So what is this thing GDNF?
Well it's Glial Derived Neurotrophic Factor
And it's a protein
And we've known about trophic factors
Since the Fifties
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 the 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 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 that protein in the brain
Because if you take it by mouth
It won't get in in sufficient concentrations
So you need a surgical delivery approach
So that was the challenge
Which is good
It's good to have something to aim for
So what do we need
This is the Bristol Brain Centre
And a minor achievement part way through this
We managed to raise one and half million
Through some other funding charitable
And through some big donors through the University of Bristol
And built the centre
And here we've got Christina having her infusion
This is the pump system here
And these are going in
And when people come we ask them about any side effects
And they come on a monthly basis
For these brain infusions
And during this study
Not only are we looking at outcomes
Like how they cope with the infusions themselves
Side effects from the infusions
Or how their motor responses
How's their tremor doing
How's their stiffness doing, how's their slowness doing
We also have brain scan imaging with PET scans
And those were done at Cardiff
So we ship people over to Cardiff
And then we sent the scans to Canada
To try and avoid any bias
So we had the University of British Columbia analysing these
And this is a PET scan
And Vesna Sossi and Jon Stossel were invovled in this
And this is trying to look and see
Whether the dopamine nerve endings on the PET scan
As a bio marker were better after the nine months
Of double blind treatment than they were at baseline
And then our principal after the participants
Are the two charities
So we've been fantastically lucky
We've got the Cure Parkinson's Trust
And Parkinson's UK
And it's been a huge commitment for both of those charities
And this was a massive project to undertake
And was fraught with risk
At the beginning I thought we were never going to finish this
Not because I thought things would all go terribly wrong
And people being very unwell
Although that was a risk
But simply the numbers involved and the size of the project
And the complexity of the project with its many parts
And so it was a big risk for Parkinson's UK to take it
And I think it was absolutely the right thing to do
To get back on in there at the forefront of research
In something that really might mean the next quantum leap forward for Parkinson's
As I say whatever this shows
So what's the progress so far
How are we doing it, how are we getting there
And are we going to get there
Are we going to learn about how to deliver drugs to the brain
So we started in late 2012 with six pilot participants
And they went through a fairly quick succession
And they had nine months of GDNF or placebo
And four had active and two had placebo
And then they had nine months of open label
So we knew and they knew that they had GDNF
And some of those people have continued to have infusions
After that in a longer term extension study
So we've learnt many things
And the reason we had the pilot study there
Was one to get some safety data
So the MHRA which is the regulatory body
Said yes you can do more provided these six go ok
And that was the point at which I gave my last lecture in 2013
So that was the point where we collected some saftey data
We were allowed to start
What we learned from the pilot subjects
Was many things about the device
And we wanted to take the opportunity with those participants
To try and perfect the device further
Bearing in mind that there were many steps here
That were new and first in human
Those early devices had a different type of silicon
And some of them blocked off
So some of those participants haven't been able to carry on having infusions
Although they have continued to be assessed
And some have
But what it does mean is that for those people
We now have more than two years worth of data
And also people who stopped what it means overtime is we'll be able to see
Whether they improved or not when on active or placebo
And then whether they improve more when they have open label GDNF
And then perhaps if they had to stop whether they start to deteriorate again
So these are very useful steps
We wouldn't have wanted their ports to block
But these are very useful steps
In understanding drug and drug development
So then we come onto the main 35
So this was when we started getting the next
And this was where Parkinson's UK were instrumental
In the recruitment
And we had those 35 people coming in
And we started with them having infusions in 2015
And we had the last double blind nine month infusion
With the last mystery infusion in April 2016
We'll have done something that's never been done on a single site before
And the reasons we had to do it on a single site were various
One of the things is it reduces the amount of variables
We've never done something of this size before
A surgical study this size in Parkinson's at a single site in the world
Ever has been done
So just getting to the end is an achievement
And another thing that is an achievement is
That we've shown the delivery system works
And that people can incorporate this into their lives
And it is very strange how this has become a part of our routine life
And the research doctors and nurses who come
Are doing this everyday and we give infusions Tuesday to Friday
And here we have a row of our participants turning up
So this is really a paradigm shift
I want you to understand that
This is a paradigm shift in the way of giving treatments to the brain
Where people are turning up once every four weeks
They come in from around the country
Some people fly down from Scotland
They stay in a hotel the night before
And they come up, they sit in one of these recliner chairs
We've got three people in a row here
They're plugged in, they have their infusion
For an hour and a half
They are monitored for an hour afterwards
And then they go home
And this is an entirely different way of thinking about neurodegenerative diseases
And their treatments
And I have to say
I am very proud when I go into the infusion room
And realise that we're just doing this
And that it's become a part of our routine lives now
