 patients. Both of these studies will help further our understanding of SYNGAP1 in the future.

Other Relevant Publications by Dr. Stanfield

Clinical and behavioural features of SYNGAP1-related intellectual disability: a parent and caregiver description

Sleep Abnormalities in the Synaptopathies – SYNGAP1-Related Intellectual Disability and Phelan-McDermid Syndrome

Here are our final comments:

Thank you very much Dr Stanfield and all your team for the work you do . You clearly summarised the key challenges in developing clinical trials, particularly the challenges in approximating efficacy in animal models and the challenges in finding biomarkers in neurodevelopmental conditions. You also spoke about barriers in recruitment, the challenges families face in being able to participate in studies and trials and how we may innovate in that area.

  • Your thoughts on data we can prepare/capture/fund to position SYNGAP1 to be best prepared for clinical trials for targeted therapeutics. Given that we as a disease are perhaps looking at trials that target the underlying cause of the disease but also may be eligible to participate in drug trials that target the common mechanisms of ID/ASD.
  • In the latter part of 2020 SRF launched our digital natural history study, a retrospective longitudinal study based on electronic health care records with partners Ciitizen. Currently close to 100 US based participants enrolled. 
  • We note Stoke Therapeutics recently described primary endpoints in their Dravet mRNA antisense trial (STK-001) are toxicity and pharmacokinetics, secondary endpoint is seizure reduction. Adaptive & behaviours on further open label studies (Vineland). Your thoughts perhaps on how this trial and others (Angelman GTX-102) might influence a SYNGAP1 (or even FXS) “smart” drug trial endpoints.
  • We are conscious of our very small patient population, likely to be ~1000 by year end 2021 and how difficult it will be to recruit for trials. Your thoughts on the future challenges of distributed trial participation?

You spoke about the importance of participant recruitment: 

  • One of the things we suffer from as a disease/disorder is underdiagnosis. I’d ask you to speak about the barriers to increasing genomic diagnosis of children and adults with learning disabilities and how we as a patient group might work to overcome this. 
  • We know in the SYNGAP1 community it’s really rather rare to get a diagnosis as an adult (we have a short film coming in the next few months about the life of a 65 year old lady recently diagnosed with SYNGAP1 in New Jersey). 
  • Sequencing does not seem to be as readily available on the NHS? We note from social media that UK families tell us microarray is performed but paediatrics are perhaps not always referring for further sequencing. 
  • We also suffer from a lack of racial and ethnic diversity in diagnosis and this must also be true for ID genomic diagnosis in general.


0:02Okay. Okay. All right. So thank you very much Dr.  Andrew Stanfield for joining the webinar today.  

0:10We at SRF are very excited to continue the webinar  series just as a reminder the goals of the series  

0:17are to get all of the parents and caregivers  closer to the science of SYNGAP1, making  

0:24everyone aware of the research that’s currently  being done and opportunities to participate in   that research, and finally empowering patient  families to in their communications with their  

0:35current clinicians. So as I mentioned today’s  speaker is Dr. Andrew Stanfield and his discussion  

0:42is titled Cognition, Behavior and Clinical  Trials in SYNGAP1. Dr Stanfield is a clinical  

0:48research fellow, an honorary consultant psychiatrist at the University of Edinburgh.  

0:55Following the completion of his training in  psychiatry Dr Stanfield took up a position  

1:01as a clinical lecturer at the University of  Edinburgh. Within this post he obtained a Wellcome  

1:07Trust clinical research training fellowship  to examine the relationship between autism and  

1:12the schizophrenia spectrum. Following this he  was appointed as a senior clinical research  

1:18fellow in the division of psychiatry and he is  the co-director of the Patrick Wild Centre. He  

1:23undertakes clinical work as an honorary consultant  psychiatrist for NHS Lothian learning disability  

1:29services including sessions for the regional  autism spectrum disorders consultancy service.  

1:35He’s also a founding member of the Tailor Ed  Foundation, a lottery-funded charity which provides  

1:42behavioural interventions to children with autism.  So after this introduction I want to let you know  

1:48that a recorded version of this webinar will be  available for viewing later on the SRF website and  

1:54at the end of the presentation you will have  the opportunity to have your questions answered.  

1:59We would love to hear from you. So please write  your questions in the Q&A or in the chat  

2:05and for those of you  who are just joining in now, welcome   to our talk today by Dr Andrew Stanfield titled  “Cognition behavior and clinical trials in SYNGAP1”.  

2:16It’s my pleasure to turn things over now to Dr  Stanfield. Thank you. Cool. Thank you very much for  Introduction to the research being performed at The Patrick Wild Centre

2:22that introduction Jess. Seems like such a long  time ago I did some of that stuff. It’s   making me feel old. So it’s I’m going to  try and share my screen first of all and hopefully  

2:33that will will work you can let me know if  it doesn’t yes so thank you very much it’s  

2:42a real pleasure to be invited to to speak to you  all today. Good morning to those of you who are  

2:50over in the US. Afternoon and evening to those  of you who are on my part of the world.  

2:57I as Jess says my my talk’s titled “Cognition,  Behavior and clinical trials in SYNGAP1”.  

3:05In fact I mean I’m what I’m going to do is  I’ll first of all tell you a little bit about  

3:10what we do here in Edinburgh just about the  kind of setup and things that we have I’ll then  

3:17talk a bit about clinical trials in general you  know including a little bit about trial design and  

3:24and some lessons that we’ve learned from  another condition which I do research in   called Fragile X Syndrome and then I’m I will  talk about some of the work that we are doing  

3:35in SYNGAP1 and plan to do. So first of  all just declarations of interest for openness sake I  

3:45have received grant funding from drug companies  in the past for trials and Fragile X Syndrome   as well as consultancy fees usually that come  to our research centre from these companies  

3:55I should also say for trials and autism  as well so I work at a thing called the  

4:03Patrick Wild Centre which is at the University of  Edinburgh in Scotland and the Patrick Wild Centre  

4:10as this kind of subheading says is a kind of  research center which set up to investigate   autism and intellectual disability I mean  a particular focus on Fragile X Syndrome  

4:19at the beginning but we are we are much, much  bigger than that and our focus is primarily on  

4:25monogenetic causes or single gene causes  of autism and intellectual disabilities and  

4:33this picture really is just to demonstrate that  families have been key to our centre from the very  

4:38beginning and the way the way it all started back  in 2008 was a family raising money for a colleague  

4:47of mine Professor Peter Kind who is the other  director of the Patrick Wild Centre with me  

4:53and that really set off an initiative within  the University of Edinburgh to it was spotted  

5:00that this was something that there was potential  for you know real advances to occur in this field  

5:07of single gene conditions you know genetic science  and lab science had moved on but one of the things  

5:12that was holding it back really was the the silos  within universities research institutions sort of  

5:20and what the idea of the Patrick Wild Centre  was was to try and bring together people working  

5:26like myself who are clinical scientists with  folks working in laboratories like Peter Kind  

5:32and his group and lots of other people around  the university to really try to advance or to   move things forward. The centre itself is named  the picture at the bottom here of the people  

5:43standing around the plaque is that is Alfred  Wild on the far left and the centre is named  

5:49after his brother Patrick who had autism and  who died many many years ago but in honour of  

5:55his parents who really provided so much  care and help for Patrick during his life  

6:04at a time and I know this will resonate even  now when there was very little care or help  

6:09available for people. You know there’s  been a few major landmarks on the way  

6:15and the opening of the centre occurred in the end  of 2010 in 2013 one of the sister centre which  

6:23Professor Peter Kind is is a part of opened in  Bangalore in India and a lot of laboratory science  

6:30collaborative laboratory sciences done alongside  them and then in 2015 Dame Stephanie Shirley who  

6:37herself had a child who had autism and  epilepsy she donated money to us to open a  

6:47series of imaging laboratories, microscopic imaging  laboratories. And then in 2017 there was a  

6:55large grant from the Simons Foundation autism  research initiative to open a centre called  

7:01the Simons initiative for the Developing  Brain and that is something which I think  

7:08takes up a lot of what we do and encompasses a  lot of what we do here in Edinburgh. Apologies  

7:15to those of you who have heard me talk before  because some of this will will sound familiar   but these are this is SIDB which is a  collaborative centre within the University  

7:25of Edinburgh. It’s headed up by Peter Kind  who’s up on the top left of the screen  

7:31and it’s primarily built around laboratory  science understanding of the biological mechanisms  

7:37underlying autism. We have a particular focus  on single gene conditions and almost all of those  

7:43single gene conditions all of them that cause  autism also cause intellectual disability and   SYNGAP1 is… Fragile X was probably the first  condition that was studied here but  

7:55SYNGAP1 is probably the the next one along  and there’s a lot of people in this picture if  

8:00you’ve done a lot of work in SYNGAP1 relevant to  it um people like Seth Grant and Noboru Komiyama  

8:07who were very involved developing one of the first  mice models of the condition and Peter himself  

8:13along with David Wylie have done a lot of work  looking at some of the biochemistry underlying  

8:19electrophysiology of models of SYNGAP1  and David Fitzpatrick he was one of the lead  

8:25investigators of the Deciphering Developmental  Disorders study in the UK where a lot of people  

8:30who we have met have received  got their genetic diagnosis from.   And then other people are here like Stuart Cobb  who’s looking at genetic, potential genetic rescues  

8:40of SYNGAP1, Alfredo Gonzalez Sulsar who’s doing  a lot of EEG in animal models of SYNGAP1. So  

8:47suppose what I want to get at is each of these is a PI,  a principal investigator, who runs a research group  

8:52and not all of them work in SYNGAP1 but a fair  number do and it is I suppose what I’m trying  

8:59to get across is that it is a… it’s a condition of  of real interest here in Edinburgh. There’s quite a  

9:05lot of research. I believe Peter has is trying  to arrange or you are trying to arrange a date  

9:12for Peter to come and talk about some of the  laboratory science work that that his group are  

9:17doing which is good because I don’t understand  all of it (or most of it). What SIDB aims to do:  

9:26it’s a sister center to the  Patrick Wild centre. It’s about delivering   a collaborative centre to look at these biological  mechanisms understanding autism and it’s really  

9:36looking at critical periods when treatments might  be most effective and whether or not you know  

9:41there’s a lot of different single gene causes of  autism and intellectual disability but look at the  

9:46pathways that these genes are involved in and then  to look at well you know, does that mean there’s  

9:55convergence of pathways? That there’s actually lots  of different genes but they converge on single  

10:00you know, a few mechanisms and that would then  mean if they do that there might be treatments  

10:06or interventions that would be you know would be  useful for more than one cause. It’s also about  

10:14stratifying and kind of just understanding  autism spectrum conditions. And then the bottom  

10:21one which is the part that I’m primarily involved  in is about thinking about the next steps along.  

