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hi let's get this session started it's my great pleasure to introduce Amy Lee bradlau speaking on
behalf of PTC Therapeutics and we are looking forward for her starting the session on the
scientific updates and welcome and thank you very much thank you so much thank you all for
being here today at the packed house which I'm thrilled to see you all we're going to talk today
about RNA splicing platforms everything you ever wanted to know or many things you wanted to know
some of the things you wanted to know we'll figure that out I'm pleased to be speaking
today on behalf of PTC Therapeutics which is a global company with more than 1300 employees
we're going to start with a little video just to kind of put us all on the same page
based on what we call a splicing which is a process it's a very complex process but if I want
I did that I'm sorry to like explain to a general audience I can use an analogy of
making a cupcake so you can think the DNA as a recipe book which contains a lot of
different recipes now when it comes to RNA it will be one particular recipe out of that book
so let's say that you have a cupcake recipe so your cupcake recipe will be your RNA and your
cupcake will be your protein now the splicing is the process where you take that message and
process differently and you come up with the different recipes so for an example if I take
the same analogy let's say that you have a message say make blueberry cupcake so that will be your
RNA now if you can process this RNA and you make a blueberry cupcakes that's one protein now you can
take the same RNA and process alternatively and take out certain words and you can make instead
of make blueberry cupcake you said make blue cupcakes so take out the berry word now you
have a different product now let's say you take out the word cup now you make blueberry cake so
you can say that the same message can be processed in different ways to produce different products so
that's the process we call the splicing so it's a very complex biological process what we do as
scientist we try to understand this complex natural process and we translate it to a
something that is useful for us in this case we're trying to make a drug out of it we're trying to
use that knowledge to develop drugs so that's what our splicing platform is there we go we're
going to talk first a little bit about Anatomy just to kind of give you a sense of where all of
this is happening we'll talk about how cells work because splicing happens inside of cells we'll
talk about how proteins are made that's the magic of splicing and some details about splicing and
then we're going to wrap up with talking about how this affects your genes genetics so we are
all organisms we're made up of multiple organ systems like your heart your lungs your stomach
um well those are organs your organ system your digestive system is your mouth your intestines
your stomach and Etc those are made up of tissues tissues are made up of a bunch of cells working
together in collaboration and molecules and atoms make up those cells so when we're talking about
the size of these things and what we're thinking of a cell I want you to think of a city Glasgow is
a cell okay proteins maybe are cars within Glasgow they're much smaller than that whole cell small
molecules like splicing modifiers are maybe like a piece of paper that could fit into a car right
that fit wildly many many many of these could be in a city so small molecules you're exposed to
these all the time every time you take a medicine by mouth that's a small molecule the molecules are
small enough to sneak through the cells in your intestines to get into your blood bigger medicines
like proteins and even bigger than those they need to be injected into your body somehow with
a needle because they're too big to trick your stomach and intestines into letting them in okay
so there are a lot of cells here I want to see can you if I move my mouse you can see that okay so we
have a number of cells here these are just from a plate in a lab okay the blue cell center here
is a nucleus it's basically the brain of the cell that's where your DNA live your DNA are replicated
inside the nucleus here the green this is what we call the scaffolding of the solid so it gives
us its shape you see this guy over here has got this long arm those green proteins there sometimes
Huntington protein acts like a scaffolding protein and can help a cell to have its shape okay now on
the outside you have the membrane of the cell and that's what holds everything in the city
inside your border of the city right but things are allowed to come in and out and you see that
happening here these two cells have some kind of communication happening maybe there's a protein
going in and out between those cells Huntington protein also helps to regulate what goes in and
out of cells so this is a very important protein that is in all of our cells in all of our body
what we were talking about in the video was specifically about splicing now DNA this is
your genes okay those what you're born from and they Define exactly what color hair you have
what color eyes you have how tall you are among other things that is then transcribed into RNA
RNA is then spliced to make different kinds of proteins okay so what we're talking about
today is mostly the bottom half of this slide now proteins sounds a little abstract although
we all know we eat protein every day right but it's still a little bit of an abstract concept
so I wanted to talk to you about proteins you might have heard of so collagen is a protein
that gives firmness and structure lipase helps you to digest your cheeseburger in the afternoon
elastin helps your skin stay smooth and elastic okay a fibrin clots your blood antibodies in the
last three years we've heard a lot about antibodies they help to fight infections
insulin is a protein that regulates how much sugar stays in your blood that's very important and then
adrenaline we all know a good Adrenaline Rush when I don't know when you're exercising or frightened
or stressed or nervous about giving a talk it helps your body to respond and control stress
and that's really just a protein that's excreted into your blood and it moves all throughout
