86 – Five Years of Funding Innovative Research for SYNGAP1

James Goss, PhD, Scientific Consultant

THIS IS FOR TRANSCRIPT ONLY:

0:02hello everyone and welcome to today’s webinar my name is Ola bod and I’m part of the team here uh singap research fund

0:09our presentation today is srf or singap research fund and our five years of funding Innovative research I have the

0:17pleasure to introduce today’s speaker Dr James GSS Dr gos is a neuroscientist

0:23with over 30 years of experience in basic and translational research including broad involvement with drug

0:29development in Academia biotech pharmaceutical and nonprofit organizations Dr GS is overseeing the

0:36preclinical development of gene therapy biologic pharmaceutical and device-based

0:42Therapeutics he currently serves as a scientific director of the stxbp1

0:48foundation excuse me a recorded version of this webinar will be available on the sof srf website under webinars and by

0:56the end of this presentation you will have the opportunity to to get answers to your questions we’d love to hear from

1:02you so please write those questions in the Q&A below for those of you just joining us

1:08welcome and again our speaker today is Dr James GS his presentation is srf and

1:14our five years of funding Innovative research it’s now my pleasure to turn things over to Dr G thank

1:20you thank you Olga for that nice introduction let me see if I can uh

1:26share my screen

1:38and let me know when you can see my slides yeah we can see it looks good all

1:45right thanks very much so yeah the the title of my talk is five years of funding Innovative research for singap

1:53one and what to expect moving forward uh so I just don’t want to focus on the

1:59last five 5 years I’m going to also talk about you know what should what to

2:05expect going forward uh in fact my outline for my talk today is the first

2:10thing I want to talk about is what has the funding over the last five years

2:15achieved and then what I want to do is I kind of want to move to uh the future

2:21and kind of summarize review different therapeutic approaches uh that uh that

2:27are coming uh uh into in the future uh and then I want to kind of finish with

2:33discussing clinical drug trial challenges that I think everyone should be aware of uh when it comes time to do

2:41clinical uh trials for simap one so what has five years of funding

2:48achieved well if I start off at a high level uh post four dozen grants have

2:55been funded through srf uh this is over four $ Million worth of funding that has

3:02been provided or committed uh at this point uh over 30 funded scientists at

3:09over 25 institutions or organizations and this has resulted in

3:15several Publications I don’t know the exact number at the moment but it’s uh

3:20but it is uh at least half a dozen in growing uh on a yearly

3:28basis so there are four main uh Avenues of I think what srf funding has achieved

3:36that I want to discuss in a little bit more detail uh those are the first is

3:41increase the number of scientists who are working in syap one and the second

3:46is this funding has developed research tools for sgap one the third is it is

3:52started therapeutic development for singap one and the fourth is an increased clinical trial readiness for S

4:00Gap one so first off increasing the number

4:06of scientists working on S Gap one has been a very important achievement in this funding so back when srf was first

4:15started the number of scientists who are actually working on singap one was very

4:21small just a few scientists and no real drug development was being done in in

4:27syap one and funding has changed all of that and the funding specifically

4:33provided by srf has done that and how does that do that well easy so when you

4:39fund research you’re are bringing in more scientists to work in a field so

4:46more researchers means more knowledge in that field has been generated and so as

4:53the number of grants that are funded by scientists uh grow the amount that we

4:58know about s Gap one grows both in its basic biology its basic function and its

5:05basic dysfunction that occurs within s Gap one disorder all of that knowledge

5:11grows this additional insights into the functions or the of sin Gap then leads

5:18to what we can refer to as new drug targets and these are so When developing

5:26therapies therapies Target something within the biology of a disease process

5:32and the more we know about singap One function the more targets become

5:37available that can be druggable for uh to develop new drugs any new drug or any

5:45drug approach that is developed from this knowledge are additional shots on

5:51goal for finding therapies that are going to work in singap

5:58one me give you three recent examples and these are uh Three Investigators who

6:06were funded in this last round of funding through srf Helen Willy who’s at

6:13University of California San Francisco uh she she was funded for a a

6:19program where she’s looking at the role of singap one in neuronal cyia neuronal

6:25cyia uh is a structure within in neurons uh most cells have cyia these cyia

6:34structures in them not a lot of is known about what neuronal cyia do um but what

6:42she has found is that syap one is expressed within neuronal cyia and she

6:47was funded by srf to get a better understanding of what srf is actually doing in neuronal

6:54cyia in this and if her research is successful

7:00uh basically a Target that can be that she can find are drugs that reverse cyad

7:07defects her her hypothesis is that neuronal cyia are defective in in syap

7:15one uh and that if you reverse that uh that defect in the cyia then you may

7:23have some beneficial effects in the disease process and this is an additional shot on go

7:31uh Baptist La cost at the University of Ottawa was also funded and what he’s

7:37looking at is the role of singap one in neurovascular development or the or or

7:43basically how blood vessels develop within the brain uh and uh and he is

7:50suspecting that the S Gap one plays a role in this uh and uh in um singap one

7:58disorder uh basically there may be a problem in the neurovascular uh and this leads to some

8:04of the problems associated in that we see in syap one uh patients uh and uh

8:13that might be able to be targeted by looking at vascular drugs so drugs that

8:18instead of are affecting the neurons are affecting the vascular vasculature of

8:24the brain and the the blood vessels again this is an additional shot on go

8:30and third Paul donin ask who’s at the University of Edinburgh is looking at

8:36the regulation of singap one expression in neuronal dendrites um and uh he’s specifically

8:44looking at the effects of what are called RNA binding proteins on how

8:50singap one is expressed and by targeting RNA binding proteins with specific sorts

8:57of drugs to make them uh either work better or increase the expression of

9:02singap one then that is another potential way of achieving a therapeutic

9:09U effect in syap one patients so yet another additional shot on goal uh and

9:16so uh bringing all these investigators into the syap one field uh is uh

9:24improving our knowledge of singap one and it’s going to lead to better and

9:31newer uh Therapeutics a second important

9:37achievement uh for the funding that srf is provided is to develop research tools

9:44for singap one so uh these include many different things but uh some examples

9:51here are ipsc patient and control cell lines uh that have been uh uh developed

9:59under srf funding uh in in these examples on this slide and in the next

10:05slides the parentheses are are uh Labs or organizations that have been funded

10:11by srf who are doing the work uh singap one Mouse models there are several Mouse

10:17models available and and srf has funded some of those Mouse model developing

10:22there’s a r model that’s being developed uh and there’s a frog model uh

10:28of singap one that has been developed all of these models help scientists better understand how syap one functions

10:36and they’re importantly used for translational research and basically what that means is taking kind of the