10:27Moving forward, experimental medicine, clinical  trials for people affected by these conditions  

10:32because that’s ultimately what all of this work  is designed around and it is hoped to lead to.Clinical Trials and Developmental Stages for (new) medications

10:42So as I said I’m going to start off by  talking a little bit about clinical trials   in general. Apologies if this is all just very  well known to you but I think it’s useful  

10:52to go through because it has relevance for some  of the things and challenges and things that   I’m going to talk about later on in the talk.  So I think most people will probably know that  

11:03there are a number of different development  stages for new medicines which run through from  

11:10pre-clinical work in the lab through you know,  initial safety work and then gradually bigger  

11:15groups looking at safety again and then moving  into what whether the drugs actually work. Do they  

11:23show the same promise in the clinic that they  did in the pre-clinical or the laboratory stages?  

11:29Now this is for new medicines. This is for  things that are being developed for example by   the pharmaceutical industry. We’re also  interested in medicines that are already  

11:37available, a thing called repurposing of medicines.  So where actually the preclinical and phase  

11:43zero and phase one studies have primarily been  done and then it is a matter of looking at the  

11:49phase two and phase three studies. So that skips out  a lot of the kind of early development stages  

11:56if a medicine is already available but maybe being  used for something else. But there’s a you know,  

12:02that’s really where you know, the two different  sources of potential new treatments are going to  

12:08come from. Again this is fairly straightforward  just so people are aware. I mean, there are  Trial Design

12:15different types of trial design. These are two  of the most common, really: open label studies  

12:21are studies they are not randomized. They’re not  blinded. So everybody who is in the study will  

12:28get the active medicine and everybody knows what  they are on. So both the person giving the medicine  

12:33and the people taking the medicine are aware of  the medicine that they’re on and they’re used   very early on in sort of safety studies or to get  some idea about whether or not the medicine might  

12:45work. You know, if you don’t get a signal that it  might work in a study where everyone knows that   they’re taking it it’s very unlikely to work  as you move further along. So they’re kind of  

12:53early phase studies or also sometimes late phase  studies. So studies where you’re actually looking   at after you’ve done your double blind trial  and people are continuing to take the medicine.  

13:02You know, looking at longer term safety  or longer term efficacy or effectiveness.  

13:10The kind of more common or later phase  drug trials tend to all be what we call randomized  

13:17double-blind placebo-controlled trials. So it  means in its simplest form: you get two groups and  

13:24half of them take the placebo medicine (the  dummy tablet), half them take the active medicine.  

13:29You measure something at the start and  then you measure it again at the end and you   see whether the people taking active medicine  are doing better than those on the placebo  

13:37and the idea is nobody knows who’s on what.  So you can’t bias it by knowing “oh well, they’re on  

13:45the active medicine so they’re probably  doing better.” These are the kind of   trials that are required to approve drugs so  you know drugs unlikely to get improved very  

13:53unlikely you’d get improved on an open label  study unless it has truly wondrous results  

14:00which has potential for some of  genetic therapies potentially I think

14:05(in some conditions). Double-blind  placebo-controlled trials can either be  

14:12two-armed studies or they can be crossover  studies. So again people may know this but

14:18in a crossover trial basically everybody  gets the active medicine at some point  

14:23but one group get it in the first part of the  study then there’s a bit of time while the other   group get placebo then there’s a bit of time in  the middle called the wash out where no one’s on  

14:31any medicines and then they swap round. So in the  second part of the study the people who got the   active medicine and the first bit are now on the  placebo and the people who are on the placebo  

14:41on the first are now getting the active medicine  and there are popular studies for sort of phase  

14:46two trials because they are you need fewer people  to do them than the other type of design and  

14:54they are quite powerful in that everybody acts as  their own comparison. So you can compare everybody,  

15:00you know, who’s on the active treatment to what  they were like when they were on the placebo.   The disadvantage of this: they take longer to do than  other studies and they are also first medicines  

15:12that have what we would call a “carryover effect”  they are not suitable. So if your treatment at time  

15:19one or period one is very good and lasts beyond  the wash out, so if it has ongoing effects then  

15:25that interferes with the way that you can analyze  the data because it biases or it affects the  

15:31the findings when you’re on the placebo afterwards.  So they are useful medicines but there are   useful trial designs but there are some medicines  or approaches that they’re not suitable for. 

15:42This is a much more simple in some ways  design: active treatment versus placebo.   As I said before measure everyone  on the active treatment at the start  

15:50for whatever you’re thinking the drug might  help with and then measure them again at the   end and you hope that your active treatment  performs better than those who are on placebo.Outcome Measures

16:02This is important and I think a lot of people  maybe aren’t necessarily aware of this unless  

16:10you know you’re thinking about and reading about  clinical trials but we think a lot about outcome  

16:15measures and outcome measures for clinical trials  are a fancy way of saying you know what do you   think your drug is going to do. So how what do you  think your medicine is going to help with? So  

16:28it’s usually divided in a primary outcome which  is that is the measure which the whole trial will  

16:34be judged upon. If you meet your primary outcome  and you show benefit to your primary outcome then  

16:40you’ve had a trial that works. Secondary outcomes are  kind of exploratory things. Things that you might  

16:45measure that you think it might help with but  you’re not quite so confident or things you’re   interested in and they can help inform  future trial designs or other things but  

16:54the trial doesn’t… you have to  say before you start your study   what’s your primary outcome and then you  have to meet that primary outcome to 

17:05be to show that your study has worked  so you have to pin your flag to the mast   right at the very beginning and as I’ll talk  about later on that’s quite complicated for  

17:14the kind of conditions that we work in so  what we need to run a successful trialWhat do we need to run a successful trial?

17:25so then by successful I don’t mean one where  we recruit enough people and we get a result  

17:31of some form I mean one where hopefully we have  a medicine that actually works at the end of it   there may well be other things these are  just things that come to me that are are  

17:39pretty essential we need to know that the medicine  from the laboratory treatment of the laboratory   models we need to know the medicine is going  to be safe obviously and we need to know that  

17:51it is going to work or at least has it work  in the laboratory model so and that is quite  

17:58important and we will talk about that in a bit  you know so but it needs if it doesn’t work in   your laboratory models then it’s not going to make  it out of the lab so it needs to be something that  

18:07seems to hit what we wanted to hit and it seems  to be safe when people are doing studies and labs  

18:13then we need to know it’s safe from people those  are some of the early phase studies that get done  

18:18and then these are some of the the big  areas that we’re interested in that  

18:25if it works in the lab does it then work on people  how likely is it that those treatments that you  

18:31think work great in your various laboratory models  how likely is it that they’re going to work in   people as well because that’s that’s ultimately  the key and then it needs to be the right trial  

18:42so you can have the best treatment in the  world but if you don’t have enough people   in your study it just your study will not  work so you know all clinical research and  

18:52all clinical trials live and die by the  number of people that they can recruit it  

18:57needs to be the right group of people and we  need to measure the right outcome measures  

19:02and because if you measure the wrong thing  it may work on it but if it’s not the right  

19:08primary outcome then your trial is not going to  have been successful and then i think we need to   make sure we actually have the right therapy  you know it’s possible that something might not  

19:19work by itself but it might be something  that might be helpful if it’s combined   with either another medicine or potentially a  non-medical therapy or non-medication therapyCautions from Fragile X Syndrome Experience

19:31and the reason I want to talk about this is you  know the subcautions from Fragile X Syndrome  

19:37which I spent quite a while at the beginning  of when the Patrick Wild Centre started  

19:42involved in these Roche and Novartis studies to  look at medicines for this condition Fragile X  

19:48syndrome some if people who know may not know  that Fragile X is another single gene condition  

19:54associated with intellectual disability  commonly associated with autism and ADHD  

19:59and it’s been around known about for quite  some time and it has been investigated quite  

20:07in some ways quite thoroughly in the laboratory  and there was a lot of excitement when I started   in this post about these clinical trials you know  that there was a lot of labs around the world  

20:18had shown that you know these particular type  of medicines were beneficial for the laboratory  

20:25models the mice models primarily but unfortunately  after several years of doing clinical trials  

20:32neither of the programs drug programs  came to being and I quite like this back of the  

20:38envelope calculation by Mark Baer who works at MIT  and this is taken from the fraxel website where  

20:44he basically calculates that given an 80% chance  at each of these steps that you’ve got it right

20:50what’s your overall chance of having  a successful clinical trial if you get the   right target and the right medicine to hit that  target you’ve got to get the right dose give it  

20:59for the right amount time to the right people  who are at the right age have the right amount   of people choose your outcome measures correctly  and then it needs to also be acceptable to the  

21:09people who are taking it and if you’ve choose  eighty percent you know you know can generous 80  

21:16percent of each of those steps you still come down  to about 13% chance of a trial working at the end. 

