6
it's awful slow the onset of progression
0:09
of Parkinson's disease coming can we
0:10
actually do this and I think the first
0:13
thing to recognize is what is
0:15
Parkinson's this is not a simple
0:17
disorder this is actually very complex
0:20
disorder and the view about Parkinson's
Its not just a movement disorder
0:22
is it's not just a movement disorder
0:24
it's not just something that's due to
0:27
degeneration one part of the brain it's
0:29
not just to do with dopamine it's in
0:31
fact may not even be a brain disorder it
0:33
might be something uh sweeps in from the
0:35
gut it's not a static disorder and it's
0:38
actually I don't think it's a single
0:40
disease at all I think it's an
0:42
individual disease and people need to be
0:44
treated as individuals and if you
0:46
understand this you get an idea of the
0:49
magnitude of the problem we're facing
0:50
and trying to do something about the
0:52
disease process now if you look at what
What weve done so far
0:55
we've done so far is we focused on this
0:58
bit of the brain and we focus on the
1:00
fact that we know that this chemical
1:02
dopamine is missing from the brain and
1:04
if we put it back then we can control
1:06
movement and we've been doing this for
1:08
60 years and we'll either give you
1:10
levodopa Sinemet matter part we'll give
1:12
you a dopamine agonist for pinroll
1:14
pramipexole we're ticketing Apple
1:16
morphine one of these drugs and what we
1:18
do is we give you these drugs they put
1:20
dopamine back into the brain one way or
1:22
another your movement comes back but
1:24
what we're not doing is we're not doing
1:26
anything about the underlying disease
1:28
process which inevitably inevitably is
1:31
going to progress so what can we do in
1:34
the future that's different well we can
1:37
do one of these three things we can do
What we can do
1:39
some neuro restoration which means we
1:42
restore or reverse than your own loss
1:44
that's going on in the brain we can do
1:47
some disease modification which in fact
1:49
means we want to try and slow down the
1:51
natural progression disease or we can go
1:54
for the big one which is neuroprotection
1:56
we want to stop the onset of the disease
1:58
or we want to arrest the progression of
2:01
the disease so does that make sense
2:02
doing this doing it three different ways
2:04
okay so if that's what we want to do how
2:08
do we do it well the first thing is that
2:11
we've got lots of stuff going on it's a
2:14
really exciting time there's numerous
2:16
different approaches to trying to
2:18
achieve the objective of altering the
2:20
course of Parkinson's disease in train
2:22
at the moment you can transplant fatal
2:25
human dopamine neurons back into the
2:27
brain to put dopamine synthesis dopamine
2:30
production back
2:31
you can modify stem cells very basic
2:33
cells to become dopamine neurons put
2:35
those in the brain to put dopamine
2:37
production back we can modify viruses so
2:41
that they contain all the genes for
2:43
producing dopamine and we can put the
2:45
virus in the brain and let it infect
2:47
neurons and start to produce dopamine
2:49
again or we can give you a growth factor
2:52
a trophic factor that will stimulate
2:55
remaining dopamine neurons to grow and
2:57
to sprout and even to spread and these
Oneoff treatments
3:00
are all very valuable of protists
3:02
they're all one-off treatments these are
3:04
potential in some respects cures and the
3:08
important thing is there's ongoing
3:09
clinical trials in every one of these
3:11
areas but these things are invasive you
3:15
need to have neurosurgery to have any of
3:17
these because you need to inject them
3:18
into the brain you tend to put them into
3:20
one brain area and that's okay but
3:23
Parkinson's disease affects many
3:24
different brain areas they're
3:26
irreversible once you've had them done
3:28
there's no going back to you can't take
3:30
these things back out of the brain again
3:31
so you need to be very certain they're
3:33
safe and the other problem is you put
3:36
them into a brain as Parkinson's disease
3:38
and who knows what the parkinsonian
3:41
brain will do to newly implant itself it
3:43
might will kill them off like the
3:45
previous host cells were killed off in
3:48
the first place so what else can we do
3:52
well we can take another approach we can
3:55
design new drug molecules to attack the
Classical drug discovery
3:57
disease process this would be what I
3:58
would call classical drug discovery we
4:01
can take drugs from other therapeutic
4:03
areas which we think might have a good
4:05
effect in Parkinson's disease and
4:07
reposition them into Parkinson's disease
4:09
and I'll tell you something about that a
4:11
little later on we can attack the final
4:14
toxic step in nerve cell death we
4:16
couldn't try to find the key to
4:19
Parkinson's disease and stop that from
4:21
happening and all of these again very