10:42basic knowledge that we understand about syap and and using that to try to find

10:51uh as I said before drugable targets and testing potential drugs so all of these

10:58models so ipsc cell lines Mouse models rat models frog models can be useful in testing

11:05drugs uh and so this is a very important um uh resource to have and the

11:13foundation has done an excellent job in funding research to develop many of

11:19these uh uh resources uh the third are developing uh

11:27of various Therapeutics and so srf has uh kind of in the beginning of funding

11:33have funded uh primarily a lot of basic research but now more funding is moving

11:39towards more applied research or therapeutic development uh and there are

11:45several examples of this that has been have been funded by the foundation so first off is drug

11:52repurposing and so drug repurposing is p taking a drug that has already been

11:58approved by a regulatory agency like the FDA that’s already for sale out there

12:03and marketed and but had was not originally intended to treat uh singap

12:09one and using it to see if it can fact treat syap one or at least some of the symptoms associated with syap one and

12:17there are and so one example is four penel berate um

12:23rii um and uh I believe that the the first uh in gap one patients uh have

12:31been treated Now by Zachary grinspan uh at will Cornell with for fenal berate

12:38for fenal beate is a drug that was originally developed to treat a Ura cycle disorder it had nothing to do with

12:46the brain has nothing to do with the neurodevelopment disorders and nothing to do with s Gap one um but uh but it’s

12:55POS but uh basic research had found that fenal berate may actually have a protein

13:03stabilizing effect and had been tested and because of that we’re tested in a

13:09couple other neurodevelopmental disorders and now is being tested in syap one and so that’s a a perfect

13:16example of drug repurposing uh the foundation has also

13:21supported large scale drug screens uh and uh this is instead of just taking

13:28one drug and testing it uh you what a large scale drug screen is you develop a

13:34way of taking a lot of uh FDA approved drugs and see whether or not they have

13:41any effect on um syap one for example so in the case of rare base uh

13:49this is a company that the uh srf uh funded a study with uh they took

13:56something like 3,000 to 4 th000 different drugs uh and tested to see

14:02whether any of those drugs could in increase s Gap one expression in

14:07neurons uh and uh and so since this is a large screen you basically this is a

14:14stepwise uh procedure you first test all of these drugs you see what works and

14:20then you do more validating experim experiments uh beyond that uh but the

14:26idea is eventually you uh can identify several drug candidates that you think

14:32may have the ability to have some effect on syap one you can increase expression

14:38then perhaps these drugs again which are FDA already FDA approved might then be

14:44able to be tested uh in sgap 1 patients fairly

14:50quickly and uh a similar drug screening is done in the chow lab using uh pla uh

14:59and then there are some small molecule drugs uh that the that are being

15:05developed in different labs and so a small molecule drug is basically this

15:13the type of drug that almost everybody is familiar with so if you’re taking a pil or anything that’s a small molecule

15:20drug uh and these are basic Pharmaceuticals um and there are Labs

15:26looking at the a drug that are structural stabilizing drugs

15:32basically this just means that they help proteins um stop being degraded in cells

15:41uh for example uh and this is a way of trying to keep the singap one that’s

15:47made in a cell or in a neuron around longer uh there’s a uh uh and uh there’s

15:56another group that are testing A drugs affect a potassium chloride uh protein

16:02uh in neurons uh with the idea of trying to rebalance the excitation and

16:09inhibition U within the brain and so these small molecule drugs

16:15they’re not FDA approved but uh nonetheless uh these are all potential

16:23shots on goal in potentially developing some of these drugs May uh move forward

16:30uh in drug um in clinical drug testing depending on how the studies that the

16:36foundation have supported turn out uh other classes of Therapeutics

16:45that the the foundation has been supported are what we call Precision Therapeutics um so the as opposed to the

16:53what I talked about in the last slide those are drugs that can affect uh uh

17:00not specifically uh s Gap maybe um but affect neuronal function as a whole

17:08Precision Therapeutics on the other hand Target s Gap uh specifically uh and there are a number

17:16of different Precision Therapeutics uh that are uh being looked at for Sy Gap

17:23one so these include anti-sense aligon nucleotides or Asos that you may have heard of I’ll talk more about these in a

17:30few slides uh there is a uh an RNA booster

17:36uh which uh is a uh a Precision therapeutic aimed at trying to increase

17:43the amount of sgap one RNA U that is made or the pro and the amount of singap

17:49one expressed from RNA uh there is Gene replacement uh of

17:56uh of singap one uh looking that’s being uh looked at in the C and

18:01kind lab the Zen plen lab uh Gene activation and uh Cell Therapy are types

18:10of uh Precision Therapeutics that are being looked at uh being investigated by

18:16uh people who have been funded by srf and as I said I will discuss these in a

18:23little bit more detail the fourth uh major achievement

18:32uh that the funding has has has brought us is increased clinical trial Readiness

18:39and this is very important uh for the future and so basically what I mean by

18:46this is that you’re getting by funding the work by funding uh specific studies

18:55uh the uh Foundation is is getting the the S Gap one population ready to go

19:03into clinical trials and getting in making singap one a uh an attractive

19:11disease for pharmaceutical companies to develop drugs for because uh what you’re

19:20what the increasing clinical trial Readiness does

19:25uh and I’ll discuss here in a little bit more uh detail is that it der

19:31risks uh singap one as a disease for Pharma to develop drugs for

19:41uh so developing drugs is very expensive uh and uh drug companies uh want to make

19:49sure that they spend their money wisely and they go after diseases where they have the highest likelihood of finding a

19:57uh anos positive effect of their drugs and will be able to uh get a drug

20:03approved uh and so making your population uh attractive to uh Farm

20:10companies to develop drugs is very important and so how has the foundation

20:16done that well uh by funding uh uh companies like probably genetic to

20:23identify more s Gap one patients so the more patients that there are available

20:29the the more likely Farm Company is going to develop U drugs for um better

20:37understanding of variance of unknown significance so uh singap is a u

20:45disorder uh that has a lot of V’s uh and

20:50these are variance or mutations in the gene where it’s really unknown whether or not the mutation is pathologic or not

20:59pathologic uh and um being able to

21:04understand uh What uh V’s are pathologic uh is very important um

21:12because if you have Us’s where you’re not really sure whether or not the

21:18mutation ha has a pathologic effect or what the mutation does in Sy Gap uh then

21:26drug companies are going to be less likely to uh utilize patients who have

21:33those particular M patients in drug trials defining the Natural History uh

21:41of a singap one disorder is very important uh and natural history is

21:47basically how the disease naturally progresses over time uh and uh uh you uh

21:56you get to understand this through a natural history studies uh chop is doing