21:22So I don’t want to be too negative though but it  is one of the things it always strikes me whenever  

21:27you know, we see there’s a lot of laboratory  work that goes on and we see potential  

21:32therapies that may be helpful to bear in mind  that there is quite a difference in the steps from  

21:40from things happening in the lab to things  happening in the clinic. However like I said, I don’t want to be all negative because just  in November there was phase two Fragile X clinical  

21:52trial of a medicine that has been through this  process that is as described in this press release  

21:57here unequivocally positive phase 2 results  which didn’t require looking at subsets, looking  

22:03at additional analyses their primary outcome  measures were met and you know really positive  

22:09news. So although the studies that we were involved  in, you know, ten years ago didn’t work there  

22:14are other targets, other studies that go on and  conditions which then do lead to positive results.

22:24So yeah I was going to talk a bit more about  the bottom two of these about translation  

22:29and about the right clinical trial I  won’t I won’t labor the points too long  

22:34because I do want to talk about what we’re  doing in Syngap but first of all: translation.  Translation

22:42So what is translation? I think it’s a term  most people are probably familiar with. You  

22:49know, broadly speaking we think about it as being  bench to bedside and technically it is bench to  

22:55bedside and back again. So it is you taking  findings from laboratories into clinic but also  

23:01taking findings from clinic back to laboratory.  And translation is probably the single biggest  

23:06step where treatment, you know, development  of new treatments fails. Some of you may have  

23:12seen when they were talking about COVID vaccines  and the early animal data from COVID vaccines  

23:20this phrase which has been around for a while I  don’t know who said it first but you know “mice   lie and monkeys exaggerate”. So this is a… it’s  a long-standing phrase about how comparable  

23:31findings and laboratory models (the mice or the  monkeys) are to those that come up in humans  

23:37and people will often say it’s very easy to treat  a lot of conditions in mice. Much more difficult  

23:42to treat them in humans and I think it’s  particularly difficult that process of translation  

23:47for neuropsychiatric conditions where, you  know, there are such dramatic differences  

23:55between the brain in a human and the brain of a  mouse. You know, there’s a lot of the  

24:01basic understanding and how nerve cells work and  and other cells in the brain work is the same but  

24:07the human brain is clearly much more complex than  than a mouse brain or even than an other the brain  

24:14of other primates. So I think it is particularly  difficult for neuropsychiatric conditions.

24:23So what are the sorts of things that we  are looking at that might help this process?  Potential Translational Biomarkers

24:30So, you know, a lot of translation depends on  looking at really animal behavior or some very  

24:41sort of basic sort of say nerve  structure or something like that. So   you know, it’s that we take a look and say  okay, we’ve given this medicine to these animals.  

24:52These animals are, you know, they’re a model  animal of say, SYNGAP1. We give them this medicine and  

24:58their behavior changes and we think that is,  you know, improved social behaviour in the animal  

25:05or that is less repetitive behaviours in the animal,  you know. But animal behaviour is quite complex in a

25:13different way from human behaviour. It’s not clear  how much these kind of tests and things actually  

25:19do translate across into humans and so what we  are interested in and and other groups is, you know,  

25:26are the things that get more brain function  that we can compare between species? So we are  

25:34looking at a few different things. We’re looking  at cognitive tests which you can administer in  

25:41both animals and in humans. We’re looking EEG.  So you can look at actual electrical function of  

25:48the brain in an animal model of a condition  and we can do something similar in humans  

25:54and we’re looking at MRI. So actually looking at  heart brain function at a deeper level then  

26:01EEG is good at looking at the brain surface fMRI  (functional MRI) is better at looking at the kind   of deeper parts of the brain as potential  ways of translating. The idea being overall  

26:13that if you can show first of all that you know  say you have a rat which is a what we would call  

26:20a “SynGAP knockout” rat. So it’s a laboratory model  of SYNGAP1-related intellectual disability  

26:28and you can show that your rat has  got cognitive changes or changes on EEG  

26:34or changes on the MRI that are parallel to  those seen in humans with these conditions  

26:40it gives you a bit more confidence that your  rat model is modeling brain function in a kind  

26:45of more accurate way or in an accurate way that is  actually a model of the human condition. But then  

26:51you can look and you can give medicines say to the  rats and look for changes in these biomarkers and  

26:58and if you can then give medicines  to humans and see comparable changes   in these biomarkers it gives you more confidence  that people’s brains are behaving in a similar  

27:11way, in a comparable way and that’s the idea  that it helps the process of translation.

27:18This is just some work sorry done in that. So  that this is in cognition which is probably   where it’s been most advanced. This was done by  Seth Grant’s group along with people who  

27:28work with me Andrew McKechanie and looking  at a condition called DLG2. So people with  

27:34a deletion in this gene called DLG2 and looking  at mice with a deletion in this gene called DLG2  

27:41and looking at how they perform on this  cognitive task but the mice actually   they come and they knows they touch this  cognitive task and it’s a measure of learning  

27:49and of what we call reversal learning so  learning different associations really and then  

27:56what they showed was that they issue comparable  difficulties in particular cognitive tasks.  

28:02So that’s the first kind of step here. The next  step would be to give medicines to both groups and  

28:09to see whether or not you saw any kind of rescue  of these cognitive tasks or improvement these   cognitive tasks in the mice and the humans and  that then would make would make you more confident  

28:18that perhaps a longer trial in humans would  yield real meaningful clinical effects. The  

28:26yeah cognition as I say that this is  the area that has been most advanced   there is we have these findings Noboru Komiyama  who I mentioned earlier along with Seth Grant has  

28:36been doing these studies in the SynGAP mouse model  and we are in the process we are preparing to  

28:44roll out into people with SYNGAP1.  The pandemic has obviously put a bit of a  

28:52spanner into that work but also making sure that  the tasks who are developed in collaboration  

28:57from people with from another university  or are working things in people effectively. So  

29:03we’re also looking at EEG and SYNGAP1 and  I’ll talk about that later on. We have done some  

29:09really nice work in MRI using MRI and Fragile X  in both rat models of Fragile X and then people.  

29:15I don’t have that data to show you  today because it’s it’s not fully complete  

29:20but it’s pretty positive and  shows what we think it should show.

29:26We’ve not been doing MRI in people with  SYNGAP1 because it’s probably too difficult to  

29:35do in everyone and I think that’s probably a next  step along for us to look at what whether or   not it’s possible for us to do functional MRI  in the group that you guys are most interested in.

29:47So the other thing which I said that  we need to run a successful trial is   having enough people. Running the right  trial. So having enough people, the right  

29:56people, measuring the right thing and thinking  about whether or not we are actually testing  

30:01the right medicine. Do we need more  than… do we need to combine therapies? So when I say enough people we’re talking  really about participant recruitment  Recruitment

30:11to studies and I mean I can’t emphasize enough  when I say it every time I give a talk really.  

30:17You know, without people taking part studies  will always fail. Because if you don’t have enough  

30:23people you’re not going to show meaningful effect  and I feel this is a very obvious thing to say,  

30:28so apologies, but recruiting in rare conditions  is difficult. You know and that’s why we need  

30:36things like patient registries  and you know where people   who are able to take part because these things are  not easy to do and we appreciate that but where  

30:46people are able to take part do register  so that they are… the researchers can actually  

30:53get in touch with them. I think recruitment is  particularly hard. Again, in the kind of conditions  

30:59we’re talking about because of the inherent  features associated with the conditions. Anxiety,   difficulties with new experiences and you know,  the amount of care and support that people might  

31:10need to travel places and so forth. So we  did a piece of work looking at why people  

31:16do and do not take part in in clinical trials  and this is run by a woman called Sarah Eley  

31:22who is our clinical trial coordinator here  at the Patrick Wild Centre. This was done  

31:29in Fragile X and it was just published this  year but I’m presenting it here because it has  

31:35I think it’s unlikely to be much different for  the the Syngap population. What she was really  

31:40wanting to do was look at why is it that people  don’t take part in trials, what are the concerns,  

31:46what are the barriers to people taking part and  then what are the things that actually might   help people take… why would they take part and  what things might help people take part. And  

31:57perhaps unsurprisingly, you know, the the largest  sort of group of reasons why people might not take  

32:03part is that they’re worried about side  effects of medicines. They’re worried about taking  

32:08a new medicine or a medicine that’s not currently  available for the condition they have. So these  

32:14kind of you know safety concerns absolutely  are going to be paramount for people.

