(upbeat music)
- Thank you so much for joining us
for our first Closer Look series,
this is a real opportunity to showcase
the brilliant science being
done here at UC San Diego
that has implications
for not only science,
but patients who have Parkinson's disease.
This is very topical as you know,
the California Institute
for Regenerative Medicine
has funded significant research projects.
But in addition, there are
a number of other areas
that have been well funded by NIH.
This is a hot research topic,
so we've got three really
fundamentally important
individuals who have
made major contributions
to the field of Parkinson's disease.
And they should be important for you,
whether you're a patient, a
family member, a scientist,
or a physician, you'll see
that we have Dr. Irene Litvan,
we have Dr. Don Cleveland
and Dr. David Higgins,
all of whom will talk
about Parkinson's disease,
but from really different angles.
I really, before we proceed,
wanted to thank our members at the
Sanford Stem Cell Clinical Center,
the Sanford Consortium
for Regenerative Medicine
and our entire STEM Cell team
for putting this together
with Jake, Marcy, Michelle, and everyone
to bring together these
remarkable speakers.
So thanks again for your efforts.
And we really wanna make
sure that this is accessible
and that we provide just
the right level of language
so we're not mired in jargon.
So please let us know if you think it's
a little too jargony.
David Higgins is very good
at getting through my jargon
so I think he can work
through these other things.
First of all, I'd like to
introduce our first speaker,
Dr. Irene Litvan, she's a
board certified neurologist
and director of the
Parkinson and other movement
disorder center here
at UC San Diego Health.
She's the tash endowed chair
in Parkinsonian disease
research at UC San
Diego School of Medicine
and diagnoses individuals
with Parkinson's disease,
as well as other
neurodegenerative disorders,
such as Huntington's disease,
corticobasal degeneration
and frontotemporal dementias.
Dr. Litvan has really helped
to get a better understanding
of Parkinsonian disorders
and dementia syndromes,
and has really sought
to develop novel therapeutic
strategies for these disorders
that mitigate the risk of progression
and also improve quality of life.
She's a fellow of the
American Academy of Neurology,
a fellow with the American
Neurological Association,
and is really internationally recognized
for her expertise in movement
disorders and dementia.
She had her, earned her medical degree
from the university of
(speaking in foreign language)
she so clearly speaks more than English
and is very talented, has trained
in a number of institutions,
including in Barcelona
and afterwards at Georgetown
University in Washington, DC.
She really leads our
efforts here at UC San Diego
having been extensively
trained in movement disorders,
including at NIH in Bethesda.
And interestingly did a
year of psychiatry rotation
at St. Elizabeths
Hospital in Washington, DC
to take into account the
psychological issues that occur
in the setting of dementia
that we see so frequently
with Parkinson's disease.
So it's a really a thrill
to have Irene Litvan here
to start us off.
Thank you so much for joining us Irene.
- It is my pleasure to be
here, thank you very much.
All of you for participating
in this phenomenal,
Closer Look at Parkinson's Disease.
These are my disclosures,
but none have anything
to do with this stock.
The learning objectives are
learning about new concepts
on Parkinson's disease, where it starts,
how it progresses, new
diagnostic approaches,
as well as novel experimental
therapeutics, current,
as well as those in development.
You're gonna understand
that this is a very brief
talk about each of these themes.
When I was in medical school,
I did learn that Parkinson's
started in the brain
and started in this area back in the brain
called mesencephalon.
And that these neurons that are in black,
that is called the
substantia nigra, though,
it doesn't really matter
the name were lost
and that can be seen in microscope.
This is normal, this is
absent of these neurons.
We know that these neurons
communicate with other nuclei,
other areas in the brain
that make us be able to move
that's the motor circuit.
And we can see that when
we do a scan of the brain
looking for dopamine, and you can see here
that you see this coma,
that is a normal striatum.
Here you can see that this is different.
And this is because this
area has disappeared
because it's a patient with Parkinson's
that has lost those neurons.
So there is a loss of dopamine
and dopamine is the chemical
that makes all the neurons move
and makes us move actually.
And I think that without it,
it would be like a car without gas.
So what we have learned is that in fact,
it is not in the brain,
but it isn't the gut
where the disease starts.
So alpha synuclein that is this protein
that deposits into the
neurons in the brain.
The cells in the brain,
is what is perhaps making the cell die.
And it is first in this place, in the gut.
And after the gut, it
is, or perhaps initially
it is also in the olfactory bulb.
So it can explain here, the
problems with constipations
here are the problems with smell,
and it also affects one of the nerves
or all the nerves that go to the heart.
So there is a denervation
that we can see as well
with special studies
as I'll show you later.
But in addition to
that, there is something
that is very relevant,
that is the presence
of an enactment of the dreams.
When we sleep, we don't
move, but if we do move,
then if we have bad dreams,
we can hurt someone else.
And I'll show you that in a second,
but in addition to those neurons
there are other neurons that are affected
and may cause depression and anxiety.
So all of these features
that are non motor
all of those appear before
we get to diagnose somebody
with Parkinson's disease,
because they have the motor symptoms.
But by then 50% of the neurons
in that substantia nigra
that I show you are lost.
And the amount of dopamine
that is in that area
that is deep in the brain,
the striatum is also
decreased significantly 80%.
Here is a patient that
has REM sleep behavior.
And he has really bad dreams.
He's enacting of the dreams
in a second, as you'll see,
and this is something that is treatable,
and it's very important to
know that if somebody has it,
even if they don't have
any other symptoms,
it is important to consult a neurologist.
So there are four stages
in Parkinson's disease.
One that we call it preclinical
because there are no symptoms,
and there we can see the abnormal imaging.
We can see perhaps other biomarkers
that we're starting to search for.
And there may be some as
well, some genetic factors
in some people, but then
in addition to that,
we have all these things
that I told you before,
and that's what we call prodromal phase.
And when the motor problems occur
that's the early phase of Parkinson's
where slowness that is key
is associated with stiffness tremor.
And then at a more advanced
stage, there is some
excess of movement
because the neurons become
with the treatment more sensitive.
There is also in some people
cognitive disturbances
that may lead to dementia in a significant
proportion of people, much more than
in the general population.
And there is also as well a lower number
in the blood pressure,
the blood pressure drops
when we stand and that it means
that there is less blood
going into the brain
and that can give symptoms.