22:01something like that for singap one now but you also understand this through

22:08a disease concept model which is basically understanding what are the

22:14major uh uh implications of sinap one on the patient and on the family

22:23caregivers uh and uh these uh in the foundation has funded studies in disease

22:30concept model uh and in in trying to understand the natural history by using

22:36citizen data for example uh another important thing for

22:42clinical trial Readiness is understanding what are called outcome measures these are the actual things

22:48that are looked at in trying to determine whether or not a drug for example is having an effect on a on a

22:56disease uh and so you have to have something that you can measure uh in the

23:03population uh and see that that changes in response to a therapeutic

23:09intervention uh and uh so the foundation has um uh funded uh some studies that

23:17are looking at different sorts of outcome measures there’s neurobehavioral evaluation tool uh that has been that is

23:24being developed EEG biomar records uh are being developed to help uh as a

23:33potential outcome measure and uh improving the seizure diagnosis U

23:40specifically from caregivers how caregivers View and look at seizures and

23:45be able to diagnose when their child is having a seizure so these are all very

23:50important Al and all things that the uh that the foundation has

23:56funded so I now kind of want to move from what

24:04the foundation is funded to uh having kind of a uh Overlook of so where are we

24:11going now that you funded these um uh these studies uh we’ve seen what the

24:19funding has achieved where is that taking us uh as far as what the real

24:24goal is which are therapies for singap one and and

24:31sinapian uh and so we can kind of look at theraputic development in uh

24:38different types of therapies so we talked about repurpose drugs repurpose

24:44drugs are currently uh in now uh and uh

24:50as I said uh with the core fenal beate trial but between now and three years uh

24:57we’re going to see more repurposed drugs I think in the singap field uh from the

25:03studies that the foundation has funded uh as I as I spoke before and so this is

25:11something that is that is coming soon and so we want to be ready for

25:17that uh kind of the next uh types of drugs that are coming after repurposed

25:23drugs are the anti-sense aligon nucleotides uh and I would I would think

25:29that within the next 2 to 5 years you will see some ASO drugs being tested in

25:36uh in singap one patients um and then following that are

25:43what we call Gene therapies or what I will call Gene therapies uh in 3 to seveny year uh range uh I would say uh

25:52you would you start to see some of the initial gene therapy trials uh in s Gap

25:59one patients so let me talk a little bit

26:04more about drug repurposing and why uh why we go after drug repurposing and why

26:13um uh it is uh something that’s exciting

26:19uh so the best way to to um to discuss I

26:25think drug repurposing is to compare traditional drug development with

26:30repurposed drug development and so on the left what we

26:35see here is what traditional drug development were how this works and so

26:42uh basically uh you a scientist has an idea uh they they have what we call a

26:50Target or disease-based research I.E they have an idea that they think uh you

26:56know I want to treat uh some disease what should I go after

27:01in that disease uh they do some basic research uh in that disease and they get

27:07what are called Le compounds or these are uh here’s a set of potential drugs

27:12that might work in the disease uh and we will do more testing of those Lea

27:17compounds and that and and that testing uh at the end of that testing you get a

27:23candidate drug and this is the best compound that you have that you think is

27:28going to have an effect on your disease and then that candidate drug

27:33goes through what’s called pre-clinical development and this is additional work on this drug before it goes into the

27:40people uh and preclinical development involves a lot of different steps but

27:45part of that are some of that are things like toxicology is the drug toxic to

27:51animals uh so you want to know if that’s the case before you give it to people uh

27:56and then uh you also do some additional animal studies to see what happens to the drug when you give it other than

28:03toxicol tox is it dox it but is it actually working in a disease model in

28:09an animal uh and uh once you do the preclinical development then you go into

28:16clinical development clinical development uh is you’re giving it to um

28:21to people uh and uh there are clinical development can take a a a while there

28:28are different uh phase one phase 2 phase three clinical trials You’ probably

28:33heard those terms that’s all part of clinical development uh you test it in

28:39people uh and then once you get the all the data in people uh you go through

28:46what we call registration that’s going to uh basically the regulatory agency

28:51the FDA you’re giving them the information that you collected from all of this that you done the FDA determines

28:59whether or not the drug is safe and effective and if it is they they basically registered the drug uh and now

29:07you can sell it to the market this takes a long time and costs a lot of money and

29:17um and it has a high failure rate uh so

29:22uh most uh probably you know from from Target disease based

29:30research to Market uh there’s probably less than 1% of uh that actually make it to the

29:38market and even at clinical development uh from Clinical development to Market

29:43there’s about a 45% uh failure rate so even at that

29:48advanced stage so what repurpose drug development does on the other hand is you already

29:56have drugs with have been clinically approved they’re already marketed uh and all you are doing is

30:03you’re taking those drugs and you’re saying okay well they were approved for this condition but I’m going to use them

30:09in my condition so um again going back to four fenal beate you’re taking a drug

30:16that was uh originally U created and and marketed for you you read a cycle

30:23disorder and you’re seeing I think this can have a positive effect in singap one

30:29so now you take that drug you do some screening and validation tests um

30:35basically just to make sure that it it’s it’s having the effect on the Target in

30:40this case singap one that you think it’s going to have uh if that does uh then

30:45you do some you do you still do some clinical development but the clinical

30:50development in this case is you may just run take that drug and test it in a

30:56handful of of patients to see whether or not it has any efficacy uh at that and at that point uh

31:05then you can go into registration and marketing uh if if uh and this is uh

31:11something that a drug company might end up doing uh you can also you don’t

31:16actually need to take a clinically approved drug and go through registration and marketing you can just

31:23take the clinically approved uh drug once you demonstrate that does work in people uh and it has an effect on

31:31disease and use it off label which basically means that it is not a it’s

31:38not marketed for the disease your disease it’s not marketed for Sim Gap one but you can use the drug off

31:46label uh there are some pros and cons to to uh either of those uh marketing or

31:53off label use off uh IDE dealing uh if you go the market route uh then

32:01basically insurance will cover uh the uh use of that drug for the new

32:11disease so now I kind of want to uh discuss the the Precision therapy

32:19therapies that we that I uh discussed in the previous slides I said i’ talk a

32:25little bit more about them uh and so I wanted to to delve into these uh in

32:31order to give you a better understanding of exactly what we’re talking about when you hear terms like gene therapy or Asos

32:39what exactly is going on um uh and how are these exactly working it can be a

32:46little bit confusing and so one type of uh gene therapy approach

32:53is Gene replacement uh and if we take a look at the picture picture on the right we have a cell we have a neuron here in

33:00our case you have a defective Gene the

33:05that Gene is within the nucleus which is that shaded area within the cell uh you

33:11have that Gene goes transcription which creates a an RNA that RNA is translated