32:22Other things and what people said when Sarah  so she sent survey to about 200 people and then  

32:28she did focus groups with a number of folk and  and what people said was that you know there’s  

32:33acceptance that any medicine that carries  risk but it’s about making sure that they   are given enough information in a way that people  understand with as much safety data as possible. So  

32:44an openness and that does happen but I don’t  know if anyone’s ever taken part in a clinical   trial but you often get information sheets with  about 20 pages in them. So I think we need to be  

32:53clear you know what and that’s too much for  anyone to read really so we need to be clear  

32:59very clear in the information we give and upfront  with people about what the the potential safety  

33:04issues side effects or other safety issues are in  so much as we we know and other reasons why people  

33:14might not wish to take part could be divided into  sort of trial procedures so blood tests swallowing  

33:21tablets were two big things you know and  we talked a lot with people about thinking about  

33:27desensitization minimizing the amount of blood  testing thinking about is there ways that we could  

33:32get people ready or or help them to be able  to have blood tests more easily and then  

33:39looking at different ways we can provide  medicines you know accepting the tablets   are hard for people so looking at liquids  or pointers that can be scattered over food  

33:48and then the other the other big reason and this  is one of the other main reasons people didn’t  

33:53you know were worried about taking part was about  the effects on their on their wider life so having  

34:02the you know financial and time effects having  to travel was a big one and that was both a  

34:07combination of the time that it took but also  the difficulties I probably do not have to tell  

34:13anyone who is listening to this about some of  the difficulties that people have in traveling  

34:18to even locally sometimes but particularly  if you’re traveling far away to a new place  

34:24where you’ve not met the people before and where  your child has not met them before that’s that  

34:29can be pretty anxiety provoking so you know  one of the things that we are considering and are  

34:38likely to do and I think that pandemic actually  makes this sort of thing more easy to do is to   look at well actually can we really reduce the  number of times people would need to come and  

34:46see us you know try and get other sites that  might be local to people but also say well do  

34:51you really need to come all this time or can we  do some of these by video you know and look  

34:57at doing remotes and remote visits the which I  think as I say all of the move to using zoom and  

35:05teams and so forth in the pandemic is likely  to make that easier and more acceptable to people.

35:13The next thing and I’m not going to talk a  lot about this but it’s about having the right  Correct group of people (age, subgroups)

35:21group of people. I don’t think we know in  SYNGAP1 what the right subgroups are.

35:27I think there’s of people that  should be coming into clinical trials   there’s an instinctive feeling I think we all have  that medicines are likely to be more effective if  

35:36they’re started in younger people you know  but there is some laboratory evidence from  

35:42Gavin Rumbaugh’s group in in recent times you know  showing that there are still improvements that   can potentially be made in young adulthood  these were done in mice not in people I should  

35:55say but you know that that it’s not necessarily  that if you if people haven’t been treated when  

36:02they’re very young that they may not be able  to social improvement and I think to be honest   what age needs treatment should be started  is going to be different between different  

36:14genetic conditions um between different  mutations potentially even within the gene  

36:19and certainly between depending on what the  actual treatment some treatments might work in   older people but they don’t work in in younger  individuals because they target different  

36:28circuits that are you know maybe more amenable  to change in in older people and it’s probably  

36:34going to be symptom specific as well it’s quite  possible that improvement can be made for example   in seizures or in some other symptoms in adulthood  whereas you know it may be harder to

36:47change other symptoms but we really don’t  know at the moment. I suppose it’s  

36:53important not to generalize them. That’s probably  my main message. I think we need more work in older  

37:00animal models because a lot of work is often done  in very young animal models. So I think we need all  

37:06working older animal models to look at you know,  whether or not treatments are effective in those  

37:12and then I think we need to do trials across the  age range in people and I think this comes from my  

37:19experience and lots or experiencing in Fragile  X that you know if medicine doesn’t work in  

37:25an adult or an adolescent it’s not a reason to  stop studying it. It’s not a reason not to look   down to younger individuals because it might  be that it might be effective for them.  

37:34So it’s important not to generalize too much when  thinking about age and so forth in clinical trials

37:43and we need to measure the right outcome  and I’ve put this including biomarkers   as a question mark here as well. I just want  to talk a little bit about outcome measures  Measure the right outcomes (incl. biomarkers?)

37:55generally. So I mean this is something all of you  will have to have done getting your blood pressure   measured I know it’s not as simple as I have  cardiologist friends who tell me that that this  

38:05is not 100 correct to say but sometimes I wish  I was doing a trial of a medicine to lower blood  

38:10pressure because you can get an objective measure  at the very beginning that is you know a number  

38:17and you can do that in all of your people  and then you can measure it again at the   end of the study and you can see if those on  the active treatment if that number is lower  

38:25than those in the active treatment than in those  of the placebo and the nice thing about that  

38:33is that we also know again it’s not quite as  simple as this but we do largely know that  

38:38if you lower blood pressure you lower the risk  of future cardiac offense so in other words  

38:46lowering blood pressure in itself i mean if we  could get a drug and we could show it lower blood   pressure the only reason that’s worthwhile is  because there’s an actual real clinical meaning  

38:53for people yeah you know so it means that later  on they’re less likely to have heart attacks or   strokes or whatever so it’s it is a biomarker  you could say it’s a it’s a you know quantitative  

39:05measure of a biological function that is in itself  not that meaningful but is a meaningful predictor  

39:15of future health so you know there’s  something that’s that’s really appealing  

39:21and really attractive about something as nice and  simple as blood pressure as an outcome measure.  

39:27Obviously we don’t have that in  neurodevelopmental conditions. So again  

39:34this is coming from Fragile X studies  that a lot of outcome measures that   people have used and continue to use are based  on observer reported behavior and that’s I mean  

39:49that’s understandable because ultimately at the  end of the day for a treatment to be meaningful it   has to make an observable difference to either the  person themselves or the people around about them.  

39:59But the problem with these measures is that  they’re very subjective and there’s a large   kind of placebo effect associated with them so  I just put this graph in just you don’t really  

40:07need to worry about what each of the lines is  but this was in some of the Fragile X trials   and the the key thing here really is that for  the first four weeks the very left-hand side  

40:18of that graph everybody had placebo and in that  first four weeks pretty on average pretty much  

40:28overall pretty much everyone improved and  some people improved quite dramatically you know  

40:35the scale on the left-hand side minus 20  is a really significant improvement you   know that’s a successful treatment  on you know in in terms of that scale  

40:45so you know and that is when people were on  placebo that’s and I should be clear as well  

40:50I mean i’ve not got time really to go into a  placebo response it’s not like it’s made up   it’s not that somebody is like oh I think they’re  better so they kind of are I mean people do show  

41:00improvements that occur just by taking part in a  clinical trial by coming along by seeing people  

41:08by for some families some of the trials that  we’ve run you know they are they’re having to  

41:15do new things so they they they come out of the  you know they get a flight to come up and see us   in Edinburgh they get the train up in Edinburgh  because they’re they want to come to this trial  

41:24and that then starts to open up the world a bit  more and the people feel more confident they’re   you know the the patient or the affected  person themselves feels a bit better about  

41:32doing some new things so they’re real genuine  benefits it’s not just a kind of made-up effect  

41:39but it is an effect that’s non-specific  and it’s not due to the drug so  

41:46this is one of the biggest problems with  outcome measures in these kind of trials   and so we need better ones or additional ones  really so I mean this is just a list of things  

41:56that a good outcome measures to have it needs to  be they need to be something that’s acceptable  

42:02that we can measure and people alike need  to see something that captures impairment   that is meaningful to people or it marks  something meaningful so like the blood pressure  

42:11measure that I talked about needs to be something  reliable so you can repeat it and get a similar   kind of finding and this ideally objective  so something that’s not going to be as  

42:22vulnerable to placebo effects and then  it needs to capture changes over time  

42:28so again the sort of things that we’re looking  at are sort of things that I talked a bit about  

42:35earlier on as potential translational measures so  measures of cognition measures of brain function  

42:41both you know the the top is doing those  touch screen tests the little picture below is  

42:47a child doing some eye tracking tests of cognition  which are really nice because they don’t have to   involve the baby in this case actively pressing  buttons or doing anything. They’re passive tests  

42:57but they can measure cognitive function and then  things like an EEG or and functional imaging  

43:04are also potential outcome measures, may  also be potential biomarkers that might, you  

43:11know, predict change. I’m not sure that  we’ll ever have clinical trials where we  

43:17give someone a medicine and then we take their  EEG and we say “oh yeah, cool. It causes to change   the EEG signal. So there we go. This medicine works.  Off we go.” What we might have is trials where  

43:28we might see changes in an EEG signal early on  in treatment and that would then motivate us to  

43:33continue on with treatment with the medicine. So  it might be a way of helping to pick out those,  

43:38as I say, predictors of future response  and of clinically meaningful benefit.Is one therapy sufficient?

43:47The other thing I’m not again not going  to labor this is, you know, one therapy  

43:52sufficient? You know, one of our families  who’s involved with us just talked about   clinical trials once as being like do we it’s  a bit like teaching someone to read in the dark  

44:03so you need to turn the light on but then you  also need to teach them how to read so a   medicine might turn a light on but you may also  need another intervention, a learning intervention,  

44:13a language intervention, a behavior intervention,  that that will then interact with that medicine  

44:18to make the biggest kind of differences you know  particularly over short periods of time so there’s  

44:24a few good examples this is increasingly common  and there’s a few good examples in Fragile X  

44:29for example yeah Fragile X syndrome but  there is also in other conditions as well  

44:35and I think if we want to try and maximize  benefits then this this is a good way to go

44:43so this is probably what you’re all thinking  I’m aware it’s not a quarter past five years   so I’m running later than i had intended to  and you know i’ve yet really talked about what  

44:53we’re doing in SYNGAP1. So that’s what this part  of the talk is going to be about i’m hoping that  

44:59you have stayed on for it I can’t see how many  people are still are still listening at home  What are you doing about this in SYNGAP1…?!