This study, I think that is very crucial
because these authors what they did is
use several imaging modalities
to be able to measure
what happens at the level of the gut.
That is those cholinergic
neurons that are affected
what happens at the level
of the heart with an MIBG
that is looking at the
amount of denervation
from the sympathetic nerve.
And then they look at
other aspects in the MRI,
as well as looking more
importantly in the local coeruleus,
through another ligand and
with a (mumbles) ligand,
they look at what happens in
the areas that are the striatum
the areas that I show you before.
And they tested, they did
all this imaging studies
in people that had these
enacting of their dreams only.
And they did also in people
that had Parkinson's disease.
And the interesting
aspect is that the people
that had Parkinson's disease
had all these areas involve,
but the people that have
the REM behavior disorder,
the enacting of their dreams,
those had all the areas,
except the areas related
to the motor system
that is the substantia nigra.
So kind of supporting
that idea that there is
that kind of a progression from a pathway
that goes from the gut
all the way to the brain.
So based on that many things
happen, one is the development
of a research criteria
to be able to detect
the disease at very early stages
when there are only known motor symptoms.
And that was based on
the fact that as we age,
we have more Parkinson's disease.
It is also based on the
presence of markers of risk.
For example, being a male is a risk
being in contact with
pesticides or the other factors
that I mentioned that
is the prodromal markers
that are the enacting of
a dream as an example.
So putting all that together
through a statistical model,
they're able to look at
what are the probabilities
that someone would have
Parkinson's disease.
These criteria was tested
in different populations,
populations that have the
REM behavior disorders,
others that had the lack of smell,
and they were able to
find that the criteria
was very specific.
Whenever the likelihood was high,
then the possibilities of
being Parkinson's were there,
but it wasn't sensitive.
So it didn't detect all the
people that truly converted
in having Parkinson's
disease with following years.
What is more interesting as well,
is that in people that
do have genetic markers
for Parkinson's disease,
genetic mutations,
when they apply this
criteria, many more people
that had a likelihood ratio
or now high probability
of converted into Parkinson's disease
that is the motor symptoms
was much, much higher.
So it's much more sensitive
and it's also very specific.
Another study looked at what happens
in people that have lack of smell
and also have problems with
the DaTscan that is abnormal.
And they figured out that in four years,
if those two things were abnormal,
someone would develop Parkinson's disease.
Of course, lack of smell, constipation,
those are common symptoms
in the general population.
So not everybody's
gonna have a Parkinson's
because they have those symptoms.
They could be related
to many other things,
for example, smoking.
So based on multiple studies,
this criteria is being updated and it's
with the hope that is more sensitive
when we will validate it,
it also help the new research
and the new knowledge
to change the criteria
for Parkinson's disease.
Before we used to think that
people with Parkinson's disease
had to have either slowness
with either tremor stiffness
or a postural instability
problems with balance.
But, now it is clear that
those problems with balance
are very late in the
course of the illness.
Therefore, the new criteria includes
only slowness and tremor or stiffness.
So summarizing what I just said,
combined multimodal imaging in patients
with REM behavior disorder show
that there was a profound
cholinergic deficit,
sympathetic heart and in another areas
that would show denervation,
but there was not involvement
of the dopamine areas
in the substantia nigra.
And that reflects this
model that was developed
by professor Braak, the
Movement Disorder Society
then created a Prodromal PD criteria
and I was happy to be part of that.
And also we modify the criteria
for Parkinson's disease.
I didn't talk about this,
but another important aspect that has
also been more lately
measured is alpha-synuclein
that protein that I said that
accumulates in the brain,
in the spinal fluid of people
that have Parkinson's disease
and compared to normal people,
it is very clearly differentiated.
So now let's go to the novel
experimental therapeutics.
So, in order to be able
to treat a disease,
we need to know what is it that causes it
otherwise it's impossible, correct?
So we knew for many years
that environmental exposures,
pesticides and other organic and metals
did lead to Parkinsonism
Parkinson's disease.
But then over the past several years,
we started to find genes that
cause Parkinson's disease
in families.
And then it happens to be
that multiple genes were found
that were not really always in families
but at times it could be
that are called modifying.
That is perhaps need more
than just those genes
to develop the disease, or
all those genes are necessary
for the development of the disease
or maybe environmental
exposures and those genes leads
to development of the disease.
So in this diagram, we
can look at the frequency
of the disease and here is a
risk of having Parkinson's.
So there are some mutations
in genes that lead
to Parkinson's disease, if
you have have that gene,
you're gonna develop Parkinson's disease.
But there are others that
are much more frequent,
that may be in the general population
and may or may not develop,
help to develop Parkinson's disease.
And as you can see, some
of them are the same.
So there is also a
difference in the strength,
in some sense of that mutation.
There are also intermediate
yet genes like a GBA
glucocerebrosidase gene that is affected.
There are multiple other
mechanisms that have been thought
and found reasons for being
that are affected as well.
And we don't know if these mechanisms
such as problems with the mitochondria,
the factory of the cell that then leads
to do oxidative stress,
or if it is inflammation,
or if it is the areas in the
brain that destroy the proteins
that lead to autophagy and
ubiquitin-proteasome dysfunction.
If those mechanisms are the ones
that lead to the aggregation
of alpha-synuclein,
or if the aggregation, the
clustering of all these proteins
is the one that basically
cause all these other problems.
But (mumbling), these are all the factors.
And what really happens is that
proteins that normally exist
suddenly change their form
or their configuration,
and they bind to each other.
So, and I'll show you that in a minute,
but all these problems lead
to the death of the cells
that is lead to Parkinson's disease.
So if we search for disease
modifying therapies,
we can prevent the disease,
we can try to slow it down
or halt it all together.
Of course we can prevent it in those
that may have some genes.
And if we have a
treatment that can prevent
the disease from appearing,
but there's strategies
that have been used.
So far, none of those have
helped in that regard.
It will be necessary to identify people
that have only the preclinical
stage that is very difficult.
Then there is a possibility
then to use different strategies
based on the possible poses
to try to modify the disease.
And one could be reducing
the oxidative damage,
the inflammation, targeting
those abnormal proteins,
or try to see if we can avoid
the spread of the disease.
So there are multiple areas
then that are affected
and that we can try to interact.