33:18into a protein if the gene is defective it makes a defective RNA and that RNA

33:24when translated makes a defective protein Gene replacement is a basically an idea

33:32where you take a nor normal copy of that Gene and you add it to the cell you add

33:37it to the neuron uh that normal Gene then makes normal RNA and normal protein

33:44um and this is a basic type of of gene

33:50therapy it is uh as far as Gene therapies are concerned the most studied

33:57uh type of gene therapy mostly because it’s one of the easiest types of gene therapies to think of uh just adding the

34:05normal gene into a cell it’s generally been utilized for monogenic disorders

34:11like syap one for example but can be used to to increase the expression of a

34:18normal protein if that’s what you want to do uh It gener generally results in

34:26overexpression of the gene of interest uh because it’s difficult or can be difficult to uh uh

34:35to uh control the expression of the gene that you’re adding uh uh in so it is

34:44permanent so once you add a gene into a cell um in this case it’s going to

34:50continue to make that normal Gene and it requires a delivery system

34:57uh and for the most part that delivery system is known as a vector a gene therapy Vector that’s what the delivery

35:05system is the thing that actually gets that Gene into the neuron or the cell of of

35:16interest uh there is uh what’s called Gene manipulation or uh instead of

35:24adding a an extra Gene in this case you’re using what we’ll call molecular

35:30tools to directly interact with the malfunctioning Gene so we have the same

35:35a system setup here on the right U but in this case uh you are adding a tool uh

35:43that actually goes and repairs for example the gene the mutation in the

35:50Gene and there are uh several types of gene manipulations or Gene editing there

35:56there direct Gene editing which is repairing the gene chrisper Cass probably heard of chrisper Cass uh so

36:05that gets in the news a lot there’s another type a couple other ways of repairing mutations and Gene uh Prime

36:12editing and base editing I won’t get into the details of those but there are several different ways of editing a

36:18mutation in the Gene and trying to directly fix it another instead of directly fixing a gene uh you can even

36:26either deactivate the mutant gene or you can try to activate the

36:32non-mutant gene so as you know everybody has two copies of each gene uh and so

36:39you can deactivate the bad copy or activate the good copy and there are a couple ways that you can do that um

36:47crisper a and crisper I are um are two ways that are being looked at uh uh for

36:54a lot of genes uh and and uh there are other sorts of activation uh zinc finger

37:00proteins are one again I won’t get into the details for that but there a lot of these molecular tools which are

37:09available uh so again Gene manipulation uh is very specific uh to the gene that

37:16you’re looking at uh one of the positives is uh it maintains cellular

37:23control over the expression of the gene so don’t get overexpression uh issues that you might

37:29get with Gene addition uh it is technically challenging it’s more technically

37:35challenging than just adding a gene U because basically you have to you have

37:41to you’re still adding something into the cell but in this case the molecular tool has to get into the cell into the

37:47nucleus find the right Gene interact with the Gene and have its effect so uh

37:54there’s a lot of efficiencies that need to uh become be overcome with that uh like

38:01Gene replacement it’s permanent once you put these molecular tools into cells

38:07they stay and they will work and they will fix the Gene and uh it will permanently be

38:13fixed and uh like Gene delivery does it also requires a delivery system

38:22uh and then there are RNA Therapies so

38:27uh in this case again we have two copies of the gene uh your defective Gene the

38:33normal Gene making defective RNA and defective protein or normal RNA and

38:39normal protein uh in this case you add something that is going to interact with

38:46RNA Asos anti senson nucleotides which uh talked about uh already these

38:54generally interact with rnas and and they can do things like either work on

38:59the defective RNA and silence it so it doesn’t make any protein or they can

39:05work on the normal copy of the RNA and enhance it so it makes more normal

39:12protein there are uh RNA uh Asos that as I said you have RNA

39:20silencing uh that the rnas that block proteins that bind to to RNA by blocking

39:28th those proteins you increase the expression of that RNA you can um you

39:35can modulate uh how RNA splices together

39:40uh in what’s called or or cause ex what’s called Exxon skipping uh I won’t get into get into

39:48the details of that but uh there are already drugs on the market uh Asos on

39:53the market that do all of these things uh and so um this is very real

40:00technology uh and as I said U on the horizon for syam um there’s also uh what

40:08are called signups uh these are basically long pieces of of RNA with a

40:16attached to a an element that enhances the expression of your target RNA I

40:23don’t know if anybody’s actually using these for singap at the moment but U

40:28these are being actively investigated for other disorders and could potentially be used for for S Gap one uh

40:36like replacing a defective Gene uh uh you could also replace RNA uh so you can

40:44just add RNA into a cell uh and see if and uh create uh normal protein from

40:52that added RNA and uh you can also use what are

40:58called readr drugs for specific types of mutations so if you have a nonsense

41:03mutation or mutation that basically stops a translation from occurring uh

41:10from an RNA a readr drug is um a small

41:15molecule uh generally uh that can uh

41:21basically allow that translation to proceed through what would be a nonsense

41:30mutation RNA therapies are simpler technology uh than Gene replacement or

41:36Gene editing uh they’re cheaper to manufacture uh than either of those uh

41:43there it’s also specific uh RNA therapies are transient so they have to be uh redosed so

41:52Asos even though they’re they’re cheaper and simpler uh using ASO as a therapy uh uh patients

42:01have to be redosed on a regular basis whether that is U currently usually

42:07every couple months or or every quarter or every three or four months uh because

42:13RNA doesn’t last uh RNA is degraded normally in cells and so will disappear

42:20and so these have to be uh redosed and as o uh or RNA therapies

42:29usually also require a delivery system though not not always you can inject

42:35just straight Asos uh into certain body

42:44fluids uh so delivery methods I don’t want to get too much into this um but uh

42:51there uh for if you’re going to deliver genes or for uh those Gene editing

42:58molecules I talked about often times um you you need some sort of delivery

43:04system to do that one way to do that are to use what are called viral vectors uh

43:09these are basically viruses that have been um basically uh uh taken apart and

43:18kind of put back together so that they don’t cause disease uh but they can be

43:23used as a delivery vehicle uh and you can think of that as viral vectors as

43:30being a truck and the gene is the cargo uh that’s contained within that truck

43:36and there are several different viral vors that can be used the most common are a and leny virus uh you’ve probably

43:44heard of aav you may have heard of lenty virus um

43:49but they all have their positives and negatives all of these have been utilized as different types of viral

43:57vectors there are what are called nanoparticles that can be used as opposed to viruses there these are U uh

44:06small uh encapsulating uh molecules some are

44:11lipid based uh some are polymeric uh and

44:16uh basically uh they form a protective barrier around whatever it is that

44:23you’re trying to deliver whether that is a gene or an RNA or even a protein um