4:24
valuable all are in ongoing clinical
4:26
trials these are easier
What causes Parkinsons
4:28
to a minister because they probably
4:29
become as tablets or injection they have
4:31
a widespread effect in the brain they're
4:33
reversible because you can stop
4:35
treatment they have a better effect
4:37
because you might also some of the motor
4:38
and the non-motor symptoms of
4:40
Parkinson's disease and what you're
4:42
doing is attacking the disease process
4:44
and that's inevitably what we want to do
4:46
in the long term it's get to the root of
4:49
this disease so if you're going to do
4:52
that you have to understand what causes
4:54
Parkinson's disease there are many
4:57
different mechanisms that can probably
4:59
lead to Parkinson's disease in terms of
5:01
biochemical pathological change in the
5:04
brain some of Parkinson's disease might
5:06
be inherited some of the factors might
5:09
be environmental and there might be an
5:11
interaction between genes and the
5:13
environment but the vast majority of
5:15
Parkinson's disease to be truthful and
5:17
I'd like to tell it as it is remains
5:19
unexplained and that's one of the
5:21
difficulties we have to overcome if
5:23
we're going to do anything about this
5:25
disease and I want to emphasize
5:28
something I want to emphasize that
5:29
people have Parkinson's disease for many
5:32
different reasons you might have a rare
5:35
gene that leads directly to Parkinson's
5:37
you might have a gene that increases
5:39
your risk of Parkinson's you might have
5:41
a gene that increases your
5:42
susceptibility to something completely
5:44
different that then gives you
5:46
Parkinson's or you might just be I aging
5:48
you might have risk factors but believe
Risk factors
5:51
it or not living in the country and
5:53
drinking well water increases your risk
5:55
of Parkinson's
5:56
it could be toxin exposure pesticide
5:58
exposure
5:59
it could be diet or even gut bacteria
6:01
the other thing is it comes in many
6:04
different forms this is not a single
6:06
illness with a single set of symptoms
6:08
people have in common the fact they
6:10
can't move but around that there are
6:13
different clinical presentations
Symptoms
6:15
different genetic backgrounds some
6:17
people get it late some get it early
6:19
some progress slowly some progress
6:21
rapidly some have tremor some don't some
6:24
people show different responses to drugs
6:26
your other major problem in addition to
6:29
movement might be you don't sleep well
6:30
you have pain your mind doesn't work as
6:33
well you might be tired there are all
6:35
these enormous presentations and does
6:38
this give you the idea it's not a single
6:40
illness
6:41
it's something which is more complex and
6:42
the more complex it is the more
6:44
difficult it is to overcome the problem
6:47
so how we've been going about this
Research
6:49
people who leave their brains to
6:51
research having post-mortem Studies on
6:54
brains from people who died with
6:56
Parkinson's disease and what we've done
6:58
is we've gone into the brain we've
7:00
looked at the damaged areas and we've
7:02
looked at the processes which might be
7:04
disrupted that lead to nerve cell death
7:08
and we found that in some people there's
7:10
too many free radicals you have
7:11
oxidative stress in other people the
7:14
ability to produce energy in cells is
7:16
impaired at the level of mitochondria in
7:19
other people you have alterations in the
7:21
handling of proteins which clog up the
7:24
cell and cause it to die but what I want
7:27
to point out again is not all these
7:29
changes occur in everybody with
7:31
Parkinson's disease
7:32
some people have perfectly normal levels
7:35
for example of free radical formation
7:37
and I'm trying to emphasize this point
7:39
again but this is not a single disease
7:41
this is complex and it has to be looked
7:44
upon on an individual basis now what
7:48
we've done without information from the
7:49
post-mortem studies is we've gone back
7:51
to the laboratory and what we've done is
7:53
we've used toxins to mimic the effects
7:56
that we've seen in post-mortem brain to
7:59
check whether interrupting various
8:01
processes for example at the level of
8:03
energy production in the mitochondria
8:05
causes dopamine neurons to die in the
8:08
brain and then what we've done is when
8:10
we found that these processes aren't
8:12
important we've looked at drugs that
8:14
block these individual biochemical
Clinical trials
8:17
changes and what we've shown in the
8:18
laboratory at least is that these things
8:21
can stop dopamine cells from dying so
8:24
the next step is logically you take
8:26
these things into clinical trial in
8:28
patients with Parkinson's and this is
8:31
where at a moment we've come unstuck
8:34
because when 38 clinical trials were
8:38
reviewed a couple of years ago what we
8:40
found was nothing that had come out of
8:42
