So what it this thing, GDNF?
Well, it's glial derived neurotrophic factor, and it's a protein
and we've known about trophic factors since the 50's
And the scientists that discovered that won the Nobel Prize
And the reason they got the prize was because these proteins have the ability to restore and regenerate damaged neurons
and this particular one, GDNF, has the ability to improve terminals, the sprouting ends of dopamine neurons
where the dopamine brain cells are those pivotal cells lost in people with Parkinson's leading to stiffness, slowness and tremor.
So if you have GDNF as your protein then where are you going to put it in the brain?
And where you're going to put it really depends on where those dopamine cells are, and the cells, which are shown here,
are down in this part of the brain called the nigra
and they send out these long projection arms where the terminals deliver dopamine in the so called striatum of the brain
and so if you take your protein, GDNF, and put it into the striatum area of the brain
then you can sprout those degenerating dopamine terminals
But the problem is: how do you get those proteins into the brain? Because if you take it by mouth
it won't get in in sufficient concentrations and so you need a surgical delivery approach
to put it into the striatum and in fact that's been done since the discovery of GDNF
and the first approach to doing this was done by putting GDNF protein into the ventricles of the brain and that was done in the mid 90's
and the ventricles, the fluid filled cavities in the brain, when they put it in there it didn't work
so that wasn't so good
but then in the early 2000's a small group of people looked at both in Bristol and Kentucky
where both the participants and the investigators knew they were receiving GDNF into the striatum
and they were putting it in, and those results were very promising and people began to improve
and everyone though "hey, we're on to something"
and maybe we're now beginning to reverse Parkinson's
We've got some great tablet treatments that can improve tremor and slowness and so on
and physical therapy can help and tai chi can help and exercise can help
What we don't have is anything that can really retard it and slow it's progression over time
and what we're saying is the status quo is not acceptable
it's not good enough to just keep giving people tablets to patch them up
and mask the symptoms, what we need is something to slow the condition down
or put it into reverse
So, with these early trials in the 2000's looking at GDNF that looked quite promising
so then we headed into a double blind study where that was done at multiple centres across the world
where half the participants had GDNF put into the brain
and the other half had placebo or dummy
And sadly when that trial terminated early at the 6 month point there was no difference between the groups
so, there had been this great hope of expectation in the open label small studies and then came crashing down again
and everything then halted and since then, 2004 time, trophic factors even though most of the community of pre-clinical scientists
laboratory based scientists recognised that growth factors probably are the most likely candidate to be the first therapy to slow the progression of Parkinson's
unfortunately everything went on hold and nothing happened for many years
So how do you then kick start that once you've had a negative trial, how do you get it back and get it going?
and that is no small task
and why is it worth getting it going and the reason it possibly is worth it is even though the double blind study
didn't show improvements if you look at some other end points there was a tantilising suggestion that GDNF may be restoring brain cells in Parkinson's
so if we look here in these top panels what we've got is post mortem tissue from a subject who sadly died in one of the earlier trials
who had had GDNF and not related to the trial itself
and what you find is that in the putamen part of the brain in this subject in one side is treated
and in the untreated side of the brain
at post mortem there were no dopamine nerve endings but in the treated side
shown with a stain called tyrosine hydroxylase you see lots of dopamine nerve ending
but the front end of the putamen in the striatum part of the brain doesn't show that
so post mortem even if the trial wasn't positive there seemed to be improvements
and not only in this single subject, although single subjects can be very important at advancing science
and across the subjects as a whole in what are called PET scans that are a way of looking at dopamine nerve endings in life
if you looked at the beginning of the study and the PET scan here shows dopamine nerve endings
and here you've got the front end of the striatum you can see some dopamine nerve endings
but at the back end the dopamine nerve endings are lost
but what you saw over a time course of the study and here it is a year later
the dopamine nerve endings around where the tube was put in to give the GDNF via surgical approach
the tube was put in and dripping GDNF into the back part of the striatum
these nerve endings were reviving
so there were two bits of evidence
One the postmortem evidence
And one the PET scan evidence that after all this protein showed something
so there was laboratory evidence it might work, there was some early clinical experiments open label it might work
then a failed trial but nevertheless there were some end points that suggested this was still worth looking at
what you will notice on this however and maybe the reason the main clinical trial didn't work
is its only this back part.