45:05but hopefully you’re still there I presented 27  people still on oh excellent here ah good the  

45:15it’s always really it feels slightly strange  during a presentation this because you feel like   you’re just talking talking to yourself the so  yes what are we doing in SYNGAP1 and some people  

45:27here indeed some people on the call will  have participated in some of this research   this is one of the big studies that we’re  running at the moment which we call the  

45:36the Neuro GD study neurocognitive phenotypes  and monogenic developmental disorders and  

45:43basically it’s a study where what we’re doing is  looking a bit like I talked about some of the  

45:52aims for said to be earlier on about convergence  and divergence looking at well what conditions  

45:58have overlaps between them and what ones have  have differences and it comes from this paper  

46:05that David Wylie and Peter Kind’s group  did about five years ago now looking at SynGAP, 

46:13their SynGAP mouse model and the Fragile X mouse  model and what they find in that paper was that   there are overlaps between these groups in terms  of how the biochemistry, biochemical pathways  

46:24and the hippocampus so the electrophysiology  compound in the hippocampus. There was a high  

46:30degree of convergence between what was working  differently in your SynGAP mice and your Fragile  

46:35X mice compared to typically developing mice and  then they also showed in this study as well that  

46:42the medicine lovastatin reversed this these  changes in the hippocampus in both of these  

46:48these mice and the hippocampus as people will  probably know as an area of the brain particularly   important for things like memory and learning  and so it was, you know, quite exciting  

47:00because a) it showed that there was similarities  and convergence between these conditions and b)  

47:06it was also I think the first study to look at  lovastatin or any I think any intervention in my  

47:14small line may be wrong with that but certainly  lovastatin in a mouse model of SynGAP.   And so what and that’s what kind of motivated  this study so we are really it says talks about  

47:25monogenic developmental disorders and it’s set up  to look at as many as we wish to but at the moment   we’re really only looking at Fragile X and SYNGAP1  and it is like I say a) to look at convergence  

47:36between the conditions. Do we see that overlap  happening that we see in the mice model? But b) also  

47:43to fulfill that other thing I mentioned earlier on  for the Simon’s initiative which is understanding  

47:49these conditions deep phenotype means we call  our understanding these conditions at a level  

47:54which will be helpful for running clinical  trials. Now we know a lot there is a lot  

48:01of this work has been done for Fragile X before  so the most novel part of it is looking  

48:07at characterizing people with SYNGAP1. So  this first group of of questionnaires  

48:15and interviews are all things that are sort of  clinical outcome measures to look at some of the  

48:21kind of behavioral traits that we you know  people think that one might display there’s  

48:26a measure of non-verbal intelligence as well and  then there is a these measures which are more  

48:33of those kind of cognitive our brain function  measures so looking at cognitive touch those touch  

48:39screen measures um looking at eye tracking as I  said earlier on a test of how the brain functions  

48:45and then looking at various different EEG  kind of signatures of cognition and connectivity  

48:52and then particularly these this  group are also translational measures  

48:59you know that we can do both in the humans  and we can do them in the laboratory model. So  

49:06it’s hitting a few different important  aspects which are going to hopefully help us  

49:13move more towards clinical trials

49:18so I’ll talk I presented some of these data  fairly recently so some of you you may have  

49:24seen them at another conference we actually have  now 28 people with SYNGAP1 in this study but  

49:33the data that we have got complete data and  all organized and sorted out this and about  

49:3918. Almost everyone’s under the age of 14 who  took part in the study we have one adult who’s  

49:44who is 34 but they most people are in the  younger kind of age groups and really this this  

49:53what we’re aiming to do here is look at whether  or not these measures might capture the the the  

49:59behaviors that people present with so that  maybe we could use them as sort of subjective   measures that we can use in clinical trials  but also just to try to describe in detail the  

50:10sort of behaviors that people present with you  guys all know and families talk about you know  

50:17how their children present and things but  actually putting it down in the scientific  

50:24literature so it’s out there that it can  be given to clinicians and so forth using   these kind of standardized measures is also  I think one of the other potential benefits of  

50:32of this study. So I’ll talk about some  of these here. One thing I’m not going  

50:39to talk about but which I think is probably really  interesting and we are starting to have a look our   analysis a little bit is what I call a qualitative  description of the general behavior so that’s just  

50:48an interview with families to say what what are  the behaviors what is your you know describe your  

50:53child what what do they like or they what are they  good at what do they struggle with what are the  

50:58what are the behaviors that cause you the most  difficulty that kind of thing because there’s  

51:04something beyond what these kind of standardized  measures can capture which we we hope to try  

51:12and get at with some of those kind of qualitative  or personal descriptions from families.Autistic Traits

51:20So this is measures of autistic traits.  The dotted line which runs up from 65 upwards  

51:29is what we would call moderate impairment. This is  a screening test called the social responsiveness   scale and if you score about 65 you’re felt  to be highly likely to… you should move  

51:41forward for further diagnostic screening for autism. Now I qualify this by saying that when  

51:50we speak to families that certainly folks  do describe autistic traits that people  

51:56will often say that, you know, it’s maybe different  from other kids who don’t have Syngap and that’s

52:02very similar to what folks see in Fragile X as well actually  that, you know, there are differences in how   these sort of difficulties present but because  our descriptions aren’t so good they kind  

52:12of often get rolled under this sort of rubric  of autism. Our kind of finding papers today have  

52:19suggested you know, 50 percent maybe a bit more  of people presenting with diagnosis of autism  

52:24certainly our findings would say that there  are much greater numbers than that who are  

52:29presenting with very high levels of autistic  traits. Now whether everyone goes on to get a   diagnosis of autism they unlikely to but  it you know when looked at in more detail  

52:42it does seem like there is you know, higher  rates of autism than are perhaps described in  

52:49some of the existing literature and then perhaps  are diagnosed the people maybe have you know quite   high levels of autistic traits but they never  actually get a formal diagnosis of autism.  

53:01Hyperactivity a.m you know can come under ADHD  but again very high levels of of hyperactivity,  Attention / Hyperactivity

53:09difficulties with attention and  you know impulsive kind of behaviors  

53:16that we see that you know and it was  one of the we had a day where we had maybe 13  

53:24or 14 families who came along and it was very  clear that a lot of children were very active   and yeah it’s one of those things I  think is it’s quite common again whether it is  

53:37ADHD or whether it is you know different  from that we we still don’t really know and  

53:45I know there’s been some I saw Jimmy Holder  present some nice work just looking at which   medicines had helped people and and from  what they’d seem to find stimulant medicine maybe  

53:54weren’t so good but medicines like clonidine or  guanfacine had been quite helpful for some of   the difficulties people had. So yeah you  know, that’s part of one of the things  

54:05that we we hope to get out of it more with some  of the kind of qualitative interviews with people  

54:11but again I think just very you know high levels  of difficulty people score highly on these 

54:16scales this is the CBCL or childhood behavior  checklist which covers a whole load of different  General Behaviour

54:23kind of domains of behavior. You know, what people  would sometimes call it difficult behaviors or  

54:28behaviors that cause people problems and again  that dotted line is clinically significant and  

54:35you know a lot of our group of people  score above this dotted line  

54:43and yeah the people have asked and I think an  area of real interest for us is what happens  

54:51over time? So you know this is a snapshot taken of  a group of people between the ages of about 3 and

54:5612 or 14 you know but how does this develop and  change over time? You know, we expect probably  

55:03autistic traits not to change we’d expect  ADHD traits maybe to get better but behavior  

55:09you know moving through adolescence is a  difficult time for any children and parent  

55:16but the you know how does people change those  behavior changes by the time and hire people as  

55:22adults and I think these are areas that we need to  know an awful lot more about and

55:27we don’t have the data at the moment. You know  we don’t really have groups of people in those  

55:33older age groups to look at but it’s something  that would be really interesting to take forward.Sleep Habits

55:40Sleep is something that families talk to us about  and you know this these are data on just a  

55:48sleep and overall sleep questionnaire and lots of  difficulties in sleep you know particularly with  

55:54behaviour overnight and sometimes not  going to bed, not going to sleep at night time.

56:01Jimmy Holder and Connie Smith-Hicks also  have data with the same kind of questionnaire so  

56:09we’re going to combine it all together to look  at it in greater numbers you know but it’s

56:14definitely something that is an issue and needs  investigated more and I will talk very briefly  

56:19about that piece of research that we’re doing  or starting soon sometime towards the end.

56:28And sensory issues again very common. Particularly  in the touch domain. You know we  Sensory Profile

56:34that people have both sensory seeking and sensory  avoiding behavior and particularly have the  

56:41hypersensitivities to touch. A lot of people  taught us about enjoying children who enjoy the feeling of water and you know but also  people who dislike certain feelings. Loud noises  

56:53is a common one and that people dislike but  yeah so very commonly people are presenting with  

57:00with sensory difficulties which  are again part of autistic traits   but may well be you know have an underlying  difference from people’s autism with other causes.