And I think that professor
Cleveland is gonna go
into more detail into all these things,
but I can tell you then
that we can try to avoid
the development of
those abnormal proteins,
or there could be ways
in which we can avoid
that the disease would spread in theory.
So, the first thing that we can do,
we talked about the gut and in the gut,
there is the microbiome,
the bacteria that are there,
and there are difference between those
in Parkinson's disease,
then the general population.
So one possibility would
be to try to change that.
And this is what the study did.
And the probiotic administration in people
with Parkinson's seem to slow
the progression of the illness.
This needs to be replicated
in larger studies.
So let's talk about medications
because this is what we
need to slow the progression
of the illness.
And I don't know if you
know how much it costs
to bring a new molecule to the market.
It is $2.6 billion, and it
may take up to 13 to 15 years
and only 11% really make it.
You can see here exactly all
the faces that the medication
is to go in order to really
be approved by the FDA.
However, if we use drugs that
already exist in the market,
using those old drugs for new applications
would cost much, much less 300 million
versus taking also less years, 6.5.
So there are many attempts to do so.
So there was this trial that tried it
to inhibit the calcium channels,
specific calcium channels
with this medication that
is called isradapine.
It is unfortunate that these study
just finish and just fail.
So there was another trial
with inosine and inosine
was given to try to see if we
can use it as an antioxidant.
In fact, uric acid is one
of the best antioxidants,
but unfortunately that study also fail.
But now, there is another
study that was done,
that is with a medication
that is used for diabetes.
It's a medication, it's
a glucagon like peptide
that is used and it has been shown
that people with diabetes
have more Parkinson's
that those that don't
and the use of this drug
seemed to slow the progression of illness.
So in, based on that, this
is why they did this study.
That is a randomized double blind study
to try to see if that would happen.
And it did happen, but
study is a very small study.
So now there is a large
study that has been done
trying to see if we can
replicate those results.
Interesting as well, I've seen also
that there are epidemiologic studies
that confirm this aspect as well.
Nilotinib, maybe something
that you may have heard
is medication for chronic leukemia,
and it was, the first study was done
in Georgetown university and
the results were phenomenal.
People that wouldn't be able
to walk started walking,
but what happened is that
that study was done with
that was what we call an open study,
everybody knew what the drug was.
And so those studies really
are not very helpful.
So now that our studies that
are what we call Phase 2s
in which we randomized for
either placebo or the drug,
and those are ongoing,
and we don't have results.
There is new Phase 1, one,
just starting to look at
small molecules that would
target those proteins,
that move from one cell to another,
that I'll discuss in a minute,
and this is moving forward as well.
So the proteins that move
from one cell to another
are these alpha-synuclein
and this is what happens
in a cell.
The protein changes its configuration
and then binds to each
other, clattered the cell
and the cell dies.
But as well, because it's
communicating with another cell,
then the disease goes to the other cell
and then it spreads the illness.
However, if we use
antibodies, we could rescue
this abnormal proteins and then try to see
if we can scavenge them and
reduce the possibility of,
or slowing the disease or
stopping the disease eventually.
This is the immunotherapy,
you may have heard that,
all that with COVID.
I think antivirus is
an exciting development
for Parkinson's as well.
I think that there are several studies
that are ongoing, that
if successful can reduce
the spread of illness by
reducing alpha-synuclein,
moving from one cell to another.
So we had these two studies at UCSD.
We did the Phase 1 that is
to try to see if it's safe.
And now we are in Phase
2 that is to look at
whether giving the antibody
it is better than placebo.
One of them just finish and
went into the open trial.
That is when everybody
knows that they're having
the disease, but here you want to know
what happens long term because
these studies last a year.
So there are other antibodies
that are being developed.
The pharmaceutical industry is very active
and it also active with creating vaccines.
So in Europe this company
AFFiRiS has created a vaccine
that actually tries to
develop the antibodies,
our own antibodies, and
this is being tested.
And apparently the results,
at least in the Phase 1
seemed to be very good.
There are other trials that require
intraoperative procedures.
One of them is the use of GDNF.
That is a nutrient as a gene therapy
for Parkinson's disease.
This is created with a modify virus
and we will be doing this study
it's been done at this
at this time at UCSF,
I will be next as well
in starting the study.
So there are other studies
that use STEM cells,
and there are several
in Australia and China
STEM cells are very important
because they provide
a continuous amount of dopamine.
This is the cells that are being given.
The problem, I think,
is that he doesn't treat
the non dopamine symptoms that
are the non motor symptoms
that are the hardest to treat clinically.
Clinically, we do pretty
good with the motor symptoms,
not perfect, but very good,
but giving the STEM cells,
what it will do is improve the functioning
of that more motor circuit,
that in some senses as
well, what DBS does.
There are many other drugs
that are being funded
by Michael J. Fox, as
well as other agencies.
And I think we should have a lot of hope
that there could be some of
them that could be effective.
So I think that for those
who have the disease
and the families, I think
it is very important to know
that this field is
moving forward very fast.
Don professor Cleveland, will
talk about one of the other
things that are other therapies approaches
that have been done at GCSE that is
converting, the astrocytes that are cells
that help nurturing the cell
in some ways into neurons.
Another important aspect
is the development
of personalized medicine,
that is if we know
what are the genes that
are affected, we could try
to give medications to improve them.
And in the general population,
we would have to search
much more in order to be able to do that.
Some of that is being done.
And it's actually been
done at UCSD as well.
That is treating patients that
have PD and have mutation.
And the medication this glucosylceramide
stimulate the enzyme that is defficient
in Parkinson's disease with GBA.
We'll see what does
that, but there are also
many other studies for that deficiency.
So the field is moving very
fast and the same for other
mutations, like LRRK2.
So I just want to say
briefly that I'm very excited
with what we are doing, that
is the development of a way
to measure the amount of levodopa
so we could manage patients
in a much better way.
Because if we know what is the level,
we would know what is the
level that they should have
even before they develop complications,
or when they develop complications,
we will know how to adjust that better.
And this is done with a
wonderful group of bioengineers
at UCSD Professor Wang,
and you can see the
the device itself is
actually very, very small.
It's this is a coin, and
this is a device per se.
So people would have it all
their time and would be able
to know constantly what
is the level of levadopa.