the laboratory and taken the patients
8:45
with Parkinson's disease had actually
8:47
had a significant effect on the disease
8:49
progression in these clinical studies
8:51
but notice I say what this space because
8:54
this year you might hear something
8:56
completely different now this is very
8:59
disappointing but what we have to do is
9:01
we'd have to try and understand why this
9:03
situation has occurred now it could be
9:06
the experimental studies in the
9:07
laboratory do not limit Parkinson's they
9:10
do not give you a true picture of how
9:12
nerve cells die in the brain in that
9:14
disorder that's perfectly feasible it
9:17
could be that when we've been around the
9:19
cell all we've done is shown it if you
Interrupting major processes
9:22
interrupt major processes in a Cell
9:24
cells die it's like saying if I impair
9:28
your liver it's going to have an effect
9:30
on your health if I impair your heart
9:31
it's going to have an effect on your
9:33
health if I impair your nuns or your
9:34
kidneys it's going to have an effect on
9:36
your health that may lead eventually to
9:39
death and really all we've done in these
9:42
studies is we've shown cells don't like
The wrong picture
9:44
their major organelles being disrupted
9:47
and so what we might have done is come
9:49
away with the wrong picture about how
9:51
Parkinson's disease occurs but I don't
9:54
think we can be completely wrong in the
9:56
laboratory I don't think we can be
9:59
completely wrong in these post mortem
10:01
studies I think there's one other factor
10:03
that we really have to think about and
10:05
that other factor is how we've looked at
10:08
these drugs in the clinic in people with
10:10
Parkinson's and what we tend to do is
10:12
take a large group of people with
10:15
relatively late stage Parkinson's
10:16
disease we give 200 of them a sugar
10:19
tablet we give 200 of them active drug
10:22
that we're looking to see if it works
10:24
and then we go away from and look at
10:28
them 12 months later and we compare the
10:30
effects of the placebo or the active
10:32
drug on the progression of Parkinson's
10:34
disease and this is where so far we've
10:37
found no statistical difference between
10:39
these groups but what if there's 10% of
10:44
people in the active drug group who have
10:46
Parkinson's for a specific reason
What if
10:49
which is different to that from the
10:51
other 190 people what if those 10% of
10:55
people were getting significantly better
10:56
in the way we do the clinical studies at
10:59
the moment we would not detect these
11:01
people we would not see an effect of an
11:03
active drug and my feeling is we may
11:06
have gone wrong by grouping people
11:07
together
11:08
and saying you all have disease for the
11:10
same reason and you're all going to be
11:12
cured in the same way so what should we
11:15
do
11:15
the answer is we need to get you early
11:18
just as Alistair stead we need to get in
Get you early
11:21
there and have the greatest chance of
11:22
affecting the disease we need to take we
11:25
need to take specific groups of people
11:27
for example small group of people with a
11:29
specific gene mutation divide them up
11:32
look at them for longer periods of time
11:35
and we may have a greater chance of
11:37
success we might ever pull out patients
11:39
with well-defined subtypes of symptoms
11:42
people with Parkinson's we've got
11:44
constipation and then have a good sense
11:47
of smell people with sleep problems
11:49
focus on discreet patient groups and
11:51
their withstand a much greater chance of
11:54
having a success with one of the drugs
11:56
that perhaps we've already tested what
12:01
else could we do
12:01
well first of all we can shortcut the
12:04
process if you take a new drug from the
Shortcut
12:06
laboratory and you turn it into a
12:08
medicine it's going to take 15 years
12:10
probably for that process to be complete
12:13
the risk of failure during that time is
12:16
very high the cost of those 15 years is
12:19
enormous and this means pharmaceutical
12:22
companies are often unwilling to take
12:23
the risk in going into such long-term
12:27
complex and expensive areas but what if
12:30
we do something I mentioned earlier we
12:32
take drugs which are already used in
12:35
other indications and that may also be
12:38
effective in Parkinson's shorter time
12:41
less risk less cost side effects known
12:44
because they're already in man and we
12:47
can rapidly explore hypotheses and we're
12:50
doing this this is a list of drugs from
12:53
other therapeutic areas that are
12:55
currently in clinical trial for
12:57
Parkinson's we have taken anti diabetics
12:59
cholesterol-lowering drugs
13:01
antihypertensive and E Council drugs
13:03
anti-malarials alkylating for us they
13:06
have been effective in experimental
13:08
studies and we're now exploring very
13:10
rapidly whether these drugs can also be
13:13