57:16This is the other thing that we are  one of the other things that we looked   at which is about adaptive behavior  what can people do where their skills  Adaptive Behaviour

57:25how well do they manage adaptive behaviors  basically the skills that you require  

57:30to move through day-to-day life and this  this test thee Vineland looks at social skills   it looks at daily living skills things like  washing dressing you know heating and that  

57:40and then it looks like communication skills  and scores of under 70 are said to be sort of  

57:46significant impairment and a lot of people are  presenting with significant impairment for the  

57:51for their age range although interestingly  some not some people are performing you know   quite well in in various parts of this  scale but it is… it’s a… I don’t think I’m saying  

58:02anything that people won’t know that you know  folks ability and adaptive behavior is is impaired  

58:09and when we look across age at first glance what  you can what it looks like is that as people get  

58:17older that their abilities get less but that’s not  true that’s because of the way this scale is

58:25done so it’s not the people are losing skills it’s  not the people are regressing and becoming worse  

58:31at things but they are struggling to keep up with  the skills of the general population so people  

58:37still are acquiring new skills you know  but not at the same rate as those people in  

58:44in the general population. Now we need to look at  this longitudinally. We need to look at this and   as I said earlier on we have very little data in  anyone above the age of 14. So we need to  

58:55find out more about the adult phenotype but the  adult the way people present this adult spot  

59:01I suppose my message is that it’s not that people  don’t learn skills but it does take them longer

59:08and they don’t require them to the same way that  some other individuals who aren’t affected do

59:17I’ll briefly touch on some of the biomarker stuff  and we this has all been ki washed for one of   a better term by the pandemic because  these require face-to-face assessments they’re  

59:26not things that we can particularly do over over  video at the moment but they are things that  

59:34we we had just started to see people again in  November time and I don’t know what the rules are  

59:43like where everyone else is but here in the UK we  are back on a total lockdown so we’re not really   able to see anybody for research at the moment  hopefully as the vaccine gets ruled out these  

59:53the situation will change but we are looking  at this reversal learning task but like i say we  

1:00:00have done in another genetic condition before and  our colleagues of mine have done another genetic  

1:00:05condition before and that it is something that  we have got translational measures for in the mice  

1:00:12models of SYNGAP1 so this is something that has to  say that’s that’s quite well worked up in the mice   models and it’s going to be a real interest to see  is it a potential translational marker in that  

1:00:23that works bet in both you know the machine  difficulties in both the mice and in humans  

1:00:30we’re doing eye tracking which i mentioned earlier  on as a passive test of cognition both to look at   people’s one of these tests is looking at you know  focus on social stimuli as opposed to you know  

1:00:40you know we are supposed to look more at faces  than we are at other parts of the body or  

1:00:48non you know non-human objects so these heat  maps can tell you how long people look at  

1:00:53things I do worry about having a mobile phone  though people automatically look towards that   but it’s it’s to get a handle on social  processing really and then one of the other  

1:01:05tests that we’re doing is you know you have this  group of stimuli and naturally people’s eyes   are drawn towards the old one out and how quickly  you’re drawn towards the old one eye is a kind  

1:01:14of measure of inspection time which in itself is  a measure is it is a cognitive function and not  

1:01:21just how quickly but also what sort of patterns of  of eye tracking that you use so the top one is a  

1:01:28much more sort of organized quickly drawn over to  the the o whereas the bottom the person is looking  

1:01:34much more but probably slightly more at the o  than the most of the other stimuli but it’s not  

1:01:39nearly so organized so and these are data that  are taken from from children with SYNGAP1 we  

1:01:44just don’t have enough to make any clear you know  statements about it we’re also doing EEGs  

1:01:54while people are to look at visual processing to  look at auditory processing and also while people  

1:02:00are at rest so we’re not looking here at seizures  what what we’re looking at is you know high  

1:02:07very primary kind of auditory and primary sensory  processing and brain connectivity so it’s  

1:02:15not so much looking for biomarkers in terms of  seizures or spiking but in terms of you know  

1:02:21differences in sensory processing. These are some  of our kind of good quality traces for  

1:02:28into a better term as I’ve said in other talks  before a lot of our traces look like this because   children with SYNGAP1 find having an EEG cap  put on and sitting and watching boring screens  

1:02:40flash or listening to you know tones not very  exciting so you know there’s a lot of movement  

1:02:46and we’ve recently kind of updated our equipment  and our protocols to try and improve this as as we  

1:02:54do move forward and come back out of the pandemic  and it will be possible it is just something that  

1:03:00it just i mean not for everybody but it is going  to be possible for some people but i think it  

1:03:05is something that we need to keep constantly  refining how we actually acquire the dataSYNGAP1 Sleep Study (PI Dr Lindsay Mizen)

1:03:11i said i would mention this briefly this is  separate from the NeuroGD study but this is   something that we have just got funded or a  colleague of mine dr lindsey mison has just  

1:03:20got funded and what she’s going to do is to look  at detailed characterizing sleep difficulties  

1:03:26in SYNGAP1 using sort of formal sleep studies  so ideally assuming that we can do this because  

1:03:35of the pandemic and assuming people are willing  to let us what lindsay and her team are going  

1:03:40to do is hopefully to visit people at home and  to monitor over a couple of nights sleep using  

1:03:49a device which monitors things like heart  rates respiratory rate but monitors also  

1:03:55a few electrodes for EEG signals and things to  really try and get a detailed handle on what’s  

1:04:01going on in sleep in part because there are  some sleep difficulties that there are existing  

1:04:08treatments for so it’s possible you know can  we actually diagnose sort of no one’s sleep   pathology wants a better term but also this is  coordinated with some of that we’re also doing  

1:04:18again I say we it’s a it’s a broad way colleagues  within the Simon’s initiative for the developing   brand are also doing sleep studies in the  rat model of SYNGAP1 so again thinking  

1:04:29about these translational markers they’re doing  various things to look at sleep staging and EEG  

1:04:36heart rate etc and thinking about these  translational markers that we might be able to   use to develop better treatments moving forwards  or better translational treatments moving forward

1:04:49I’m moving looking forward you know I’ve  talked before about I mean we the whole idea  Looking forwards

1:04:57of setting up what what we want to do is to look  at clinical trials and you know and there is some  

1:05:03animal data that come from from colleagues of  ours to let’s say lovastatin may be effective  

1:05:09more recently and this is published as a  pre-print at the moment Peter Kind’s group have  

1:05:16shown that the medicine ethosuximide which is an  anti-epileptic drug was particularly effective in the  

1:05:21rat models for seizures and whether you know  there’s lots of people out there who will have had  

1:05:29ethosuximide and which may or may not have  been beneficial but whether it’s worth  

1:05:34us pursuing that in different dosing or possibly  in combination with other medicines is something

1:05:39that we are we’re considering at the moment.  I’m also interested in what people think you   know these lovastatins targeted at underlying  biochemistry. Ethosuximide is targeted at seizures.  

1:05:49There’s obviously, and I’ve not talked about this,  but there’s obviously interest in things like   genetic therapies which are targeted at you know  real you know the underlying sort of core features  

1:06:00of the conditions but there are also medicines  out there that are used quite widely in children  

1:06:06and in adults for things like ADHD and anxiety  and you know which are prescribed and given to  

1:06:14children but which with you know some some of  your children may well be taking them but we we   don’t have good evidence for what the best type of  medicine is that we should be giving to people so  

1:06:24could we look at doing trials of medicines  that are for symptoms not so much targeted   underlying core features but actually saying you  know what’s the optimal overall treatment strategy  

1:06:37if you’re looking at medicines that you should  choose to consider someone with SYNGAP1 who   presents in this way or with this difficulty. And I  think there is also definitely we and this is not  

1:06:51something we are actively pursuing at the moment  but I do think that as I say to maximize the   chance of success we want to be combining our drug  treatments with non-medication-based interventions  

1:07:04and I think if I’m honest in the first  instance and this is something that we are   we are talking a lot about here is looking to do  a feasibility study using one of the medicines  

1:07:16from the above or if there is other  potential candidates you know to say actually  

1:07:22can we do clinical trials in SYNGAP1 for us in  the UK but also looking worldwide you know to see  

1:07:30about if overcoming these barriers. How do we  do them? What are the logistics and you know   are people able to come? Can we do the things? Can  we do a lot of it remotely for medicines that  

1:07:40are known to be pretty safe to take? So you  know, actually looking forward and saying you know,  

1:07:45the first step is to do a feasibility study of our  best candidate open label trial and to see does it  

1:07:52you know, does it help? But also well to say is  it possible? Because I think if we you know we  

1:08:01need to start with small studies that show that  we can then move on to do bigger studies. So  

1:08:09i think that is it. This is just the various  funders, people we want to thank that’s our  

1:08:16the bridge the gap sitting up day family day that  we had in Edinburgh in 2019 2020s was cancelled  

1:08:24but we have a date for 2021 which was attended  by at least some of the people on this call and  

1:08:30this is the most up-to-date photo of my specific  research group this is our christmas card this   year which you could only do socially distanced  by a zoom lindsay mizzens up in the top left  

1:08:40that she’s doing the sleep study i’m the terrible  fool on the top right Aisling and Damian who  

1:08:46are doing a lot of the Neuro GD study and who  some of you will have either met or have met  

1:08:52by zoom over the last while Andrew mckechnie  who’s done some of that work that i showed with  

1:08:58the translational cognition and who’s  been involved in a lot of the clinical   trials and then sarah eli at the bottom who is our  clinical trial coordinator here in the center  

1:09:08these are the people who’ve done most of  the work that I’ve presented and we’ll be   taking things forward so thank you i am happy to  hang around I’m aware i’ve gone over my time but  

1:09:18I’m happy to hang around and take questions if  people have them I’ll just try and stop sharing  Questions and Answers

1:09:27we do have a couple of questions in the Q&A  they’re coming in I just wanted to say first  

1:09:33thank you very much Dr Stanfield and to  your whole team for the work that you do  

1:09:38and you clearly summarize the challenges  that we have in developing clinical trials   particularly in approximating the efficacy  between animal models and the humans and the  

1:09:48challenges of finding biomarkers i also spoke  about the barriers to recruitment and also the  

1:09:53challenges that the family is facing you know  being able to participate so we appreciate that  

1:09:59so I will start with the first question which  was what is generally the minimum number of  

1:10:06participants required for trial so it depends it  depends what type of study you’re doing what type  

1:10:15of trial you were doing the you know you for  a definitive study you know, for the kind of study  