So the patient is helped
and the physician as well.
This is where we are and in conclusion,
emerging therapies are
directly or indirectly
targeting alpha-synuclein to
slow the disease progression.
The therapies are attempting
to avoid alpha-synuclein
aggregation, they change
the clattering of the
proteins or the spread
or modifications of the microbiome
with different approaches.
And I think that this is interesting
because it has move
forward in multiple ways.
And I think we will see
that one of these therapies
will be very helpful.
So this is our group and
thank you for your attention.
- Okay, thank you Dr Litvan, I can see
that there's a lot going on in the field
as can everyone else on this
presentation, this WebEx.
There is a question about
cardiac dysfunction.
Does that derive from autonomic
nervous system dysfunction?
And secondly, when does this appear
in the course of Parkinson's
disease progression?
- This appears very early and
it doesn't give any symptoms.
So if someone has symptoms
with a heart such as pain,
and they have problems
with the coronary arteries,
there is absolutely nothing to
do with Parkinson's disease.
So this is just a marker for us.
It doesn't really affect
in any way, the heart.
- I had a question about the microbiome.
So Rob Knight and others
published a paper suggesting that
as you were alluding to that,
the microbiome could promote
motor dysfunction and neural inflammation,
in Parkinson's disease
and there are people
with ulcerative colitis and H pylori
that maybe at slightly higher risk.
It looked pretty interesting
to look at probiotics.
What about just antibiotics
targeting H pylori
to prevent the production of metabolites
from these microbiota?
What about that as a clinical trial.
- It hasn't been done and we didn't know
that the problem with
antibiotics is that there is
development of some resistance.
So I wonder how long
would you have to do that
for this to be effective
and could you modify
your microbiota in bad ways.
So it's complicated--
- It's all about the balance.
Got it and then there was other question,
are there any trials
going on in North America
for ambroxol?
- Yes they are, you need
to look@clinicaltrials.gov,
and you're gonna see all the places
that all these trials are being done.
All those that I mentioned.
- Sorry, I just we're running out of time,
but what induces apoptosis
of dopaminergic neurons,
is there one specific
therapeutic vulnerability
that could be targeted?
- We don't know yet, we don't know.
I wish we would, but we don't know.
- Okay, so we're going to have to move on.
There's a question about alpha-synuclein,
but I think that we can
move on to Dr. Cleveland.
Thank you so much, Dr.
Litvan, we really appreciate
the time you've taken to
discuss Parkinson's disease
with us and they're really
exciting therapeutic strategies
that you've put in place.
- Thank you.
- Thank you.
I will move on now to Dr. Cleveland.
So Don Cleveland is here,
he's at UC San Diego.
He's a distinguished professor.
he's actually the chair
of the Department of Cellular
and Molecular Medicine.
I also remember the Ludwig Foundation
and our Ludiwg Institute
was the prize winner,
the Breakthrough Prize winner,
I believe it was in 2018 for
his remarkable discoveries
regarding how to target
some of these abnormalities
in ALS and more recently
in Parkinson's disease
with antisense oligonucleotide strategies.
This is really a fundamental breakthrough
and shows how great science
leads to great medicine.
So thank you so much, Dr.
Cleveland for being here.
- Absolutely, my pleasure to be here.
If you, you can see I've,
this has given me an opportunity finally,
to get properly dressed for
the four months of COVID.
So what I'd like to do today
Just to follow Dr. Litvan's
introduction to Parkinson's
with a story of the
development of a strategy
of using what I call designer DNA drugs,
to target individual genes
that are really fundamental
to individual neurodegenerative diseases.
The story began with the recognition
that all of the major diseases of the,
of aging nervous system
Alzheimer's, Parkinson's, ALS
Huntington's, you know, all those cases
where we know of a gene or genes
that can cause the disease,
those genes are expressed very widely.
And as a followup discovery,
especially by a team at NIH
initially discovered that
if you inherit an extra copy
of a normal gene, the gene
that encodes alpha-synuclein,
and as I'm sure you all
know, you usually inherit
one copy of each gene
from mom and one from dad.
But if you, by a quirk
of genetics, you end up
inheriting three copies of
a completely normal gene
that encodes alpha-synuclein,
you will get Parkinson's disease.
So too much of a good thing.
And similar story emerged
in Alzheimer's disease,
where if you inherit three
copies of a different gene,
the amyloid precursor protein gene,
you will get Alzheimer's disease.
And recognizing that then an
on disease mechanism therapy
directly targeting what initially
goes wrong would be the,
the high level of
synthesis of those genes.
And therefore just turn the gene down.
And we set out beginning
in 2003 to do that.
And the way we're going to do it
is to use a little designer, DNA drug,
which if you get it
inside the target cell,
it can pair with the
intermediate from the gene.
The intermediate is called an RNA,
and it makes the RNA a substrate
for an indogenous enzyme
that degrades the RNA when paired
with our little designer DNA drug.
And that enzyme is present
in almost all of our cells.
And you can thereby
destroy the intermediate,
turn the gene off.
And over the years, the
medicinal chemists have modified
here's a little a strand of DNA
the substance of our genome,
and they've modified it
in a variety of ways.
And those modifications have
produced an amazing drug.
So as we've learned single
doses of these designer,
DNA drugs, when administered
in the nervous system
give you really longterm efficacy.
You know, when you take
an aspirin, you get three
or four hours worth of relief.
Well, for these drugs
in the nervous system,
we don't get three or four
hours, we don't get three
or four days, We get three or four months.
And so we're going to dose patients three
or four times a year to
silence a disease causing gene.
The disease we started
with is the one that
the Americans call Lou Gehrig's disease,
or amyotrophic lateral
sclerosis, or for short ALS.
It's a disease where the
neurons, the ones in the brain
that come down the spinal
cord, and then the ones
that extend out to innervate the muscles
and to trigger the muscles to contract
those nerves selectively die.
And, well ALS is not a
particularly prominent disease.
There are about 5 million people now alive
who will die from ALS and the hallmark,
the landmark discovery that
opened the era scientists
of designer therapies
in ALS was the discovery
of mutations in a gene
called superoxide dismutase
are causative of a
proportion, about 2% of ALS.
And we demonstrated those gene mutations
are encoded gene product that is toxic.
It's not because the gene
doesn't make doesn't have
encode a protein with a normal function
it's because the mutant
gene product is toxic.