44:30and again they have some positives and negatives associated with them uh

44:35they’re used much less frequently than viral vectors but there’s a lot of research involved in looking at these

44:42and trying to develop these uh as delivery uh vehicles for various types

44:49of precision therapies and the third are exomes uh

44:54and exom are basically uh structures that are

45:02already created by cells and released by cells uh and they are uh basically

45:10a membrane like a cellular membrane uh that’s encapsulating a solution of

45:17different compounds uh those compounds can be proteins or nucleic acids dnas

45:23rnas uh as I said normally made by cells normally released by cells uh and but

45:31they can be engineered um so that you’re making specific sorts of exomes that

45:36contain specific molecules in them uh and those can be used for uh uh

45:44delivering Therapeutics uh and in fact uh uh the foundation supports uh working

45:53this by by one of the grantees in plenty at the University of uh

46:03Nebraska yeah I want to kind of finish up my talk on talking on discussing a

46:09couple clinical trial challenges that I think uh everybody needs to kind of keep

46:14in mind as uh we move into Precision therapies and start doing uh ASO uh

46:22clinical trials and gene therapy clinical trials uh and uh also small molecule clinical

46:29trials uh for for singap one and uh so

46:35some of the challenges are obviously there’s a small population of

46:40zapiens uh and uh this is something that uh you always have to keep in mind uh

46:48the population isn’t large enough to have large clinical trials for many for

46:54most diseases that occur in the general population when testing a drug hundreds of people

47:01will go through a clinical TR be go through clinical trials to test the drug

47:07we obviously can’t do that with s Gap one uh so we’re Limited in trial

47:14participation uh the a given trial will only be able to use a handful of of

47:22simap one patients uh and uh the population uh obviously uh is

47:30small and distributed among multiple countries and regions and so this has to

47:36be kept in mind and this is something uh that I think the foundation uh will

47:44probably need to uh get a uh will be important for the foundation to

47:51understand and to maybe guide patients into what clinical trials should

47:58participate in um uh as I said uh and

48:04hopefully you uh there’s a situation where there are so many uh good uh

48:10potential therapies uh that a lot of clinical trials will come up that would be a great problem to have um but you

48:19may have to pick and choose which clinical trials would be best to take part in uh another challenge is clinical

48:26trial design so traditional clinical trials have uh Placebo groups which are

48:33a group of people who get a uh no drug treatment basically uh and this again is

48:41a difficult thing to do in a in a rare disease like syap uh we can’t really

48:47afford to have traditional Placebo G groups in clinical

48:52trials uh but there are ways of clinical trial design that can get around that

48:58for things like for drugs that can be redosed like small molecules or

49:03Asos for Gene therapies uh ideally you don’t want any

49:08placebo group because some Gene therapies like it’s it’s a gene therapy using an aav Vector you may not be able

49:16to redose people so you can’t actually give them a placebo which would be an

49:21aav uh Vector without the S Gap in it right so you can’t really use that as a

49:30placebo group because that would preclude those patients from getting an active drug later so uh this is

49:38something that uh is uh

49:44uh is being discussed with the FDA uh with a lot of different rare disease

49:51groups uh uh and we need to find ways around uh uh having to use Placebo groups uh so

50:00far the FDA has been uh uh somewhat

50:05reluctant to get away from having Placebo groups in gene therapy trials uh ideally but regardless we have

50:13to maximize the amount of data that’s obtained from each participant in any uh

50:18clinical trial uh that’s uh that’s done um and because again uh with the small

50:28population the other other things to keep in mind are clinical trial outcomes I’ve talked about these already um but

50:36uh out these clinical outcome measures are difficult uh for a lot of neurodevelopmental disorders like s Gap

50:43one uh how do you determine whether or not somebody uh is improving on a drug

50:50uh obviously if the drug is having an amazing effect uh that’s easy to

50:56determine but if a drug is having a limited effect uh then how you measure

51:03your outcomes are going to be very important uh in getting a drug

51:09approved so uh you have clinical outcomes which look at multiple domains

51:14communication movement uh cognition uh what have you uh within the population

51:22and then do those approve um the ability to harmonize clinical outcomes between

51:29trials which basically is if you’re going to run a number of clinical trials

51:34with different Therapeutics you want to be able to measure the same outcome in

51:39all of those trials and so um that’s what I’m talked about with

51:45harmonization and the use of biomarkers and development of biomarkers to help

51:50with the clinical outcome measures do you see changes in EEG do you see changes is in some sort of marker that

51:58you can see in the blood and then timing also uh is important when do you treat

52:05uh patients the earlier you treat them is that the the best time to treat them

52:10can you treat adults um and how long do the clinical

52:16trials need to last so for a lot of clinical trials and most diseases uh the

52:22clinical trial May last uh you know a couple months to look for an effect of a

52:27drug but for uh a neurodevelopmental disorder it might take a long time

52:34between the time when you treat somebody with a drug or therapy and you actually start to see an effect so clinical

52:41trials may need to take longer uh in the population and I think I way overt

52:47talked but I needed to talk but uh uh sorry about that but uh I will I will

52:53take some questions if anybody has any hey Jim thank you very

53:00much that was super uh comprehensive oh

53:05yeah sorry that’s okay I wanted to I I actually have a couple questions about

53:11trials so um first off I mean it’s it’s so great to see the history of of what

53:18srf has funded and uh you know new new avenues and stuff so thank you very much for that summary um but you’re right

53:24that the future is what we’re always really interested in and so you know for our first early trials we’re really

53:30looking at um children who have countable seizures right so countable

53:37seizures is really what the FDA understands how to deal with but that’s

53:43not necessarily our entire population but it is some of our population so if we start there um and look at that I’m

53:50wondering what else do you see measuring on a short time scale and

53:57what do you see measuring on a longterm long longer time scale and then can

54:03we have sort of like phases where you know getting something to Market might

54:09be on the shortterm scale but then what can we do for you know you know

54:15understanding the longer term might end up being what somebody like my own kid who doesn’t have that many seizures

54:22thank thank you very much but is very Del you know has severe severe cognition issues right and

54:28so that may take longer and then and then the final question will be um with

54:36development you know I might see him getting better but he might actually be harder in some ways right like so if you

54:43can’t uh let’s just say when he was first born he didn’t he didn’t you know

54:50attend to the world at all right and it took him a really long time to even attend to the world and so he’s a very

54:55easy baby but then as he grew he got harder and harder right so as his development increased his ability

55:05to show distress really increased right and so you can imagine

55:12someone getting better getting getting um sort of older able to do more things

55:17but also getting more frustrated or getting do do you see what I mean so it’s like from a from a parents point of