And we have to collect a lot of data
So every other visit people will come off medications
And will have collections
Here's one of our participants
Who always wears fantastic shirts and we're very glad of that
And we have something called a case report form
This is a lever arch file
Each participant now has four lever arch files
And this is about one third of the room where the files are kept
And we have about 20,000 sheets of data
And data monitoring, cleaning is all part of the clinical trial
So everything has to be absolutely right
So that in the end if this works
We get all the way across the river
And this can be submitted to regulatory bodies
Not only in the UK but in the states and the rest of Europe
So if this is a new treatment for Parkinson's
It can be rolled out and available
And therefore it has to be acceptable to regulatory bodies
So as I mentioned
The study is already a success
In that we have given more than 800 infusions to the brain now
So 800 times we've infused different participants coming up
We've infused the brain in these 41 people
We've done over 500 assessments
And in the first nine months and in the second nine months
No one dropped out
Amazing
All 41 people continued
So full retention
And in the first nine months of the study
With everyone coming every month for infusions
So 41 people coming every month for infusions
We missed three in total in that nine month period
So absolutely amazing commitment really
This is down to the participants
And the administrative team
And getting everyone back in the team on the ground
That everyone wanted to keep going
But does it work is the key question
And what we can say is that
The surgery is doable and achievable
And appears to be within the realms of neurosurgery to be safe
It is a device that can work and continue to deliver to the brain
So the device works
And we appear to be able to convect our treatment
Throughout the striatum part of the brain
So that works
The GDNF itself from the assessments we have so far
Appears to be safe and tolerable
And that people can tolerate coming for monthly infusions
So all of those things are key findings
What we found at the nine month point
Which doesn't necessarily surprise me
Was that although there was a separation between the GDNF group and the placebo group
Where the patients on GDNF were doing somewhat better
That didn't reach statistical significance
What I can say here is that we're now exploring the full data sets
And there is more to come and more to learn from this
And there are other end points including the PET end point
And there are other end points that we are looking at
Not only movement end points
But fluctuations end points
How do people in a diary day improve in terms of having dyskinesia
Or stiffness and slowness how did that fluctuate
How did their medication change over the time of the study
How did they perform on walking tasks over the time of the study
How did they perform in other aspects that we're looking at
Like physiological statues
Like depression and anxiety
How do they perform in cognitive tasks
And particularly importantly what happens during the second nine months
And do we need longer treatment
And is there then greater restoration
And perhaps more important than that
Are there some
When you're looking at group statistics of means
You may wash it out
But are there some people who do respond and others don't
And then how do we understand that
And how can we improve it for those that don't respond in the future
So this study in total has cost north of several million pounds
To get through
Further studies including larger scale studies at multiple centres
Would be of the order of 100 million dollars
And at that point it's really for pharmaceutical industry to come in
In the interim step between this and a large multiple centre study
We would be looking at hopefully the participants in this for a longer period of time
Perhaps with or without a dose increase in the infusions they're receiving
And at the moment we're further analysing the PET and MRI data
And there's a meeting in New York in the week of December 12th
To decide what Pfizer will do with the extension study
But my hope is that this will continue
And as we come to understand the results more
We will understand how better to give growth factors to the brain
So what does the future hold?
Well I think the future is better for having done this study
The successes of this study are
We've got a device now and a system
For getting treatment into the brain
That may be applicable not only to Parkinson's
But other neurodegenerative diseases
Like Huntington's, Alzheimer's disease and brain cancer
So at the moment in Bristol and London
About to start using the same delivery system
That has been worked out in people with Parkinson's
Is a study in children with brain cancer
There's another study that's just starting in the early part of next year
Looking at a different growth factor called CDNF
That is happening in Sweden and Finland
And that's using the same device system and this approach
So we really have with this study and with Parkinson's UK
And Cure Parkinson's Trust backing
Kicked open the door to this approach now
And this is taking off and moving forward
So these are important things
We've understood and learnt that we can use this
And the things that we're learning from this study
May then be applicable to other types of therapies
Like gene therapies and how to give genes that are helpful
And implanted into the brain using some similar surgical techniques and so on
So the future I think is good
There are many other things that are happening
You don't just have to take part in brain surgery research
Both Parkinson's UK and CPT are leading on
Cure Parkinson's Trust with unique clinical trials
And there's a dossier of drugs that CPT are looking at
That may slow progression in Parkinson's over time
So I would say that although we've perhaps learnt much
About the neurobiology of Parkinson's over the last 20 years
Over the next 10 years I think things will come in
I know it's always 10 years
The next 10 years I think things will come in
That will begin to slow the progression of Parkinson's
I still believe that GDNF could be one of those
And I believe that we will hopefully be able to go forward
And show that with our current approach in Bristol