And it's a little embarrassing
to the research community
that almost 20 years later, we
still, almost 30 years later,
we still don't agree on
what the toxicity is,
but you would be directly
on disease mechanism
if you could just turn off
the disease causing gene.
So I'm gonna show you,
I know this is not a scientific audience,
but I hope everybody will
be able to follow this.
This is the founding experiment.
The first time and a
designer DNA drug was used
in the mammalian nervous system.
And we're gonna dose an animal that has
an ALS causing mutant gene.
And when we dose with a DNA
drug that doesn't have a target,
here's the level of expression
of that ALS causing gene.
And look at the level when
we add the right drug,
we can lower it to about
30% of its original level.
Actually, if we add more drug,
we can lower it down to 5%.
So in a dose dependent
manner, we can lower the,
the synthesis of the product
of this disease causing gene
and even more when we
do, we introduce the drug
into the cerebral spinal
fluid, the fluid that bays
the brain and spinal cord.
It gets pumped around throughout
the entire nervous system.
And you get gene silencing
throughout the entirety
of the nervous system.
And when you dose one of these
animals, it's gonna develop
fatal ALS like disease very
rapidly progressive ALS
like disease, if you dose them
with just a saline solution,
oh, they only live 25
days after the initiation
of the peril paralysis but if we dose them
with our designer DNA drug, they now
we slowed disease progression after onset.
We doubled survival after onset.
This is the founding example and we then,
and we began this effort
in about 2003 and in 2006,
we demonstrated that
we could deliver these
designer DNA drugs broadly throughout
the mammalian nonhuman
primate nervous systems,
an even better example of a
use of such a designer DNA drug
would be in the disease
Huntington's disease.
A hundred percent of Huntington's
is caused by mutation
in the same gene, the Huntington gene.
And it's very clear that the
mutation causes a toxicity.
So here again, if you could just
an on-disease mechanism
therapy would be to lower
the synthesis of this
mutant Huntington gene.
And we tried that and when we did that
in animals that develop aspects
of Huntington's disease,
we dose them once mid disease.
And what we noted with
great enthusiasm was that
by dosing already affected animals
that we got sustained disease reversal.
So that then led to a first in-man trial
in Huntington's disease, for
which the outcome was announced
the initial outcome in December of 2017,
a sort of holiday present.
And here you see that
Washington Post described it as
a phenomenal trial result
and it was phenomenal
in the sense that we lowered the,
we demonstrated, we
lowered the level of the
mutant Huntington product
to the level intended,
and that then led a big
pharma Roche to license
the approach from the
San Diego company Ionis
and Roche is now conducting
a large efficacy trial
with a 660 patient trial and
we are awaiting the outcome
of whether we've been able
to affect the disease course.
A further example came
with the discovery here on,
in September of 2011 of the
most common, the most frequent
cause of inherited ALS,
but it also happens to be
the second most frequent,
the most frequent cause
of the second most frequent dementia.
And this designer DNA drug,
we can design the drug to hit
the intermediate target
from individual genes.
And the absolute truth
is that the discovery
was published on September
21st, we designed the strategy
on September 22nd, we
achieved proof of principle
that we could change disease course
in animal models of disease
in, four years later.
And we dosed the first
patient and these patients
are being dosed at UC San Diego.
We dosed the first patient
almost exactly seven years
from the initiating discovery.
Okay, and then one last example,
and then to Parkinson's.
So the last example came with
the discovery of the gene
affected the most in sporadic ALS,
two teams, my team, and a team at Harvard
co-discovered this gene called stathmin-2
in January of 2019.
And what we've done
subsequently, even with COVID
just last month, we
demonstrated proof of principle
of being able to use a designer DNA drug,
to restore the normal
synthesis of stathmin-2
which gets ablated in sporadic ALS.
And we're proposing now
are planning proposing
to get to clinical trial in 2023.
Now shortening the span from
identification of the target
to in-human clinical
trial, to what we hope
is about four years.
Okay, so now what about
Parkinson's disease?
And as Dr. Litvan introduced in her talk,
there are mutations, the
most frequent mutation
known to cause Parkinson's disease
is in the gene called LRRK2, and it's
most mutations in genes
frequently inactivate
the ability of the gene to
make a functional product.
But that's not what these mutations are.
They hyper activate the
LRRK2 gene and indeed here,
Dr. Jamieson mentioned
that I won this prize
Breakthrough Prize in Life Sciences,
here's the prize ceremony
and it was presented to me
by Sergey Brin, the founder of Google
and Sergey Brin is probably
the planet's most famous
individual with an LRRK2
mutation that he went public
with this in 2008 so
there's nothing private
about this story.
He has this LRRK2 mutation,
which makes him very likely
to get Parkinson's disease.
His mother has Parkinson's disease.
My father died from Parkinson's disease
and Sergey has, this LRRK2 mutation.
And we, an on disease mechan therapy
would be to turn down that gene.
And indeed we initiated with
Ionis partnered with Biogen,
initiated a trial using
the designer DNA drug
to suppress the LRRK2 gene for this form
of inherited Parkinson's
gene started just at the end
of 2019, and even more so,
as Irene mentioned earlier,
alpha-synuclein is found
misaccumulated broadly
in Parkinson's disease, in
most Parkinson's in patients.
And we know now that if you just inherit,
as I introduced before three copies
of the alpha-synuclein
gene, instead of two,
that absolutely will give
you Parkinson's disease.
And so the, an obvious approach now
would be to turn down
the alpha-synuclein gene
as a non disease mechanism
therapy for almost
all Parkinson's disease
instances and excitingly for us,
I think early this year,
using the designer DNA drug
to suppress alpha-synuclein
that trial was initiated
by Biogen and is now in progress.
Okay, so here's the
summary of the development
of designer DNA drug therapy
for nervous system disease.
We know that we can deliver
these drugs very broadly
throughout the nervous system.
We can turn genes on or turn them off.
We have long lasting
efficacy from single doses,
more than three months,
it's commercially feasible.
And it's been through five safety trials
and for various indications and all five
have been proven to be safe.
And indeed we have one approved drug
for a childhood disease,
it's actually one of the most
frequent inherited diseases of children in
the disease called spinal muscular atrophy
approved at the end of 2016.