55:24view you’re watching your child but then there’s always new problems right but

55:30but we’re happy with it because they’re developing so anyway I just I kind of want to talk about that a little because I feel like some of the scales don’t

55:37necessarily measure just how low we’re starting yeah this is a major issue with

55:44all neurodevelopmental disorders and um let me kind of go from the beginning and

55:50and yes you’re right so sorry that was a lot that’s that’s that’s all I have yeah no that’s that’s fine yeah yeah you’re

55:57right I mean for the first trials really you’re looking at um seizure frequency

56:04because as you said the FDA understands that it’s something that is objective uh

56:09that can be counted and uh because it can be counted uh it’s easy to say okay

56:15did seizure frequency change due to drugs right U but you bring up a good

56:21point not all kids have seizures and depending upon the disorder uh and and

56:28I’m you know I I can speak to scx vp1 where seizures uh where most of our

56:35kids have seizures but the the seizure frequency is fairly random and and is

56:41really dependent upon kids I’m not sure what it is with sgap one but that may not be the best uh but again that may

56:49not be the best outcome measure to look at because of that right so if kids go through long sequences where they’re not

56:56seizing and then have shorter sequences where they’re seizing a lot it could be difficult to time a clinical trial

57:03correctly right so but in a good clinical trial even if

57:08that is the main outcome measure clinical trials will often have or should have uh different outcome

57:16measures that they look at right so it may not be the main outcome measure that

57:22the FDA is going to utilize the whether a drug is effective but there will be

57:27secondary measures uh that need to be looked at and this is really where this

57:34is really where the natural history study and the disease concept models that you’re developing uh come into play

57:43because these are telling you how the disease is progressing and if you’re

57:48using measurements let’s say like uh that you may be familiar with the violin

57:54and the Bailey and U you know as standardized measurements uh that are

58:01utilized for you know development in in kids they’re also utilized in uh

58:08neurodevelopmental disorders and as you said you know the the it’s difficult to

58:15sometimes use those measurements as they were written because you know

58:21Sans don’t develop the same way as as neurotypical children

58:27do but they but those uh those scales can be used uh if they are adjusted uh

58:35or if you’re using what instead of the normal uh uh usually in Bailey you’re

58:43comparing to the normal or to an age range instead of comparing the age range

58:48you just look at the base number values for example you can uh you can kind of

58:55utilize some of those scales but sorry so you’re just comparing to yourself yes you have each each

59:02participant compared to self over time yes got it okay yeah and uh but this is

59:11but the that’s part of getting ready for uh

59:17clinical trial right is to understand what outcome measures work within the

59:22population right so if seizures aren’t going to be if you seizures can work in

59:28in some and that becomes a measure right but also how do we measure communication

59:34for example how do we measure movement um you know so there are there are scales that look at different motor

59:41abilities or movement abilities gross motor abilities spine motor abilities

59:46how do we gauge those and can we use those in our kids

59:54right and and if we can use them how do we need to adapt the scales that are already utilized that the FDA already

1:00:00recognizes as usable scales to evaluate these particular domains uh in kids how

1:00:08do we adapt those in to scapens right uh

1:00:13to to to uh um uh evaluate a drug right

1:00:19so that’s that’s work that needs to be done now that is being done now that’s

1:00:24starting to be done now right so I know that you know running a starting the

1:00:30natural history study at chop so they’re running many of those measures and that’s kind of the the things that

1:00:36they’re looking at uh for yeah so let me interrupt you on that

1:00:41and then then you can keep on with your train of thought um so uh you’re saying there are some validated measures but I

1:00:48know where else people other validated measures other measures are in development and trying to be validated

1:00:54so is the idea to get as many of those as we can into our patient you know sort

1:01:00of like Baseline for as many patients as we can and then sort of try to figure out which which validated measures does

1:01:07the FDA have a list of things that it accepts or is there like how do we you

1:01:13know do we like Go lobby to say this is a great measure for us will you please accept it like what’s that what’s that

1:01:19process like yeah that’s basically what you have to do so the FDA does not have

1:01:25a list of measures that they that’s acceptable for uh you know

1:01:31neurodevelopmental delay disorders as a whole right uh which would be great now

1:01:37maybe they will in the future but they don’t at the moment so basically what

1:01:42you have to do is you have to go and and look within your population and utilize

1:01:49these outcome measures and say hey look you know if we take the you know if we take let’s say the bailees and we say

1:01:56let’s take a look at you know one component of the bailees and and uh you

1:02:01know we adjust it we either adjust the questions that we ask or we adjust how we rate the kids uh and we say hey look

1:02:09now if we do this if we take a look at our population we see uh

1:02:15scoring that is uh uh distributed within

1:02:20our population so that’s important that that you see the scoring is distributed

1:02:26because that means that the scoring can increase can get better right so if

1:02:32you’re taking a measure where kids score zero if they you know if you get a small

1:02:40Improvement or an improvement uh if they’re so far below zero you’ll never get higher right so that’s a basement

1:02:47effect so you need to have uh evaluations or scales where your PO

1:02:54population of kids have a range uh and

1:02:59then you can uh the idea is you show that within a you know a certain number

1:03:06of the population and unfortunately there’s no magic number where this works

1:03:11it’s just convincing the FDA with the data that you generate to say hey look

1:03:17we’ve looked at 50 100 uh kids with s Gap over this age range

1:03:24we see this uh in this particular scale we see that there is a range of values

1:03:32uh and ideally we see that uh it increases with age or something or it

1:03:41has it it it uh is associated with some other some some biomarker or some

1:03:48other uh you know another scale some way but at any rate you’re convincing you

1:03:55need to go eventually convince the FBA that this becomes a useful scale in our

1:04:01population and that’s what a lot of the neurodevelopment disorders are doing now

1:04:08right so the so the disorders that we always talk about who are ahead of us uh

1:04:14you know D syndrome for example uh you know that’s what they’ve done uh is you

1:04:19know they have looked at you know different scales what works in that PO ation uh and you try to go um to the

1:04:28Regulatory Agencies and you say this is what we have uh and uh we think that

1:04:35this will work and then it’s basically up to the FBA will accept that they’ll

1:04:41say okay you know uh if you show us this changes um you know you can convince us

1:04:47that this becomes a valuable uh uh uh scoring or a valuable scale

1:04:55so uh even a scale that are subjective scales the FDA will accept uh so uh you

1:05:04know clinical evaluation scale uh just Global assessment right so you see your

1:05:10pediatrician and the pediatrician says oh you know your child looks much better

1:05:16today than the last time I saw them six months ago right so uh that is something

1:05:23that the FB can accept I will say that the FDA tends to be less acceptable of

