So next we have a talk about a topic
that we've started to get more and more
questions about which is gene editing
and fragile X syndrome in recent times
there's been a few news articles that
have obviously piqued people's interests
as well as the broader awareness and
discussion about gene editing sort of in
the media and so mark Hearst is one of
our specialist advisors and is a senior
lecturer in human genetics at the Open
University and a couple of years ago
mark did a talk on this topic at the
European fragile X Network which was
just such a wonderful balance of
scientific information and that was
really accessible and and sort of a
broader view on what the sorts of things
we might be thinking about when it comes
to gene editing so I'm really really
delighted to introduce mark and we will
transition as we I thought I'd start
actually with a picture of the recent
fragile X day where they turn Agra for
steel which I thought was pretty cool
and I'm thinking we want to try and do
something like that and it probably
sounds a better chance than any of the
UK cities but I thought those people
didn't know they they lit various things
up until then my egg was quite an
accomplishment so it would be really
nice to try and do something next year
we've got a whole ten monster to get it
right so I can offer puppy officering in
Milton Keynes but not that so so I
should just quickly say a word for
myself I see a few familiar faces
I've given various talks on and off over
the years I have a link back to to
Edinburgh back almost 30 years ago now I
was a PhD student studying genetics and
got very interested
in working on human genetics
particularly excellent so I moved to
Oxford partly because of two reasons one
there was a research group there led by
her research called Kay Davis who was
doing some very early work on fragile X
genetics this was in nineteen that the
mid-1980s but also because there was a
wonderful clinician there who had set up
a new Institute called David Wetherill
who had written a book called gene
therapy and as an undergraduate I
thought it was such a great idea which
was to actually rather than use
pharmacological approaches to treat
disease to actually look at doing
something with with genes with DNA and
sadly David passed away last year I'm
not really seeing the feel deliver but I
think what the reason why I was asked to
give this summary today and it's going
to be a complete contrast because we've
gone from real life that andrew has
stepped you through to we're about the
top of the ivory tower here we are
talking about the top end of research
where lots of things are thought about
lots of things are tested lots of things
are explored very little of which will
actually reach real practice and will
delivery and the timescales could be
anywhere from five years to 15 years to
20 years it can take a long time for the
types of things I'm going to talk about
today there's a lot of enthusiasm for
the idea of editing genes to cure
disease there's also a lot of hype
around and I suspect a lot of that
enthusiasm and hype that comes from
various places he's feeding through into
the photonics hot line as it were so I'm
gonna try and take you through where
we're at I don't personally work on gene
editing I work with people who work a
lot on delivering things into the brain
my own interested is up he's actually
looking at different aspects of genetics
in individual brain cells and I still do
work on on fragile X but I'm also
involved peripherally with
more recent work to do with developing
therapies for treating Huntington's
disease in terms of getting things into
the brain to have an effect upon the DNA
the gene that causes the disease so I
keep an active area in this injury
interest in this area so I'm gonna tell
you a lot about what other people have
done the frozen aware none of this work
is actively going on in the UK at the
moment which is a shame so I'm going to
start right try and explain now
obviously talking about the background
genetics and science can be quite
complex and a try make it as easy to
understand as possible I've drawn very
simplistic representation of what a cell
in the brain what we call a neuron is is
functionally doing on the right hand
side this represents the DNA that's
inherited a V sits in a component a
small component of that cell you have
about a hundred billion of these little
connections where the cell is talking to
lots of other cells it's complicated
and I think if we were to try and even
pretend the wiki really how this works
we'd be lying it's very complicated and
very complex but effectively all those
can all that interaction between lots
and lots of cells in the brain gives
rise to everything we do in terms of our
physiological functions out behavior etc
so it's complicated and the protein that
we know is involved in fragile acts
plays a very important role in the way
these cells behave the way they function
within the brain and the protein you
probably all know the name of F of our
pea protein is encoded by the gene it is
important in the way cells talk to each