And we have, there are
five ongoing trials,
three in ALS for two inherited
forms, one for sporadic ALS.
We also have a one in
Huntington's disease,
one in Alzheimer's disease
and as I just indicated,
two initiated over in the last year
for one form of inherited
Parkinson's disease
and for sporadic Parkinson's disease.
And now I'd like to
close with an even more
extravagant example.
Dr Litvan introduced this before,
and it's the use of an
antisense oligonucleotide
designer DNA drug to execute
what I call identity theft
as a mechanism to generate new neurons,
to replace those lost as disease.
And indeed, this is a strategy
that has been implemented
a strategy to induce to
replace neurons lost to disease
has been a goal for now for 40 years
with the first trials
in Parkinson's disease,
initiated in the eighties
and then nineties.
And as you can see here without
going through the details,
many different applications
have been tried.
None have really been fully successful,
and I'm gonna propose a new one today.
And it is to use these designer DNA drugs
to reset cell identity, and to do that,
to convert abundant
non-neuronal cells in the case,
in our case, one's called
astrocytes and to convert the,
get them to convert from
the non-neuronal neurons
to real neurons, to replace
those that have been lost
in disease.
And the strategy is outlined here.
My colleague, Xiang
Dong Fu at UC San Diego
has identified six genes
in two three gene circuits.
And if you have the two circuits
set to the right position,
you are a neuron.
And what he realized was
that actually astrocytes
this abundance cell type
within the nervous system,
a partner of the, of
neurons that the astrocytes
already have the second
position, three gene switch
set to the neuron position, and look here
where the astrocytes have
high levels of one gene PTB,
the neurons have low levels of PTB.
And these circuits, you can see the,
the green bars show that this
genes represses this gene
represses this gene, they
all repress each other
so you have a high level
of this one you're locked
in that position, so our strategy will be,
what if we just turn down
the PTB gene to make it
look like a neuron will an
astrocyte convert into a neuron.
And so here you go, we're
gonna, what you're looking at
in this image is the blue is
looking at all of the genes
stuck on their chromosomes
inside the nucleus this culture
in a plastic dish culture of
astrocytes, human astrocytes.
And now they have, they do not express any
neuronal proteins, but
when you suppress PTB
using an antisense
oligonucleotide you now,
and wait four weeks, these
cells are just sitting there
on the dish, they convert into neurons
expressing neuronal proteins one of which
is labeled green here, and
one of which is labeled red.
So, and almost all the
astrocytes turn into neurons.
And so now does that
really work in animals
in the real mammalian nervous system
and we're gonna test this,
we're gonna test this
in an animal in which
we're going to induce
Parkinsonian disease.
So if you look over on
the left here, well,
what you're seeing here
is the substantia nigra
that the neurons of the substantia nigra,
the ones that risk in Parkinson's disease,
there they are in green and
oh, and they send processes
they innervate a region of
the brain called the striatum,
and there they go there,
their green processes
come up into the striatum and their job is
to synthesize a chemical
dopamine and to deliver it
and release it here in the striatum.
Now we're going to use a
toxin, a chemical toxin,
which when injected
unilaterally only onto one side,
you can see it's, it has killed most of
more than 90% of the neurons
of the substantia nigra.
There're very few green ones left,
and there's almost no
innervation of those neurons,
the remaining neurons
in the substantia nigra,
sorry, in the striatum
and the dopamine levels
in the striatum plummet.
Okay, so now what are we gonna do?
We're gonna lesion these
animals, we're going to
test them behaviourally to
determine that they do have
a Parkinson's phenotype
we're then going to inject
a designer DNA drug to
suppress PTB, and then ask
and wait three months and
ask, have we made new neurons,
have the new neurons
innervated the striatum?
Are they now releasing and
restoring dopamine levels
in the striatum?
Oh, so if you take unlesioned
animals, normal animals,
and you measure them with a
variety behavioral measures,
but here they're normal at the beginning.
And three months later,
they're still normal,
no surprise at all.
But if you lesion animals, what happens?
Well, actually, as you inject this toxin,
what you see is that sometimes you ablate
all the, the nigra neurons, and
sometimes only some of them,
and here the animal
with the largest lesion,
wait three months after suppressing PTB
to convert astrocytes into neurons
and look, the animal gets better.
The next one, it gets better
over that three month period,
the next one gets better,
the one lesioned less,
but it still gets better.
The next one gets better, gets better.
Six of seven lesioned animals
got better when we treated it
with this designer DNA
drug to suppress PTB
look, and while one animal
just didn't get better at all
we obviously failed to
deliver the drug correctly
in that animal.
So we argue from this that we
can indeed use identity theft
in the mammalian nervous system
that we can use our designer DNA drug
to convert astrocytes into
replacement, nigral neurons
that somehow know where to go.
They reinnervate the
striatum, they redeliver
dopamine to the striatum and
they reversed disease course.
And we would further propose
that this kind of designer DNA
drug mediated conversion of astrocytes
into replacement neurons
may be broadly applicable
for restoring neurons in a variety
of different neurodegenerative diseases.
And so let me just close
by just pointing the folks
who've really done the work
that I've described today.
They were a trio of colleagues, Tim Miller
now runs his own team,
runs the ALS trials.
He's now at Washington university.
Richard Smith is a neurologist
who's been in San Diego
for 40 years and he was
adamant that we try this.
Frank Bennett is the chief
scientific officer of Ionis.
And with him, we got
this strategy started.
Frank partnered with Adrian Krainer
at Cold spring Harbor to
develop the approved therapy
for spinal muscular atrophy.
Holly Kordasiewiez led to
Huntington to effort first
at UC San Diego, now
at Ionis demonstrating
that she could get disease
reversal by a single
dose administration to
suppress Huntington synthesis.
Clotilde Lagier Turenne now
at Mass General Hospital
in Harvard partnered
with me and John Ravits,
a neurologist here at UC San Diego
in the development of a strategy to target
the most frequent cause of inherited ALS.
My current team, along with
Clotilde Lagier Tourenne
there's my current team who
has identified staff men
and is as a target for sporadic ALS
and who will develop it into a therapy
in the next handful of years
and then targeting Parkinson's
demonstrating that we can
generate replacement neurons
is a, my colleague Xiang Dong
Fu, his (mumbles) Hou Quan
and a pair of researchers in
my team who have demonstrated
that we can with antisense
oligonucleotides,
designer DNA drugs, we
can use identity theft
to make new neurons.