1:05:31of global evaluation scores from caregivers than they are from

1:05:39providers okay and do they care that it’s the same provider over and over or it’s any

1:05:45provider uh they do they I can’t say that they don’t care um but generally uh

1:05:53I don’t think that’s a huge issue with them uh you yeah you can make an argument that it’s best to have it as

1:06:00the same provider because they’re basing their Global impression on the same

1:06:06thing uh but on the same hand if you want to be if you have a true effect

1:06:13that should be observable by any provider right right okay okay thank you

1:06:19well I want to go to the um Q&A uh Olga who introduced you has a question do you

1:06:26want to read it or do you want me to read it out loud I have

1:06:32the so I’ll just read it to the audience with Gene replacement therapy having

1:06:38potential to overexpress do we know how overexpression can affect patients in

1:06:45general and secondly uh the effective overexpression of syap 1 protein yeah

1:06:52yeah so that’s an excellent question and that’s one of the reasons that I pointed out the fact that something like Gene

1:06:58replacement therapy can cause overexpression because there are some

1:07:03proteins that are highly regulated in um

1:07:09in in neurons or cells in general and they’re highly regulated because if they

1:07:15are overexpressed they can actually have a negative effect uh on on cells or

1:07:22neurons uh for singap one I don’t know whether or not that’s

1:07:27known so uh and the easiest way to do

1:07:33you know that’s something that would have to be preclinically determined by basically taking a let’s

1:07:41say an aab that expresses singap one and putting it into a

1:07:47mouse uh and just overexpressing and see if you have any if you can see any

1:07:53negative effects of doing that um and uh

1:07:59obviously you’re limited to what models are available you can overexpress in you

1:08:06know neurons in a plate and see whether or not you see any uh large changes in

1:08:13other uh uh proteins or other genes or anything and and get an idea if if you

1:08:19have any sort of negative effect on that uh you can do animal models you can do

1:08:25you know zebra fish or mice or or uh flies or rats or whatever to see uh what

1:08:32you if there are any negative effects you can look at non-human primates to

1:08:37look at that uh you know there’s no but obviously there’s no guarantee that you

1:08:43know it’s going to be different in people right so uh that is always a

1:08:50concern uh with Gene therapies because those types of gene therapies as I said

1:08:55are permanent so if there was a negative effect uh for a lot of types of gene

1:09:04replacement therapies there’s not there’s no way to get rid of that negative

1:09:11effect so that’s that is a very good question but for most but I would say

1:09:17for the vast majority of proteins and genes there does not seeme to be in

1:09:23issue with ere expression well sometimes if if if they’re the cell may have a way of

1:09:30getting rid of anything that’s overexpressed uh that uh it doesn’t want

1:09:36uh and for others it doesn’t really matter so um are there I I’m surprised I

1:09:42don’t know this off the top of my head are there any uh diseases single you

1:09:47know monogenic disorders neuro or not for which an aav is an a gen replacement treatment is

1:09:57approved [Music]

1:10:02um I mean I can imagine maybe a blood or liver one but I’m not I don’t know uh I want to say yes but I’m not

1:10:10sure that it’s on it’s for sale any long so one of the first Gene therapies that were approved was I believe a gene

1:10:17replacement therapy um I forget what the this disorder was but it was

1:10:24uh I I don’t think it’s no longer marketed because it it it never really sold it was for uh I think it was an

1:10:32enzyme replacement therapy right so not not a you know

1:10:38brain brain has a different different whole different solid organ that has more issues than than blood okay

1:10:48um anything I should be asking you that I haven’t asked you uh no so

1:10:54uh but if we go back to the uh uh the

1:11:01overexpression uh issue so apart from Gene replacement

1:11:07the other thing that uh that you need to be aware of is that certain mutations in

1:11:14genes can cause what’s called a dominant negative effect which means the mutation uh the problem with the

1:11:20mutation isn’t that it makes a defective protein the problem is that it makes a protein that is uh is having a negative

1:11:30effect on the cell as a whole right so for a lot of monogenic diseases we think

1:11:36of those diseases as being uh Hao insufficiencies which means that you’re

1:11:43just making half as much or of the normal amount of protein and so that’s

1:11:48what’s causing the disease but for some mutations uh the M

1:11:54the Protein that’s made and these are usually uh going to be missense

1:11:59mutations uh the that protein is being made but that protein actually has a

1:12:05negative effect it’s having a biological effect that biological effect is a bad effect though and so it’s actually worse

1:12:13to make more of that protein so if you had a therapy that was designed to increase the expression of uh of protein

1:12:24in general um and it could not like an ASO for example that increased RNA but it

1:12:31could not uh tell apart the the mutated RNA from the unmutated RNA right from

1:12:41the the good G the Bad Gene it would make uh it would increase the expression

1:12:47of both the good protein and the bad protein so you would not have so it wouldn’t work in fact it may actually be

1:12:53worse because you might end up making more bad protein and have a more

1:12:59negative effect so that is one of the reasons why for example it’s important

1:13:04to understand how the variance uh what the the pathologic effect of the variant

1:13:10are especially missense variant if I hope that made sense I’m

1:13:18not sure yeah well I’d say the do the one thing I would add to that with dominant negative is a dominant negative

1:13:25is where the pathogenic variant is interfering directly with the wild type

1:13:32variant yeah so because you can also have something that just does something

1:13:37new and random but isn’t yeah isn’t uh it’s mode of action isn’t through the

1:13:44wild type protein so that’s what dominant negative is and it can be yeah it’s it’s really

1:13:51mystifying so that’s why we need need good asset that’s why we’re funding four different projects to look into what is

1:13:59going on with the missense mutants and for that we need structure uh you know sort of structure

1:14:04and stability data we need assay data we need lots lots and lots of stuff so

1:14:10[Music] um yeah that the I guess the one

1:14:15question I always come away with is what are the like I I think most of the trials

1:14:23that have this period where they look at negative effects right and so with small molecules I understand that you can say

1:14:29what are the side effects oh we tried tried a few different anti-seizure

1:14:36beds antiepilepsy drugs and one of them was like oh yeah the

1:14:42people who learned about singap they think this is going to be the best one the very best one and so we try it and

1:14:48his negative behaviors just go through the roof like nothing nothing gets better except that he gets incredibly

1:14:54incredibly aggressive and people had thought oh that’s the opposite of what we thought was going to happen and so

1:15:01you wait a while and then the drug washes out and then you don’t go back to it and then in his chart it says he’s

1:15:07allergic to it you know he’s allergic to it because he had this bad reaction right that’s how that’s how my medical