1:10:24that say the Fragile X trials for example that we  were looking at that we were involved in that   we’re looking to see about potentially getting  a medicine license those were studies which had  

1:10:32you know 150 plus people in them which is big  for our fields but small compared to cardiology  

1:10:42studies and those sorts of things and you know  it depends how effective your treatment is likely   to be as well if you’ve got a really effective  treatment then you don’t need that many people  

1:10:51to show that it works I would say if we were  doing and we heard we’re talking about this at   the moment you know what for a feasibility study  we’d start off with maybe 10 or 15 people in an  

1:11:00open label study to show that you know this might  work get some idea a signal of potential benefit  

1:11:08I think then if you’re moving into a kind of  crossover study if you can get 30 or 40 people  

1:11:13together and these are you know back of a envelope  calculations that that would you know have a  

1:11:19reasonable chance of success but you do  need to get into the hundreds to really   I think prove effectiveness in in a way that  say drug regulators are going to be happy with  

1:11:33the one big caveat to that is you know if you’re  doing some of these genetic trials or genetic   rescue studies that are done you know where  they’ve got very massive effects and conditions  

1:11:42you know some neurological conditions and  very young children you don’t need those sort  

1:11:48of those sort of numbers so you know it it depends  on how effective you think it is and also what  

1:11:57yeah what what you think it’s going  to do what you’re actually testing   people let’s see Mike is this handoff yes can  i throw a couple questions in sure sorry two  

1:12:11biggies Dr Stanfield and of course first thank you  that was that was comprehensive and very helpful  

1:12:17Fragile X I think is an interesting one that  I’ve come to appreciate a lot of our patients get  

1:12:24when the younger kids present the clinicians  are more familiar with Fragile X because it’s   been around longer better understood  and some clinicians including my own  

1:12:35test for Fragile X and then they get a negative  and my clinician at least was like okay it’s not  

1:12:40genetic which was obviously a silly thing to say  and that’s why they’re no longer my neurologist   but I think it’s helpful for the community to  understand like the Fragile X and I’m just going  

1:12:51to say this and invite you to correct it Fragile X  is a much bigger population much better understood  

1:12:56and very often our kids that’s the first suspicion  but then good neuros generally keep going with the  

1:13:02testing so phenotypically that’s interesting right  we we have a lot of overlap of Fragile X. Fragile X  

1:13:09has been around much longer, spent much more money  question one assuming everything I just  

1:13:15said was directly correct question one how can  we benefit from all the money that Mike and the  

1:13:21team at the Fragile X foundation have spent  on that work and then getting inside the body  

1:13:29why is it that our kids look like Fragile X is  it that all kids with NDDs kind of look the same   in the early years or is there something there  in your overlapping expertise between those two  

1:13:39syndromes the the what is the relationship  between Syngap and Fragile X because   it keeps coming up so that’s my first  question and I have another one okay  

1:13:48so the how to benefit from the  work that has been done I mean I think  

1:13:56some of what I you know talked about in terms  of trial design I think the Fragile X field is  

1:14:03probably fairly high up in terms of the  way it’s thinking about running trials in  

1:14:10children you’re combining them the forward study  which is being run by Liz Berry-Kravis at Rush is  

1:14:15you know combining, looking in  young children with a good length   of time of treatment and along with a kind of  another intervention as well. So you know, even  

1:14:25the sort of the failures in Fragile X I think have  led to us having a better idea about how to do  

1:14:34trials. In terms of, you know, their  actually understanding the you know that the  

1:14:44affect overlapping kind of pathways  basically in the synapse which you know,  

1:14:50if you look at these diagrams of you know,  FMR yeah the the gene that affects Fragile X  

1:14:57FMR1 and Syngap, the proteins at the synapse  in the brain they you know, they all  

1:15:06I wouldn’t go so far say they form part of the  same pathway but these pathways overlap and they   cross over and they converge which is  what motivated Peter’s group to go and look at-  

1:15:15look for that convergence in the animal  models. And it’s actually a big  

1:15:20part of what motivated looking for convergence  across other models as well. So you know, I think  

1:15:27that there’s the the work that’s been done in  Fragile X points somewhat to potential things  

1:15:35that might be helpful in Syngap that was  why people tried lovastatin and it had been shown   in Fragile X and then that was one of the reasons  to look at it and Syngap in that barnes paper  

1:15:45was done here five years ago or so so  you know I think there is a I think there’s  

1:15:50some learning that can be done. I don’t want to  overstate the convergence so you know I mean I   think part of the reason clinicians  always look for Fragile X is because it is  

1:16:00one of the more common you know genetic findings.  It’s been known about for a long time I’d say   people are familiar with that you know and  there are definitely features which which overlap  

1:16:11but as you say good clinicians everyone  should be checked for Fragile X. Syngap may not  

1:16:19be that much less common it’s just much less  commonly identified because the tests required  

1:16:25are more complex, more expensive and not as widely  available. That’s changing. I hear certainly are  

1:16:34not you know our clinical genetics department that  you know thanks in part to studies like the DDD  

1:16:40study you know where and actually exome sequencing  which does identify a lot of cases of Syngap  

1:16:46is becoming a second line but available test  within the UK health service. So you know it is  

1:16:54not it will take a while I think often for people  to get it unfortunately you know by the time  

1:16:59people go through as everyone knows the delays but  it is changing and I think we will see a lot more  

1:17:04I mean we’ve already seen more people diagnosed  with Syngap and people diagnosed through   clinical more clinics and awareness should  grow I would say as well that one of the big  

1:17:13frustrations in the Fragile X community is that  doctors still don’t seem to know a lot about it.   Most of them go oh yeah I remember that at medical  school it’s causes learning difficulties doesn’t  

1:17:24it and that’s you know and I think  that’s unfortunately anything that is of  

1:17:29even the one in a few thousand rarity that is  often a problem that people are going to meet  

1:17:34unfortunately yeah and I think i wanted to follow  up with that as well because obviously we  

1:17:39we suffer even even more from the under diagnosis  so I was going to ask you to speak about  

1:17:46some of the barriers involved in diagnosing  adults because as you mentioned during the   talk you have very little data on the adult  population and and you know as a community we  

1:17:55know very few diagnosed adults as well  so i appreciate your thoughts on how we as a  

1:18:02parent lives advocacy organization can help  try and reach some of those people and get them a  

1:18:07diagnosis. Yeah so this is something that I- this is  something I’m really interested in. A lot of my clinical   work is actually with adults with intellectual  disability and you know we work in a specialist  

1:18:19you know centre where there’s been a long history  of interest in genetic conditions and about  

1:18:2540% of people within our clinical services have  had (adults this is) had some kind of genetic test  

1:18:31at some point of their life. So that may mean  that they’ve had a look down a microscope at   some chromosomes when they were four, you  know, or something like that. Very, very few  

1:18:42are investigated as adults using exome sequencing  and looking for these kind of genes and  

1:18:48that’s not because it’s  not available it’s just not taken up by  

1:18:55clinicians and I think there is a “hearts and minds”  operation to be won with clinicians and I think we  

1:19:02are beginning to get there a bit to say it is  useful to test in adulthood. I think there is a  

1:19:11I think there is a and I think this is  the wrong view but I think there is a view  

1:19:17from some people saying well you know they’re  adults now what does it it’s not like there’s   a treatment so what does it really matter? And I  think organizations like yours like the explosion  

1:19:26of the internet of your parental support  organizations and advocacy groups and things   are changing that conversation to say you know  actually even just to have a reason and then a  

1:19:37group that you can connect with and you can hear  from other families, peer support that in itself   is a good enough reason and i do think that is has  changed but I do think there is a it is a kind of  

1:19:47clinician “hearts and minds” sort of battle to  be won. A study I’ve not mentioned that we are  

1:19:55slogging our way through the permissions required  to set it up it shouldn’t be this complicated  

1:20:02but it is but is to actually start doing exome  sequencing in adults with intellectual disability  

1:20:07moderate to severe ID within our population to  demonstrate to people what that both that  

1:20:14it is you know a feasibility study that  people wanted families wanted you know  

1:20:19and then to start to look not not how many folks  there are with different conditions but to try  

1:20:26and start to see well what are the adults what  do people look like as adults you know where  

1:20:31because I think we just we don’t most of these  likes Syngap and a lot of the new single gene   conditions where you’ve got diagnosed on  sequencing we just we just don’t know it’s  

1:20:40all done in children so I sort of hope my hope  is we’re doing a feasibility study on the first   entrance looking at maybe 100 people but the idea  is that we will expand that to get the sorts of  

1:20:50numbers we where we will be picking up undiagnosed  cases we’ll pick up plenty of on during those   cases of genetic disorders with it and to start to  answer these questions by adult phenotypes and I  

1:21:00think that will help to win this hearts and minds  operation from my side i think there is a parental  

1:21:08and you know that that kind of advocacy work which  is you know important I think to do with  

1:21:16clinicians how you reach them adults are often  not they’re not a school service they’re not in   education it’s harder to find you know but carers  organizations and things like that more generally  

1:21:25are often places where where family members you  know are kind of are so you know for undiagnosed  

1:21:31individuals or other you know broader learning  disability charities but yeah it it’s we’ve  

1:21:38been talking about this for 10 years i mean but I  first had a conversation about trying to increase  

1:21:44the diagnosis in adults it was 11 years ago at a  conference locally and i don’t think there’s been  

1:21:51much difference since then I think the arrival of  excellence sequencing is cheap we’ll change that   conversation now because that wasn’t the case  back then Jess can I please can i please say a  

1:22:00couple things yeah sure go ahead I’m actually  going to share my screen if you don’t mind  