Thanks very much.
- Thank you so much,
Don and for showing us
so elegantly that DNA is not destiny
if you use designer DNA drugs.
So I really appreciate
everything you've put forward.
There is I'm sure the
rest of the audience does
there's one question, what are the effects
of using designer DNA drugs?
Are there specific side
effects that are unique to this
kind of antisense oligonucleotide?
- So like every, any drug there,
there can be minor side effects there
they've been limited to,
some patients have reactions
to the actual drug, but
we're only dosing patients
three or four times a year.
So if you have a headache for two days
and three times a year, these are very,
very acceptable side effects.
There was a fear that they
would, that they might be
immunogenic and that there would be
that our immune systems
would attack the drugs
that has not been seen
in any of the trials yet.
So we are cautiously
optimistic that will not appear
as a longterm problem.
So we are actually, it's worked
out better than expected.
We can deliver them very broadly,
very longterm efficacies.
I think the real question for them is
how much do you wanna
turn those genes down
for the genes we're turning down
and for the genes that were turning up,
can we turn them up far enough?
- Yes, certainly challenges
but very exciting
problems to have in the
sense that we didn't have
anything before and now you're
creating a whole new field
with antisense oligonucleotide therapy.
Thank you so much.
There's one question,
but I think it's better
for Dr. Litvan from
somebody who's confused
about alpha-synuclein
and she's been giving
her husband with Parkinson's
disease alpha-synuclein
supplements and wondering
if it's making things worse.
- I'm not aware of those supplements.
So I cannot really talk about them.
I have never heard
anybody taking supplements
of alpha-synuclein, but I
certainly wouldn't do that.
I don't think that anybody
should try mitigations
that have not gone through
experimental trials
and have been shown to be effective
because there are thousands of things
that people can sell and are really bad.
And that, in fact, it's one
of the problems in our area
as well, that there is
a lot of fake sales men
that do sell STEM cells and
those are not really tried
so I think I would say I wouldn't take it.
- Okay, so before we turn
it over to the esteemed
Dr. Higgins, there is a question
about the converted neurons,
the identity theft neurons
from the astrocytes, do they
project to the forebrain?
- So precisely where they do, so there,
I should have said, I know
the answers to the questions
before you ask them.
So the answer is we don't know,
so this is the tiniest tip
of the iceberg, and I
suspect there's a very,
very big iceberg so these
are questions that now
need to be addressed.
How many of those neurons become
the right kind of neurons?
In the case that I just described
in the Parkinsonian example
about a third of the neurons
in the animals became exactly
dopamine producing neurons.
And they went the right direction
that we were amazed at that
some didn't go the right direction
and we need to know, we need
now to test, can we fix that?
And so for the specific question, yeah,
we don't know that we do know,
and I'll just leave it there,
we do know that if you it's sort of future
(mumbling) futuristic, but we do know
if you take a normal animal a gene animal
and you ask, can you produce new neurons,
say in the region of the
brain that is really involved
in cognition, the hippocampus,
can you make new neurons
in the hippocampus?
And the answer is yes, you can.
So I think that there's, there are many,
many things that we will
be able to do with this.
We have not demonstrated that
we can do most of those today.
We, and indeed if I think
I failed to point it out,
but the demonstration that
we can make new neurons
and reverse disease
course in Parkinsonian,
in an chemically induced
Parkinson's disease
that was only published
on June the 24th, 2020.
So we are, what I showed you today is
this is what we have, this is an,
we sort of opened the notebooks.
That's what we know, we will
know a lot more next year.
And I think we've activated an Armada
of individuals worldwide.
It's not true, we cannot make new neurons
in the mammalian nervous system, we can.
And I failed Catriona, I
failed to point out one beauty
of the approach of converting
of this identity theft,
which is that it does not
require immune suppression.
These cells are your, are
the individuals own cells.
They are marked with
the cell markers of self
that the immune system see
they're marked perfectly.
Whereas in all those other trials,
there were real immune
issues and immune suppression
was required throughout for most of those.
And here we are, they're your cells.
We are gonna convert them in
place and we're gonna do so
with a really easily to deliver drug,
which and we can do it
over and over again,
if you want to make more and make more.
- Sounds like another
Breakthrough Prize Don,
anyway, we will move on to David Higgins.
So Dr.Higgins got his
PhD in molecular biology
at the university of Rochester.
He was actually faculty
at SCSU and the president
of the Alzheimer's disease association
or our Parkinson's disease association.
He's been a stalwart champion for people
with Parkinson's disease has worked
with the California Institute
for Regenerative Medicine
to ensure that research funding is applied
to finding new strategies.
David, unfortunately we
only have a few minutes,
but we really wanted to end with you
because we think you'll provide
the appropriate perspective
as always, and really get us on track
to really focus on the
most high priority items
when it comes to working
with Parkinson's disease
and the research, both
clinical and scientific.
David, please take it away.
- Thank you, Dr. Davidson,
I really appreciate,
actually me being part of this today.
I'd like to thank, thank
Dr. Litvan and Cleveland
for being here as well.
These are the folks in case
those even in the audience
don't know these are the
folks in the community
that are making things happen,
the San Diego community,
as well as the community of the world
and Parkinson's, so
you are very privileged
and very, very special to see this today.
I don't know anything about supplements.
I wanted to throw that out first.
I've never heard about
alpha-synuclein tablets,
it doesn't sound like it
makes sense, but you know,
we keep our notes are
your ears to the ground,
and that's not one that we've heard about.
Okay, so they're really,
I'll try to keep with that,
the short amount of time we have
the really three points
that I wanted to make today.
And this is a new world that we live in,
it's a good new world.
And in this respect, and
that is medicine is changing.
We've become a patient centered care
has become the focus of medicine today.
And in some sense, that's
driven by patients,
but it's also really driven by clinicians
and people like Dr. Jamieson
and Dr. Litvan are onboard.
They're leading the fight,
they're not slowing it down
or getting in the way.
So it's really important to understand
what a patient-centered medicine is,
how the medical world is
views it and is employment it
and how it impacts Parkinson's.
Some of the elements of
a patient centered care
is it's collaborative, it's
coordinated, it's accessible.