other and it's probably affecting a
whole stack of other ones I've put up
some names of proteins or the systems
you may well have come across the most
famous one problem you've heard of will
be M glue R but there are others of
their those are all targets for
a drug based therapist so when that
communication goes wrong he goes wrong
because principally of the absence of
the FMR protein trying to change that
communication network the way it works
is a target of most of the medical
medicines drug therapies and to our
trials there's a whole series of other
trials targeting lots of other drugs you
may have heard of metformin as a as a
trial so four or five ongoing targets
that are currently active I'm not going
to talk about any of that that's all the
pharmacology what I'm going to talk
about is gene editing so this isn't
working at the business end the way
cells talk to each other it's working
where this whole thing starts which is
the gene that actually encodes the
protein how can we do something that
actually potentially replay reactivates
and puts the gene back so you don't need
all this down all the types of therapies
so that's what we mean by gene editing
going in and change in the DNA in the
cells brain cells in this case but lots
of other people are developing types of
therapies targeting other types of cells
so that's really what we're talking
about gene editing
I think at the moment they're talking
about treating without independent
adults and children not not looking
developmentally I does have a really
good point I'm gonna come back to that
near the end actually because some of
the data suggests that isn't the case
which is quite nice so I thought I'd run
through I'm going to talk a little bit
about the genetics just so we all know
where we are
I'm gonna run through watching editing
is because is that there's a lot of
misnomers and misunderstandings about it
and i'm going to give you examples of
what has been developed in reserves labs
different strategies different
approaches and actually quite a very
positive set of outcomes which is
probably where a lot of the enthusiasm
and height comes from but I'm going to
put the brakes on and say actually this
is research and there's still a long way
to go but I'm also going to come back
right at the end to it to some other
stories which is successful which I
think are actually quite positive
so you inherit an fmr1 gene and that
encodes for the FM RB protein and the
proteins the reason why it's probably
has such a dramatic effect when it's
gone is because it's influencing
probably something like 600 other
proteins in the brain a lot of those
proteins seem to be also involved in
other types of autism so it's quite a
complex disorder we know that the change
that happens in the fmr1 gene you
probably all know this thing called the
CDG repeat it gets bigger to a certain
size in what we call the premutation you
still get FM RP protein produced to a
reduced sense and then what happens over
a certain length the whole gene gets
switched off by process we call
methylation and in the presence of
methylation
you make no ethyl RP so that will be the
situation in some who has what we
classically call a full mutation and if
that full mutation is present in a boy
because the only have one x chromosome
that would essentially be little or very
little FM RP protein in in the neurons
in the cell which means a lot of other
proteins are disrupted and as I've said
that cell-cell communication breaks down
and the consequence is all sorts of
developmental processes that normally
happen in the brain happen in a
different way or happen more slowly so
that's the basic genetics and I've
highlighted the ones that are left
because those are going to be the
targets for anybody trying to do any
type of intervention what we're talking
about is can we change those genes to
have a positive effect upon the presence
of FM RP that's really what a gene
editing is so the first name can we can
we reduce the size of that repeat and
make the general effectively have that
chromosome generating more protein
that's the first aim can we edit out the
repeats they've got larger an
effectively restore normal functioning
to that gene however there's also a
second way of editing which is a more a
slightly more sophisticated more
recently developed technical which is
I'm going to explain in a minute there's
a way of editing to actually take off
that silencing mark remove the
methylation so those are the two
approaches that I'm going to talk about
today and I'm going to describe papers
that have been published probably in the
last two to three years this is a very
active field there's a lots going on an
awful lot of the developments with this
technology and technology you will have
probably come across is something that's
called CRISPR Kass that's the kind of
system that we're talking about the
genetic system by playing with here
you've probably come across this term
it's
you revolutionized the way in which we
think about potentially using as a
research tool but also potentially
treated things so that is a huge amount