Now this slide is truncated so in fact the striatum part of the brain goes right up here and so even if you are restoring these endings
you're probably only restoring them at the tail end of the putamen
about 1/6 of the structure and you actually need to deliver your protein across the whole structure
and that's quite difficult to do and it wasn't achieved in the earlier trials
and it wasn't achieved because they were dripping the protein in continuously from pump systems that were inserted in the abdomen
so to get GDNF back on track
One, you've got to rescue it back from being in the doldrums which is quite difficult to engender the community and funding and participants to take part
and the other is you've got a difficult task because we knew we weren't giving it right the last time and it's really restricted here back to the back end of the putamen
and that's why you're only seeing recovery in this little end here
which is just a few millimetres beyond the tube or catheter
what you really need is to get recovery in this whole end of the brain
and spread it right through
so that was the challenge which was good because it's good to have something to aim for
and then we decided to bring it back to life so what do we need
the first thing you need and the thing I really want to take my hat off to is you need participants
so there is something remarkable about the 41 people who've taken part in this study
41 people with Parkinson's who've put themselves forward for novel neurosurgery that's not been done before
to have a novel device inserted in their brain that's not been done before
to have a protein put into their brain that's experimental
to have a protein put into their brain intermittently which is the way we understood that we had to do it to get this protein to spread through the whole putamen area of the brain
to then come every month to Bristol and have an infusion into their brain through this port system that I will tell you about
for 18 months and every other month did they have to come off medication over night and have an awful time in the Holiday Inn
unable to move so we could assess them drug naive, as it were
every two months basis to see if we were indeed improving them over time with this and restoring dopamine nerve endings
and on top of that they also had to have multiple brain scans including travelling over to Wales
these are people who had to go through a tremendous amount and they could have just carried on
so hats off to them we couldn't have done it without them and they come from all over the country
and the recruitment of those participants were absolutely possible because of Parkinson's UK
so when we did this video a few years ago at the Royal Institution that went out on YouTube and then Parkinson's UK helped us field the more than 500 calls
helped with some pre-screening and were fantastic at providing information
So we would have never recruited these participants to time and target as it is
and got through the study without that input of the charity
so it's not just about money, it's about having a network community of people with Parkinson's working with the third sector
so the other people that we needed involved was a biotech company
so we had a biotech company, this a Canadian biotech company called MedGenesis
and they make the protein so the protein GDNF is available in all of us but we need it at a pharmacological higher concentration
so it was made by a company in Switzerland and MedGenesis have been terrific
not only just providing the protein for free but funding some parts of the study and providing real expertise
in terms of clinical trial design
so we needed participants, we needed a biotech company, we needed a hi-tech company
That hi-tech company is called Renishaw which are based in Wotton-under-Edge but are a global company
and they manufactured this device delivery system for us and what it is is a port put behind the ear
here's a person with a port behind their end
so as I say this is a port system there, with a little septum of silicon and then that connects to tubing inside
on this model here the tubing goes in, there's a series of filters to catch bugs, microbes
and then those tubes go down along this schematic here
they go down through the brain and the red shows the drug being infused into the putamen part of the brain
and you have four tubes going in, two on either side
so two going down into each putamen
people are wandering around with this port in and they can be clipped on with this thing on the outside
that goes back to pumps that every four weeks over approximately an hour and forty minutes infuses the protein or the placebo
or later just the protein in the open ended part of the study
now to put that port in, so not only is the port system new and that was designed by Steven Gill, our professor of neurosurgery
who has been the pioneer in what's called convection enhanced delivery and delivering drugs to the brain
but to put that in you also need advanced neurosurgery so the neurosurgeries involved robots
so this robot doesn't look much like a robot, I was a bit disappointed, I thought it would have arms or something
But, this is a robot, it is quite useful for targeting in the brain as it has millimetre accuracy
and one of the things we have shown is that the catheters have hit the target striatum part of the part within one or two millimetres on each occasion
and the surgery when we started took about 12 hours for the first person and by the time we were finishing it was down to about four hours
and people were typically out within a few days
so it's not an over big procedure
but it is nevertheless an undertaking
And I've got pictures of people going down water slides, pictures on roller coasters, I've got someone abseiling down the outside of the Shard
and we've got this person here who's jumping into the water from this castle coast
so this is an important discovery that wasn't known before, you can have a port system in your head to deliver drugs in a targeted way to the brain
to get those drugs in time after time and you can live with the port and it doesn't restrict your life
You can do all these other things
You have to clean it, usually clean it twice a day, a bit like cleaning your teeth
you have to clean around the port
We did have some slight infections around the port site in some participants
but they can live with this
and the key question is does this delivery system allow delivery of the drug
and if you use the right regime of infusions with port pumps and so on and you're infusing this drug in
So we're putting this radiopaque dye down the catheter system
And here you can see one of our participants in an MRI scanner
and what we're filming is the infusion going in
This is the dye going in and what we're showing is rather than the delivery as it was in the phase two failed study back in the mid 2000's
being just at the back and you can see this dye is going right the whole way up
And this is unprecedented coverage of the striatum
so one thing we've proven in this study and this is a success whatever the drug itself does
is that you can deliver this to the putamen and we can now get protein or growth factor into the brain
And if this one doesn't work there will be other protein growth factors that can be tried
So we've got this growth factor now spreading right through the brain
We've demonstrated unprecedented coverage and the patients were scanned several times during the study and these catheter systems
continued to deliver in this way