1:22:07i just want to i just want to share a couple  things with Dr Stanfield and the audience  

1:22:14so you guys seeing in google right now yep yeah  so if you go to syngap dot fund slash incidence  

1:22:21that’s my short link i’m i like thanks to this  article in which i tackled the issue of sight  

1:22:27prevalence Dr Stanfield and I walked through in  here all the studies the little cohort studies  

1:22:33that have gave us that one to half a percent of ID  and then I talked about Dr Lau’s group’s work

1:22:41on his predicted incidence and how it talks  about Syngap but basically this is interesting  

1:22:48because it suggests that we’re radically under  diagnosed in all geographies number one and number   two there was a cohort study in denmark that I’m  sure you’re familiar with where they looked at 200  

1:22:57and they found once Syngapian. So that’s just  interesting. The other thing I want to shout out  

1:23:03is in the states and we’re going to invite  in april we have this digital natural history   study SRF is funding with Ciitizen and this is  my personal logon right so what Ciitizen is is  

1:23:15we don’t nobody gets on a plane we just collect  collect patients existing medical records and  

1:23:21then you and any other researcher would get  an anonymized normalized version of this data   so you wouldn’t get the PDFs because those are  identifiable but you would get the full clinical  

1:23:30history of every patient who’s in the study it’s  freely available the IRB is written very flexibly  

1:23:35and just as an example I as a parent if you called  me up and said let’s do an interview hey has Tony   done a Vineland I can search I must be spelling  that wrong because it worked five minutes ago  

1:23:47i can search for vineland or whatever or i can say  yeah i know he’s done a Vineland he did it at Palo  

1:23:52Alto medical and i could search for medicines  or what have you but i have Tony’s complete   i have every page of Tony’s medical record  here including by the way MRIs and imaging  

1:24:03and we have about a hundred US patients in  here and we’re going to invite Brits soon   i’m so bummed out that the Vineland is not  working because i promise it did it before  

1:24:11it’s that’s how you spell it isn’t it yeah yeah  i’ll come back but this exists and it’s available  

1:24:18to you and any researcher for free and we  have a hundred patients so while you’re under   COVID lockdown it might be something you you and  your colleagues would be interested in exploring  

1:24:27and the last thing this is not public yet but I  can’t help myself we have found that a 65 year  

1:24:34old patient in the US and we’re so excited about  her we made a brief movie about her life that will   be releasing for Rare disease day on February  26th so a little bit more collateral in your  

1:24:46arsenal around getting people to to think about  adults because her life story is quite fascinating  

1:24:52and we haven’t announced this yet but i just  want to tease it because you’re exactly right  

1:24:57i think part of our job as SRF is to and we’ll  do a UK screening with SRF UK too is to let  

1:25:05people know these patients are out there and  just because we don’t diagnose them as kids   they’re still sitting they’re still sitting  somewhere right and we’ve got to figure out  

1:25:14what happens to them and and i  think there are both therapeutic   both drug and you know services implications once  you understand the monogenic cause of disease and  

1:25:24so it’s it’s hard to think about my kid  growing up being an adult with this disease  

1:25:31but it’s even harder to think about adults with  this disease that haven’t even been diagnosed  

1:25:36so i’m really i’m really heartened to hear  that you’re you’re focusing on that okay   it’s it’s one of the things so it i mean i’m  aware of the ciitizen stuff and it is definitely  

1:25:45something that is on our on our radar the it’s  one of the things that we would hope to look at  

1:25:51as well with what we’re doing with the the adults  is to do what like linking data to existing health  

1:25:59records as well which you know there’s certain  there’s the way the UK there are certain health   records that are available nationally that we can  actually link and look at hospital admissions and  

1:26:07and things like that so you know because I just  think it’s something as you say we know we we know  

1:26:13nothing about I think there’s adult patients out  there who aren’t diagnosed and that whose families   also aren’t able to get kind of support or  things as well which is yeah it’s a big issue  

1:26:24all right i’m just going to pick up another  hopefully simple couple of questions before   we wrap up we had a question regarding  the sleep study uh and whether or not your team  

1:26:33collaborates with dr alex byers from hospital san  juan de doo i hope i’m pronouncing that correctly  

1:26:40in Barcelona yeah so honestly the one below by  interchange of information would be reasonable  

1:26:46so i i have i don’t know dr bias um i i mean  i i i knew him academically i am aware of him  

1:26:55but i don’t know exactly what they’re  doing we would it’s helpful to hear that if  

1:27:01they’re also doing sleep studies because we will  get in touch and we had a i had a video conference  

1:27:06with jimmy holder and connie smith hicks to talk  about the sleep work that they’ve been doing as  

1:27:11as well we are dead keen on sharing information  we’re very open with sharing what what we’re doing  

1:27:17and sharing our data because you know we will all  get further forward if we work together so that  

1:27:24that’s helpful i will send dr bias an  email and by way of introduction great excellent  

1:27:31um i’ll take another question uh from katrine  deckers uh who’s the chairperson of srf in the uk  

1:27:38uh and she’s asking if there’s any positives as  a result of the COVID-19 vaccine development  

1:27:43that will help inform drug  development that we might benefit from

1:27:48oh i don’t know you know that the covert  vaccine development was so quick because everybody  

1:27:56i mean hey the tools were all there but  b the regulators went through it immediately  

1:28:02and quickly you know that that’s why it was  so sped up in that sense you know you were  

1:28:09people were writing trial protocols in a few days  and then the drug regulators were approving them   in a day or two you know which that six months  a year is a normal process and i don’t think that  

1:28:21we’re going to benefit from that if anything it’s  got harder at the moment to do other research  

1:28:26just for practical reasons and and there’s a big  focus on COVID and i think from my point of view  

1:28:33which is a i sort of alluded to before i do  think there’s a better a greater acceptance of  

1:28:38doing stuff remotely and that for rare conditions  is going to be much more helpful so we are  

1:28:44having discussion with the UK drug regulator  not the European one anymore but the UK drug  

1:28:51regulator about you know the remote assessments  and what sort of things are acceptable in terms of  

1:28:58safety and efficacy assessment and what we can do  across across videos and things because and i i   think that conversation is easier now and so yeah  that’s probably the main thing that i can think of  

1:29:09um but yeah hey i i’m sorry i i have to i have  to i have to save some phase here for a second  

1:29:18i wasn’t capitalizing so when you capitalize  vineland in in citizen i immediately go to three  

1:29:24paces in his record where the Vineland is noted and  i click on it and i can see the exact page of his  

1:29:31six thousand pages of medical records where  his vineland results are are mentioned   or or noted so just offering it up if you  want to expand your cohort quickly and easily  

1:29:42we have almost 100 people who have this at their  fingertips and they’d all be happy to and the IRB  

1:29:47is written in such a way that you could easily get  access to this data okay okay sorry yeah and i  

1:29:54think speaking as a british parent in living in  the us i i do see them doing a lot more of these  

1:30:01standardized evaluations uh when you’re going  through the process of getting an autism diagnosis  

1:30:08and even just for entry into preschool or  regular kindergarten you need to go through   the Vineland so all parents should have these  available to them their children of a certain  

1:30:19age so we’re working very hard to you know talk  to families about how to participate trials  

1:30:25you know convince them of the benefit of  participating in the studies uh that we are   very very small population so every single  person matters every single child counts  

1:30:35in terms of learning more about the disease so  uh we’re trying very hard to uh recruit as many  

1:30:41people as we can and definitely would love  to spread the word about the Neuro GD study

1:30:48yeah yeah i mean and that’s i think and i really  appreciate it these things take time you guys   are busy you know but it is it is as i say if  people can it is as you say every person counts  

1:31:02you know if you’re recruiting 40 people  every person is two and a half percent of   your total population you know so it adds up  very quickly what one person’s data can do so  

1:31:11and this is why we we’re so  gung-ho on ciitizen right because  

1:31:16people are busy parents are exhausted and you  say to a parent what happened two years ago i   don’t know what happened two weeks ago number one  number two if it wasn’t for citizen there’s no  

1:31:24way on god’s green earth i would be able to find  that report so for longitudinal data how is it you   know these patients you can now go back the Vineland  was two years ago three years ago and look at how  

1:31:34patient x is perceived and also those are  clinical appointments that you are going to  

1:31:39anyway it’s not like you’re traveling separately  to come for a research study you know and so this   taking advantage and leveraging the  data that’s already there is great

1:31:50okay so we did go over by 30 minutes i really  appreciate we all really appreciate your time   dr Stanfield and uh if anyone has any  follow-up questions please do email us  

1:32:01or get in contact with us i’m sure  we can pull those on to dr stanfield’s team  

1:32:07yeah i normally i realized right at the beginning  i normally stick my email up at the end but i   i didn’t but you can find you can find me online i  mean it’s just andrew.stanfield.ac dot uk and i’m  

1:32:17happy to hear from people i don’t those of you  who do you know me from time to time will know   i’m not the best at getting back  immediately but i do usually get  

1:32:27back so and if i don’t you can email me  again i don’t mind repeat repeat emailing  

1:32:33and everyone who’s still listening i would  advocate for participating in the NeuroGD study  

1:32:39Aisling is a lovely person to speak to i spend  a good hour with her talking about your child  

1:32:44um and then this packet of forms to fill out  so uh obviously not as fast as citizen but  

1:32:50it’s definitely worthwhile to take part in  that so get in contact with SRF get in  

1:32:55contact with Dr Stanfield and we can forward you  the details of how to get involved in that study

1:33:03thank you both absolutely thank you excellent  thank you very much thank you and good evening  

1:33:13thanks now bye-bye

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