of research in human genetics involving
these systems in virtually every type of
disease you can think of some cancers
through two other rare diseases the
great thing about that is the technology
is moving incredibly quickly so their
ability to do things as a researcher
when I first started out it would
potentially take me I had to make my own
reagents to work in a lab for example it
is possible to call the company and have
a CRISPR tool delivered to your door
literally by overnight so it's in the
pace with which the research has
happened in the last few years since
this technology became widespread again
the Nobel Prize a few years ago is it's
just amazing and if you ever look on
YouTube you'll find guys called gene
hackers who have actually ordered it by
mail order and injected into themselves
not something I would recommend
personally but they are out there and
you will find them on YouTube so what is
this thing CRISPR cash you probably come
across the name well I'm gonna go right
back down to basic bacteria you and I
when we can get infected with something
our immune system usually kicks in
pretty well we might get a little bit of
illness but power immune system usually
is pretty good at fighting off well
those little bacteria have immune
systems as well and effectively what
CRISPR casts is is a bacterial immune
system and I'm gonna tell you how it
works
bacterial infections like viruses just
like we do virus DNA goes into the
bacteria and the bacteria chops it up it
chops it up because it has a little
pac-man like protein called the Cass
protein and that little Cass protein has
effectively a little sensor on it it's
recognizing the genetic code of that
virus and what happens is it uses a
little thing like a postcode
so the next time the virus comes into
the cell it has a copy of it and it
directs the little protein to digest it
chop it up so effectively that's called
the CRISPR erina the post coding system
so the bacteria keeps a little record of
everything that's ever infected it
produces lots and lots and lots of
different little enzymes little Pacman
and effectively that does the chopping
so what works in bacteria has
effectively been harnessed and stolen
and we're talking about using it in
human the reason that works is because
the way proteins work in a Cell is
universal the way DNA works in a self is
universal so it's not difficult but to
do at all you can the things you can buy
literally online there's a pot that
contains the cast protein and a crisp
RNA very easy to do so how was he
actually used well those are the systems
I just told you about but what we can do
is effectively if you want to tweak
something in a Cell what we've got to do
is give it the gene that will make that
cell make the protein so you need the
protein to actually do the work so you
have to give a gene but what we can do
is that little postcode system we can
just simply change it to anything you
want so in this case you change the post
coding to direct towards the DNA
sequence of the pathology the CGG repeat
for example is a common so effective
what you've now got is something that if
you put in a cell uses the little post
coding tag the crispr RNA to send this
little Pacman and what will happen is it
will do exactly what it would do in a
bacteria and he will chop chop the DNA
what we need of course is the target
most usefully kafaja likes fmr1 gene
someone that has a lengthened CDG repeat
it's all training to do is effectively
direct this little piece of protein to
go in and chop the DNA so what happens
first thing is to get the stuff into a
cell that's relatively straightforward
if you're doing this in a lab the little
Pacman does its job you get a big chop
in the DNA
so chops in DNA are never good they're
the types of things that when cells go
wrong you don't want DNA to be damaged
it's often what happens in cancer cells
it can cause all sorts of issues because
cells don't necessarily always know how
to deal with DNA damage like that what
actually happens in most cells is your
cell starts to just nibble away at the
ends
they're very hungry things and then most
of the time the loose ends get stuck
back together again
it sounds awfully wrapped them and it is
awfully random but that is a normal cell
process so effectively this job he's
nibbled away naturally by the cell and
get stuck together again and it's almost
a random process the things I'm talking
about today rely upon this to happen
normally yourself if you imagine that
chopping away is removing CGG repeats
and you're sticking it back together
again you've got something which has
fewer CG repeats so you're effectively
going back from a full mutation to
something which is shorter and
potentially in a range that you consider
more normal in terms of producing
ethanol proteins that's that's the
theory
what really wasn't known for fairly
recently was whether this this process
would happen efficiently in human nerve
cells in human neurons thankfully we
know it does in
in a laboratory I don't think we really
know their works in cells in the right
so that's the principle I'm kind of