your body and it changes how you interact with the world right your palms might get a little
sweaty your heart might raise that's just one protein doing something reliably in your body
now when we're talking about genes the DNA that recipe book mentioned in the video it's pretty
complicated right there's a lot of information in there not all of it is used to make a protein the
parts that are not used are called introns and they're all over the place now the DNA
is transcribed as exactly as is possible into RNA so RNA is very very like your DNA
when we want to it's this is true for humans and for other organisms even as down to yeast but you
see ours are pretty complicated there's a lot of in and out a lot of introns and extrons in there
so we take all these introns out to make one continuous blueprint or recipe right and that
is what is made into a protein because we have a lot of proteins that we need you can think of
maybe how many cars there are in Glasgow there are so so many proteins in a Cell more than we
can actually encode with DNA we have a lot of DNA but we don't have enough DNA for all of our
proteins and the way that's possible is splicing right so when you make that perfect RNA copy
the mechanisms inside there are these little machines inside your cells called ribosomes
they say I'm going to take these parts but not these parts and they make different proteins
from the same RNA strand now we use that knowledge this is already happening from yeast all the way
to people this is already happening but we use the scientific understanding of that to make a drug a
small molecule drug that will actually change how this is done so this is what it looks like sort
of it's a picture of it so your nucleus is right here this is the cytoplasm where all the action
is happening DNA makes RNA and then it's processed right here this is splicing into something usable
and then those little ribosome machines come along and they read it bit by bit they read a few they
pull an amino acid off and add it to a protein pull another one and eventually this protein chain
is made and it folds up to do something useful so when we're talking our analogies within the city
proteins are like a piece of plastic you can fold this plastic into a binder to hold your
paperwork from the conference or you can fold it into a chair to sit on right it's the same basic
underpinnings but they they do wildly different things might be the bumper of one of our cars
so once the protein is made the RNA is degraded splicing that occurs right here allows us to
restore or reduce a protein depending on what's wrong so splicing modifiers can be used for a
lot of different diseases okay now let's talk about how this applies to Huntington's disease
in Huntington's disease its chromosome 4 that is affected there is a CAG repeat that is too
long in Huntington Gene okay now everybody has CAG repeats it's only a problem once they become long
enough to cause a problem and that's around 40 or more so that's the genetic story of Huntington's
disease so the gene we've already talked about this but we're looking at it again the gene DNA
becomes RNA RNA becomes spliced and that is turned into a protein so specifically with Huntington's
dot protein has that repeat CAG length and the ribosome didn't know to stop right so it gets
longer and longer and longer and it just folds and folds and folds and it doesn't fit the right
shape right maybe a binder with some chair components they're in the way it doesn't work
right what this causes in the body these proteins Clump together they see each other and they Clump
together we call that aggregation and they kind of settle in the cells and they gum up the works
the cells aren't able to do what they want to do how this affects the brain is as a response to
that trauma the brain over time shrinks a little bit as almost scarring not exactly but almost
and scientists believe that if we can make less of this mutant Huntington protein the aggregation
won't happen the trauma in the brain won't happen the shrinkage won't happen this is the belief
so how does that actually happen there's an Exon that is inserted that doesn't that isn't
naturally encoded in the DNA but it's told to be inserted by the splicing the drug okay
this excellent has a stop sign on it it tells the ribosome don't you're done the protein is complete
when really it isn't and it degrades because the body knows that this is a useless protein
it doesn't know that with the mutant Huntington protein interestingly enough right that's that's
why there is a disease in the first place the body didn't identify it as a protein that doesn't work
right but with this stock code on where it's placed it stops the manufacture of the protein
and the protein is recycled to go off and make more things the RNA is also recycled to go off
and make more RNA okay now in this slide it says specifically down here mutant Huntington protein
obviously that's the therapeutic goal is you want to reduce the mutant Huntington protein
but I think it's important that I tell you that right now splicing mechanism Technologies
the the molecule cannot tell the difference between a health healthy Huntington protein
and a mutant Huntington protein it lowers both equally so that means that in a clinical design
it would be important to find the right amount of lowering that is effective and still safe
okay and then finally genes how does this affect people's genes because all of the
action of splicing modification is between RNA and proteins it really doesn't affect genes at all
so a person who had a disease that was treated with a splicing modifier if they got pregnant
they would have just exactly the same chance of passing that on to an unborn child as
without the splicing mechanism and right now the technology is so new that you wouldn't want to
try a pregnancy with a splicing modifier we just don't know what that might do to an unborn baby
and that's everything I wanted to share with you today have you learned everything you wanted to
know about splicing modifiers maybe a little bit more I'm going to stop now and take any
questions so we can complete your knowledge and answer any questions you might have had
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