effective in Parkinson's and this will
13:15
cut the process down from 15 years to
13:17
something like three to five years and
13:20
here's an example this was in
13:22
newspapers 'no lafayette a drug that's
13:24
used in a form of leukemia this drug has
13:27
interesting biochemical effects and it's
13:30
been moved from oncology to neurology
13:32
and in neurology v very early
13:35
preliminary open studies have shown some
13:38
very significant effects on the symptoms
13:40
of parkinson's something that we can now
13:42
develop and do better and more intense
13:46
clinical investigation one other thing
13:49
we can do if we're not going to attack
13:51
subgroups of patients with parkinson's
13:53
what we can do is look for something
13:55
that all parkinson's patients have in
13:57
common and one thing that most people
14:00
with parkinson's have in common is that
14:01
when you look in the cells that remain
14:04
in the brain you see these intracellular
14:07
inclusions which are known as Lewy
14:10
bodies and Lewy bodies are the
14:12
pathological hallmark of the disease
14:14
process in Parkinson's disease now what
14:18
we know about Lewy bodies is they are
14:20
packed with this protein alpha-synuclein
14:23
absolutely jammed packed with it and
14:25
this protein seems to be something that
14:28
sweeps through the brain as Parkinson's
14:31
disease develops and we've been very
14:33
focused on why this protein is so
14:36
prevalent and how it might be involved
14:38
in toxicity to nerve cells and what we
14:42
found is that this protein goes it's
14:45
synthesized within cells but as it is
14:49
processed it goes from being in very
14:51
small clumps to forming in very large
14:54
clumps that eventually form into Lewy
14:57
bodies but what we found is it's these
15:00
little bits in the middle here which are
15:02
much more toxic than the big bits of
15:05
protein which eventually accumulate and
15:07
what these things which are called
15:09
oligomers or proto footballs do is they
15:12
interfere with the major processes that
15:14
maintain nerve cells in a viable state
15:17
so this protein appears in various forms
15:21
to be highly toxic not only to dopamine
15:24
cells but to other nerve cells in the
15:26
brain and what we can now do and this is
15:29
ongoing because clinical trials have
15:31
started we can stop this protein
15:33
aggregating we can prevent the
15:35
nation of aggregates we can prevent the
15:37
formation of the protein we can prevent
15:39
the toxicity of the small bits and we
15:42
really need to get the grips of how to
15:45
tackle this protein and what we need to
15:48
do again is start early it is too late
15:51
when motor signs appear you need to get
15:53
in there and stop this protein sweeping
15:55
through the brain in the first place and
15:57
here's just one example of how this is
16:00
being done this is a small drug which
16:03
you can take by mouth which gets into
16:06
the brain and interferes with the
16:08
ability of alpha-synuclein to become
16:11
toxic and this drug is in clinical trial
16:14
but with a drug company called UCB and
16:17
this will be something which may be very
16:19
exciting in terms of eventually
16:21
controlling parkinsonian symptoms and
16:24
looking at the spread of disease and
16:26
progression of pathology but this is my
16:30
parting message don't expect a single
16:34
treatment to work in everybody this is a
16:37
syndrome this is not a single disease
16:40
you have different patterns of pathology
16:42
and biochemistry going on the brain you
16:45
have different symptoms there are
16:46
different subtypes of PD there is no
16:49
single cause and no single pathogenic
16:51
mechanism and what we have to do is get
16:54
over the fact that we do our clinical
16:56
trials in one way we are not going to
16:58
find a drug which fits everybody if I
17:01
told you I was going to cure cancer you
17:04
would ask me what form of cancer I was
17:05
going to cure and what subtype of cancer
17:08
I was going to attempt to cure and
17:11
Parkinson's is going to turn out to be
17:13
different and very individual to
17:16
everybody who's afflicted by this
17:17
illness so the conclusion is there's
17:21
fantastic amounts of work going on stem
Conclusion
17:23
cell therapy gene therapy clinical
17:26
trials ongoing stopping the disease in
17:29
its tracks of stopping it starting in
17:31
the first place is a much more difficult
17:34
challenge modifying things like
17:36
alpha-synuclein and its accumulation
17:38
might be a significant way forward but
17:41
we must start all of this early and what
17:44
do is must concentrate on the pathology
17:47
that occurs in all parts of the brain
17:49
not just the dopamine bit if we can cure
17:52
that that's fantastic but we need to
17:54
cure holistically the brain and rid
17:56
people of this illness thank you very
17:58
much
17:59
[Applause]
18:04
[Music]
Comments
Post a Comment