hoping everyone's still with me does
anybody not with me yeah we're talking
about going in dropping in something
which won't shop the DNA chop the gene
and the cell your own cell actually does
the good stuff which is get rid of the
repeats and sticks it back together
again hopefully everyone's okay so
that's what we're talking about for gene
editing in terms of clipping the CDG
yeah yeah so the question what well the
comment really was that if you remember
the little green RNA fucking up where
the pointer is this little thing here
what it's doing is recognizing the the
sequin the DNA sequence which is a
series of letters c ug c ug c ug they
occur lots of other places in your
genome I've shown you a picture of it
very nicely only going to one of those
places which is the place we wanted to
go the fmr1 gene but it doesn't know
enough ml one gene from another stretch
of the same sequence so those are what
we call off target effects it is a huge
issue there are more and improved
systems which allow much more specific
targeting there are ways you can make it
recognize the gene you want to recognize
but actually off target effects I'm
going to come through later for one of
the huge unknowns we just don't know
what the potential of the effects are so
yes it is an issue so three papers have
actually published successful outcomes
on this so what they've all done is take
cells in a culture these are cells human
neuronal cells established yeah usually
from by taking so every now and then
clinicians like Angie will scrape scrape
some fiber bar cells off your skin it's
possible to turn those cells into stem
cells and turn those cells into neurons
in a lab it's the way which you can
study neurons in a dish established
simply from a skin biopsy from an
individual who has a particular symptoms
such as fraudulent so they nearly all
used a similar system so what they're
doing is trying to put in the crisper
cast target into a cell where the fmr1
gene is a full mutation and usually it's
also fully methylated and the question
is do they see they find the right
button what they do find is that the cam
they do they do delete the repeats and
the cells start to express FM RP just in
case that wasn't obvious that's a good
thing that's actually what we want to
see so three individual papers the
federal once the references I can supply
them have all use slightly different
systems it's been reproduced
three times with different degrees of
success but actually it's remarkably
promising one we now know that if you
can target the gene it will remove the
repeats that was completely unknown it
was it kind of let's be honest it came
as a surprise to me they weren't quite
as well as it did more importantly it
looks like it does actually work in
neuronal cells so actually it's both
very promising observations that it does
look as if the systems at least in the
cultured cells and these are all in this
case these were all human are capable of
actually responding this technology
would die immediately if this had not
happened if we know for example that
neurons
cannot edit it looks as if they can so
that internal process in the self seems
to seem to work so that's actually very
positive they can repair they can cut
repair and you start to see FM RP
expression coming back into those cells
which is quite nice I'm gonna stress
that these are cells in a dish
they literally grown in a laboratory got
a small plastic dish so these are very
very heavily experimental systems but
it's actually quite encouraging I think
I think it's it's use throughout life it
regulates lots lots of protests so the
question was why can't you just put the
gene back in that would be the classical
sort of idea behind gene therapy can you
stick the normal gene back into cells
that's not been achieved by anybody that
was originally David wetherall's idea
for treating thalassemias and sickle
cell anemia by simply putting a single
gene back into the cells that produce
red blood cells in that case they could
struggle many many years to try to do
that in a cell system that's very easy
to isolate and have no success so if I'd
in most cases those approaches have not
even gone off the starting blocks so
this is kind of the new kid on the block
as it were
I'm in there - protein no you need you
you wouldn't bill - it wouldn't get into
cells and do its job as a protein it
sorry yeah I've misunderstood your
question
there's another question
but I I agree completely I will mention
it but I think at the moment forget
doing this in humans this is luck this
is the battery this is Cal what can we
learn from what's going on in a lab and
what might need to happen to get to a
point where you even need to start to
think about those things I think I think
I'm gonna wind back some of the hype
that's around so the other big study and
this is probably the study that probably
I suspect elicited most most interest
was it was a very clever adaptation
which doesn't go in and do the just
adding doesn't chop the DNA doesn't rely
upon the cell to reduce those repeats so
therefore has an element of being less