1:15:12chart reads for him so um so I don’t quite

1:15:20understand the the safety stuff for um for the Precision medicines I

1:15:27guess for the Asos you can try a low dose so I guess there’s a do there’s dosing I guess the a I guess the gene

1:15:34replacement is the only one that I don’t I guess it’s sort of mystifying to try to figure out what is

1:15:40the what’s the pathway towards finding out if it’s safe sure yeah so the uh so

1:15:48for a gene replacement therapy the

1:15:54you still do a dose res you’re still dosing patients but generally how gene

1:16:01therapy trials work is that um you you start with a low dose and for a gene

1:16:07therapy trial the FDA requires that a do that as being a dose that can have a

1:16:13positive effect can or cannot can it has to have it has to be able to potentially

1:16:20have a positive effect okay it to be the lowest dose where you would that predict

1:16:26doses on animal studies right but so you take the lowest dose that you saw positive effect on animals and that

1:16:33basically becomes your human dose in a clinical trial uh adjusted for S there’s a

1:16:41mathematical formula to adjust animal in human doses so but you use that as your

1:16:47low starting dose uh and uh you U basically basically

1:16:53treat a patient usually you start off with one patient and you see is there is

1:16:59there any immediate negative effect right do they have an immediate bad

1:17:04reaction to that uh and and and then uh

1:17:10you might dose a a second patient that second patient may be dosed uh a couple

1:17:15weeks or a month later U because you’re you’re observing that first patient and that’s usually how this goes and you and

1:17:22you you know three patients at a low dose at the lowest dose and then you follow them

1:17:29for a couple months sometimes up to six months the FDA will decide on kind of

1:17:36what that uh time period is and that’s exactly why you’re doing that is because

1:17:41you don’t know you know um it’s not going to wash out if there is a negative

1:17:47effect uh and hopefully that negative effect that there are uh Adverse Events

1:17:53events from the gene therapy um they can be managed uh because they’re

1:18:01uh uh you know some sort of systemic issue uh for

1:18:08example uh but yeah it it obviously it is a chance you you are rolling the dice

1:18:15with that but for the most part there really hasn’t been uh from you know huge

1:18:22uh issues uh there are there have been some uh uh with

1:18:28aav uh some most of the serious uh events uh that have occurred are liver

1:18:36toxicity uh due to dose uh and some toxicities associated with dorsal root

1:18:43ganglia which are neuronal structures along the spine

1:18:48um and so but those are toxicities that are known uh and and you know there are

1:18:54ways to try to get around some of those

1:18:59toxicities and then if you don’t see any any Adverse Events or serious Adverse

1:19:04Events then you go up to the next dose yeah yeah okay well I feel like I could talk

1:19:11to you for a few more hours um it’s 10:20 you may need to go how how are we

1:19:17doing uh I’m fine yeah yeah okay well I just wanted to mention that you know for

1:19:23spinraza for ASO spinraza was the first one that I know of and that’s a you know

1:19:28a a case where people are literally dying without it and so that that’s a

1:19:34case where people want to try something and it worked great so that was that was

1:19:40really interesting so I’m just wondering what’s a I I mean I’m just thinking out loud I’m wondering you know maybe for ALS or you know maybe there’s some kind

1:19:47of uh brain disorder where people really you you

1:19:52know it’s sort of a last chance and maybe that’s what will be first in the

1:19:58aav gene replacement and we’ll get more understanding there I don’t know

1:20:05that’s what makes sense to me because my child’s not dying I mean it’s got a ton of problems and I’d love his life to be

1:20:11better but making it a lot worse seems like you know I went through really hard times with him and we’re on the other

1:20:17side of it and it seems oh yes that’s absolutely that

1:20:23people are going to have to balance when you know these new therapies come along

1:20:28is you know first Do no harm right we want to try something uh to help our

1:20:35kids but we don’t want to make anything worse right so that’s obviously that’s a major concern with the FDA uh and as you

1:20:43said for uh for a a disorder like spinal muscle or SMA

1:20:51the uh you know the issue is you know it’s treatment or you know you’re

1:20:58treating kids who are going to die right and so that’s an that’s an clinical

1:21:05outcome that’s easy to measure not dying and yeah over the natural history

1:21:12of the disease yeah yeah you’re like typically 90% of patients have died by this age and these now these patients

1:21:18are all alive past that age so yes yeah so uh in that case yeah it it was kind

1:21:25of an easy decision and with those those are ASO drugs uh and so they are um you

1:21:32know if there had been a negative effect Asos will wash out because

1:21:39U and so those that’s one of the things that makes Asos safer obviously which

1:21:45make them and that’s why a lot of companies are looking at Asos and why you know those will probably be the

1:21:51types of precision therapies that come for will be quicker to be developed for

1:21:57syap right and but again the

1:22:08uh Asos might you know work well

1:22:13U but you know Gene replacement May ultimately uh be a more permanent

1:22:20solution right so that there are positives and negatives and uh we don’t

1:22:26we just don’t really have that enough information to to make a decision as to

1:22:32what’s going to be the best way moving forward right so I guess our our role at

1:22:37srf is to figure out what are the things that we need we have to know for our own patients and then where do we who do we

1:22:44look to to see who’s doing stuff that we’re not going to be doing but we need to see what their results were so I

1:22:50guess that’s always our that’s always our thing is like what’s what’s our little Focus what what what do we have

1:22:56to do because only we will do it or only you know it’s it’s really patient specific and then keep keep a breast of

1:23:02all the because we’re obviously you know every every monogenic disorder wants to cure have a cure so right right yeah and

1:23:11and you’re you’re perfectly correct in the fact that by the time you know there’s a gene replacement option for S

1:23:18Gap uh something like that will have already been done uh in another disorder

1:23:25and we’ll have a much better idea about uh you know how that worked uh for for

1:23:33specific neon neuronal disorder right and maybe and maybe even to AUST

1:23:38question too about expression levels and you know there’s lots of things that we could know more

1:23:44about yeah I mean yeah and they’ll they’ll be specific for each each

1:23:49engineered construct but yeah anyway okay thank you so much Jim H you’re

1:23:55welcome so uh I hope uh people enjoyed it or if they are watching at a later

1:24:01time they enjoy it and you know if anybody has any questions I guess I should have put my email address up on

1:24:08one of the slides but uh um I you can

1:24:13get me at the I give you my general email which is James rgos

1:24:20outlook.com so be happy to answer any questions I also have a a singap

1:24:25research fund email address so I think you know k s Gap let’s see see if I can

1:24:34put that up can I put it I don’t know how to do this is there a text

1:24:39yeah is it is it writing there we

1:24:46go so you said James are go at Outlook

1:24:54there we go peoples you saw it

1:24:59here okay well thanks so much Jim oh you’re welcome thank you bye

1:25:12bye