potentially less hazardous less
dangerous because it's not going to
cause those types of DNA damage events
what they what they very cleverly did
was rather than having the little Pacman
that does the chopping they replace it
with a protein that white off the
methylation from a gene this was very
successful effectively in these cells it
wiped off the methylation and actually
did restore protein expression that
comes as a bit of a surprise to many of
us because what he didn't do was alter
the length of the repeat and we know the
cells that have a very long repeat
generally struggle to make a large
amount of protein so this approach is
effectively the equivalent of switching
the gene back on and generating enough
protein with not having to do any of the
deleterious dangerous types of editing
that was the first reason why it made a
lot of press the second reason was this
was actually done in in human cells in
culture rather like the last set
sells but what they then did was they
took those neurons from a dish that
they'd now switched on FM R P so these
were full mutation neurons that have
been reactivated
they put those neurons into the brain of
a mouse that was the knockout man
so this broke this mouse didn't have any
functional FM RP and actually showed
that the cells continue to express
protein for three or four months which
is the longest they looked at but also
that those neurons started to integrate
they started to function which is
actually that's probably why I got so
much publicity and hype because it was
the first real evidence that it might be
possible that a cell that has switched
every month peopie con is actually it's
possible to get enough protein made for
it start to restore some other function
which is which is I think quite
remarkable and again I don't think many
people would have predicted they'd see
this result so again this gets a smiley
face in the sense of it's going in the
right direction
it's types of basic science that tells
you that these things are potentially
possible in the future so I think in
terms of the science I think what we're
saying is I think there's a proof of the
principle this system seems to work
releasing all the experimental systems
that they've looked at it does seem
possible to erase methylation and it
does look as if that will actually give
rise to ethyl RP so actually they're all
very positive signs that that
notwithstanding all the limitations I'm
about to go on a venture that the site
says this this is ticked every box as
well that's quite impressive and it's
done so in a very very short period of
time I'll have to say
yeah
I mean you mean I I don't think anyone
has looked the I mentioned the fact that
that once you get to very long numbers
of repeats usually the gene struggles to
make protein and that is proportional to
the length the length that they chose
for the methylation study was I think I
remember it's been about three to four
hundred but I I don't think anyone
really knows at the moment so my guess
would be those are the types of studies
that will be going on to do now to do
precisely precisely those studies after
say it's probably one of the original
gaiter which was published probably in
the late 1990s one Steve Lyons in the
laboratory probably one of the reasons
why everybody assumed this their this
approach would not work because they
suggested that you would probably get
less than ten percent of the normal
level of protein and although it's the
laboratory system and it's artificially
created but I put in neurons back into
the mouse brain it may well be that that
small amount could be potential
functional we don't know so in terms of
the buret rework there's a whole slew of
work that's probably going on in really
any she's lab who's the lab we've
developed this methylation thing and
nearly all of this work moves on to
principally mouse that's the most
accessible model and usable model for
first scientists involved and there's a
bit of a problem there for the community
which is there are a very limited number
of mouse models around we don't actually
have a model for what we'd call the full
mutation ie a mouse that really carries
the repeat which is methylated so it's
very difficult to see
where those studies go at the moment
because the methylation said is because
of the limitations and mass moments so
that kind of fit in a bit of a
bottleneck so then obviously one of the
big issues here if we're going to think
forward and say and I think rather quick
refers to your question if you're going
to do this you've got to do this in a
brain what we're talking about is going
in and making genetic changes in
someone's brain I'll come back to a lot
more issues around that but there's one
other paper which was probably other
paper that triggered all all the really
interesting stuff in fragile X which is
I'm going to back to what I said
originally most of you have heard of
this idea that part of what we know is
in fragile X the absence of FM rp1
particular signaling system that's
important in that cell cell
communication is called Engler and that
virtue a significant number the clinical
trials for drugs have been trying to
down switch down and glue our activity
so many people here probably even had
family member who's taking part in the
trials even perhaps through three
hunters laughing so that's been the
target to try through drugs to reduce
and lower activity what some other
clever person decided to do was actually
target the M glue our gene in the brain
well if you can't knock him knock it
down by drugs is it possible to just get
rid of the protein in the first place so
one group have done this and actually
shown that it's possible to deliver
crisper
the important thing here is they did it
in the brain this isn't doing it in a
lab this is now making the equivalent
little Pacman the post coat now says
take me to the gene including mu R and
chop it up and because of the way
they've done it the chop even though
it's repaired actually destroys the
function of the gene so those cells now
are no longer capable of making
this bottle system was then used
effectively to try and ask if we do this
in the brain of a knockout Mouse that in
theory has elevated into our what
actually happened so they managed to
successfully demonstrate that you could
deliver the reagents to specific area in
the brain they were looking at a
particularly called the striatum which
is particularly important in in motor
activities and what they found was that
they got the job they get indeed
knocked down and lower activity in the
brain and the reason why they chose that
particular system to target was because
some of the phenotypes of the ways in
which fragile the FMR knockout mouse
behave the closest type of types of
behaviors that the animal biologists to
think parallel types of repetitive
behaviors in fragile eggs that you can
see similar behaviors in the knockout
mice and they principally rely upon
motor activities that's what they're
trying to say is if we knock it out
we'll see an effect upon the way the
mouse actually behaves repetitive so
it's where they vary marbles in sound
light and remember
what they found was that it actually
restored a relatively normal level of
activity so this is important because it
actually shows that you can deliver this
thing in a mouse prior so that's quite
quite an achievement
so again just actually get a smiley face
okay so everything I told you about
looks very positive I know we never get
to know about the results that failed or
went miserably wrong and never get
published but I can guarantee you for
every one of those are probably at least
ten that never made it to the lab to the
two publications so we're very mind that
research breakthroughs are not
necessarily representative of the
reality they're the success stories and
just because somebody tells you they
worked
and they designed in a particular way
and they delivered exactly what they
were showing there's often a bit of
creativity behind that and there are
probably lots and lots of technical
things that we don't know about that
will come to life but I think from the
perspective of the laboratory basics I
think it looks incredibly promising I
think I mean I've been working on human
genetics for over 30 years I think this
has gone from zero to hero status in in
a remarkable length of time so it's in
terms of shifting within a laboratory
sphere within the research fear it's
being remarkably impressive but this
this is what we need to stop think
because we're not talking about doing
this in a laboratory what I'm talking
about doing it themselves we're actually
talking about could this therapy ever
make it into doing this in humans I'm
not only doing any humans but doing it
in a be the most complex system the
brain which we don't really understand
so what are the hurdles I think we
raised this issue a couple of times what
we call off-target effects we don't know
basically there are ways of people are
working on improving the accuracy this
little post coding system there are
different versions of the protein for
example there are different tweaks you
can make that make it more accurate and
I'm sure there are lots of developments
still to happen but genuinely we don't
know and the reason that's important is
because there are an awful lot of stuff
that you don't want to mess around with
in in a Cell the principal cause of
cancers is DNA damage DNA damage at
genes that will make a Cell grow and
controllably and the last thing you want
to do is start to mess around with other
genes so you don't want to go in with
the intention of trying to fix one gene
and cause damage to other genes and I we
just don't know maybe people have heard
about
to do what we call germline therapy to
with the babies in China that we're done
for so many reasons the wrong way but in
the sense of there are people who have
done at CRISPR experiments so we just
don't know we genuinely really don't
know either whether or not these systems
are going to be seen by your body has
some how dangerous and foreign we there
are there are clinical trials involving
delivering systems any type of delivery
that was used as a therapeutic drug has
to go through an inordinate amount of
safety regulatory elements before they
even get to stick something in somebody
and there is at least one trial that's
got almost that far in terms of sticking
this stuff em but the system we're
talking about easily wykel easily
accessible systems that things like
behind the eye inside of the eye sits
kind of outside of your immune system
it's slightly look it's slightly
protected it's things like cells in your
bone marrow it's things like muscle that
can be isolated sticking something in
the brain we just don't know about we
also don't really know how he would
deliver it but like I said there's a
lots of people working on it
good question and in fact you preempted
kind of kind of the next question a
chief for me this is one of the big ones
even if they sort out all the other
technical stuff they're targeting in
terms of deleting the CGG repeats this
isn't something that you would take as a
medicine every day for the rest of your
life
this is going in and making a permanent
change that's what that process is
you're going in editing you don't get to
do the second time you don't need to do
it a second time which also means that
if it goes wrong or you inadvertently
edit something else by mistake that is
also permanent it's a completely
different ballgame it really is I think
for me this is the thing I don't even we
have a fantastic trial system most of
the real world class methodology behind
clinical trials have been developed the
systems their ethics overviews that
processes have been developed a lot of
them in the UK and I don't think they've
even got their head around how you now
approach making permanent changes
potentially in someone's brain I don't
even know how it would get to a phase
one kind of cool I really don't think
it's it's kind of baffles me I don't
either thing we don't know courses we
have no idea where you might target yeah
not kind of also goes back to this other
question which was if you now
effectively theoretically what you're
talking about doing is making those
cells gain the protein and those that
protein will now make the South brain
cells communicate properly more
effectively and therefore you would
start your theory to be able to really
gain the what we call plasticity so
learning could in theory be rebooted but
we don't really know because there is no
no one's ever tested that system to know
whether or not what happens in normal
development of the brain and the brain
develops probably till the mid-twenties
whether or not if you went back and
kick-started it how you would go back
and actually reprogram
oh yeah I mean oh you're in such
hypothetical ground here I don't think
anybody really knows I mean it's a it's
an interesting question because I didn't
think that was even really ever
addressed in the drug therapies in terms
of what you might have to put in place
to try and kick starts and process I
think true I don't think anybody ever
really
I don't even think I I think you said I
think even for the trials which are
involving things like Anglo inhibitors
and all the other trials are ongoing I
don't think any them have really cut
rest precisely your question fine I just
don't think they have so to a sin extent
it's likely that they will try and do
something before this would even get to
a point where it will be being done but
you are in such hypothetical ground here
that yeah
yeah I think I basically this
connectivity will continue throughout
your life
what tends to happen is the final mature
white corn mature system is usually kind
of considered to sort of finish off
development in your mid-twenties well
I'm not the expert brain development
that I think that's the usual oh well I
don't think you ever stop learning new
sell new things certain systems you
normally classical human brain
development it's considered until the
twenties but doesn't mean to say your
brain stops functioning from them anyway
so let's carry on and what this kind of
goes back to the same thing which is we
don't really know that a neuron in in
the context of a brain this reprogram
will actually respond because whilst you
can edit them in a dish and put them
into a brain and they can work if the
question is what they respond in the
brain itself so I think the hype around
of science and the laboratory
breakthroughs are all incredibly they're
all positive results but you can see
these are all rather big issues I don't
think a lot of this has been sorted out
for the current types of trials let
alone where this may potentially go and
so from that perspective it's it really
is on the way out I mentioned this I
think
permanent permanent head it says I don't
know how they're gonna saw that one
outfits it's interesting something else
is that a lot of a lot of startup
companies a lot of investment for new
therapies is going into developing
CRISPR based gene editing therapies and
there is a danger that actually this
kind of acts as a bit of a a beacon for
funding and that may well distract from
ongoing trials and so there is a there
is a danger that there is only so much
investment around in any unary area but
fragile X and it's possible that I
wouldn't want to see it deter or reduce
funding for us out there normally as
well so that's quite important but I
want to come back and actually I don't
mean to be negative in the sense of I I
think the reality of editing someone's
gene in a brain well I'm not gonna say I
want him to see it but I think it's a
long way off but you can't things can
happen I mentioned right at the start
that coma gene therapy is almost one of
the reasons I was interested in doing
human genetics and there's a particular
development that's happened very very
quickly which was you may have seen it
particularly for a disease called spinal
muscular atrophy which is effectively
going in and switching off a gene using
genetic technology now that sounds
completely different to what we're
talking about but in terms of getting a
therapy from seeing something happen in
a lab to delivering it getting it safely
through safely through clinical trials
having a good set of outcome measures by
which you can judge the success of a
trial
and then getting that into clinical
practice this approach has kind of
almost gone in the background
it's almost revolutionary the the phase
3 clinical trials for the spinal
muscular atrophy one day they decide to
stop close them early
because it was very clear to the
clinicians that the success rate was so
high and the FDA approved it literally
in a day to connect and it was in the
clinic about two weeks later so is so
successful what's important though is
the way in which they delivered these
therapists this is a disease that
primarily affects the spinal cord and
they were delivering gene therapy into
the spinal cord and it also will get
into the brain the Huntington's disease
trials are using a very similar probe to
deliver therapeutic RNAs in this case
pins into the brain so these very
successful that it's one of the strategy
trials actually say you can actually
develop these things and they can get
through and can work
what's important is these guys have
actually developed technology that works
it's a potential way in which an glue
arm might be knocked down in Foggia legs
for example and I know there are people
working on that and give you an idea of
the time scale for SMA from the first
real real proof of principle that you
could do this through to delivery and
Travis was something like 12 years so
that's for something that was proof of
principle what they've done though in
working their way through is actually
gone through a lot of the regulatory
hurdles it develops a lot of approaches
which means something coming on
afterwards has a few URLs there but
getting regulatory approval to deliver
the Huntington's disease therapies that
are in trial of moment was made
considerably easier because SMA had
established all the benchmarks the
delivery systems all the systems in
place so HD has gone through clinical
trial much quicker than SMA because of
those hurdles were reduced so everything
that goes in advance means that in
theory things might happen quick
yeah that's certainly one of the reasons
why they worldwide were working them in
the first place I don't like to be
cynical about drug companies but I will
one of the reasons this technology is
this is this is gonna become quite a big
technology one of the reasons is because
this isn't a cure this is a this is
something you have to continue to take
so if you're a drug company thinking
about delivering a drug you you know it
is part of your you part of your
economics is you don't make a product
it's like something everlasting light
bulbs or clothes I've never need washing
you know effectively part of the
economics the reality we live in the
part of the economics that the way drugs
are developed is that there has to be
some commercial return they these trip
types of drugs which require continual
infusion every I think it's three to six
months for Huntington's are tick tick
that box whereas an edited a gene a
permanent gene edit Connor doesn't
inside I don't know
yes yes
yeah that's a good point thank you so so
I'm gonna finish that
I think I hoped I'd kind of explain some
of the science and almost certain that
you've come across this type of
technology there's been a huge amount of
hype about it I think you should I'm
hoping you can see that there there are
a huge number of issues
first of all just going from any
laboratory science into any type of
clinical use is such a long time line so
my pathetical there are possibilities
that doing other types of things with
combinations as well so drugs and these
types of Americas but I think on the
positive side there's a lot going on and
the technology is developing very
quickly there are almost certainly going
to be clinical trials delivering CRISPR
into the brain for other diseases that
will happen before it would ever be
contemplated for such a life so it could
well be the hurdles that we perceive at
the moment and maybe not that we just
don't know but I don't think this is
happening so my personal I got me that
negatively and I'm happy to take
questions and I will be around ever
lunch as well