It focuses on physical comfort
as well as emotional
wellbeing of the patient.
And one of the key things is,
is that the patient's family
and friends and coworkers,
or whatever, whoever
has something to offer
needs to be involved.
And that's really unique,
so in patient-centered care,
you're at the center of the
carriage as you'd imagine,
and you provide teams,
medical teams provide,
all the resources that are
needed for the various functions
to address patients needs.
And for the most part,
it works really well,
except when it doesn't.
So a great example of this is a model
a team put together for this patient
and what happened was they
were not in the computer.
So the best laid plans
couldn't be fulfilled.
And that's probably the next
and major barrier, if you will.
it's where the electronic side of
all the physicians out here
know about electronic records
and that kind of thing, and
the cumbersomeness of that.
But what's the role,
what's a patient advocate
and I'm gonna distinguish
this between patient centered care.
So patient advocate is a component
of patient-centered care.
So a patient advocate can
be anybody, can be you
it can be me, any person
with the mandate of
improving the wellbeing of patients
and the outcome of their medical care.
With doctors like Dr.
Litvan and Dr. Jamison,
that's a no brainer.
You've got the best
people who understand that
it's the outcome of the
patient's medical care
that that's key.
But when a patient ever needs
to have sincere interest
in the wellbeing of patients,
it can be a spouse, a parent,
a child, a sibling, I
need to be able to explain
why things are going the way they are.
And that means explain to
your patient relatives,
why this therapy works the way it doesn't,
it needs to be done this way.
It needs to be done
this particular details.
And as well as the physician
has something to learn
from the patient advocate
from about the family,
what are the family's expectations?
If there's a disalignment between the,
what the physician thinks
that you should be doing
and what the parent or the family thinks
they should be doing, it can be disastrous
and disastrous is in unnecessary ways.
Patient management, meaning
patient-centered care
is very complex process.
You've gotta identify the
patient needs, listen to them
what they need, hear what they're saying
not listening is a physical
act of just being in the room
and having your ears open
and hearing is really
understanding or paying attention
to what they're saying.
You need to translate that
into technical aspect.
One of the slides that
that Dr. Litvan showed
that was so important was
this multibillion dollar cost
of drug development and
the high rate of failures.
Well, if we had a more focused view
of what a successful drug needed to be
by asking patients who
were gonna be the customers
buying them and using
them, that would help us
reduce the number of so called failures.
'Cause they may not be
failures in a scientific sense,
but they may be failures in a sense
of really changing people's
lives in a positive way.
And so that's communication,
communication is a science and medicine
they have a unique language.
They have vocabulary
and everything about it
it's doctor speak, I mean, you think
you will watch a episode
of Grey's Anatomy on TV
and you think that they
sit at home at night
and think about ways to say it,
to put words together, to
make a 10 syllable words,
to describe something small
but communication is specific
and have jargon in a specialized
field helps people talk
quickly and communicate more effectively.
So what do patients want
and what do patients need?
Are those the same thing?
Not always, but usually what,
when you get down to it,
they are.
What's the benefit do
they need from a drug
and what's the side effect.
We talked about side
effects, I think Dr. Litvan
talked about side effects
and Dr. Cleveland maybe did as well.
And the side effects are critical
because if it's not
working or making you worse
than you were when you started, then it's
that people are not gonna
appreciate the value.
So why is a patient
advocate worth the problem
where's the trouble.
Each patient has different needs.
Newly diagnosed patients are
assessed and managed by a team
that's when you really can
grab hold of these people
and change their lives.
I think Dr.Litvan would tell you that
a number of stories where
she's had new patients being diagnosed
and depending upon how
they walk out the door,
whether they want to partner with her
or whether they would just wanna run hide,
that has a big impact on
their ultimate health.
The physicians, I can
speak specifically for UCSD
the physicians with the right attitude
and the right training and
the right medicine are there.
The patient has to be ready
and a patient advocate can help up
help deliver that.
Each patient has kind of a subset
of different needs in Parkinson's
patient advocate and patient,
for sure, a neurologist, yes
nurse practitioner,
yes, social worker, yes,
support groups, yes, physical
therapist, yes, exercise.
But also Parkinson's is
one of these diseases
that has a buffet of symptoms
that may require speech therapy
or swallowing testing,
occupational therapy.
Neuro-psychology, neuropsychologist
which Dr. Litvan is
a neurosurgeons which there's
a whole surgical program
for people with Parkinson's
and someone to manage that.
So a patient advocate fits in here by
being the great or the great
product manager of that.
But, I say this as if
patient advocate is a job
that you go apply for at the hospital.
Patient advocate is you for
your spouse or you sibling
or your parents, it's somebody who has
any kind of close relationship
with somebody else.
Going to the doctor alone,
you just shouldn't do it.
You're gonna get so much information
that for one person to try to digest that
and especially if it's troublesome news
that that's very difficult,
it's asking a lot.
But patient care can be game changing
by communicating the details
of what the patient expects
and hopes for.
Beyond the patient,
then advocate can serve
as an individual, it doesn't
have to be just for a relative.
It can be in serving a community.
It can be taking the community,
the Parkinson's communities
goals and needs and
effectively turning them
into social change what involves
perhaps money and funding
educate the pubic when it involves
what the public needs to know
consultant need new therapies.
Again, going back to that
slide that Dr. Litvan had
which is wonderful about
the drug development,
having patient advocates
have their 2 cents
worth at various stages
is a phenomenal benefit
to the (mumbles), the ultimate
patient, as well as the,
the developer of the drug.
In fact, I might steal that from her,
obviously something I'm very proud of
I have a personal interest
in as a board member,
this is a beautiful
building, but also is full of
very smart, very
motivated, very successful
scientists and clinicians.
And we should be very proud
in San Diego that we have
one of five of these institutions
and this one is by far the best one.
So probably there are many
of you in the audience
that don't think yourself
as a patient out here,
but you are, if you
help a spouse or parent
or somebody, family
member deal with an issue
you're a patient advocate.
And that's a good thing,
that's an essential thing
for someone to have a
good medical experience.
So one example then I'll wrap up.
Remember the TV shows back
in the day when TV was new
and a grandmother was in
hospital and they just
discovered that she has lung cancer.
So the doctor and the
children and the husbands
sort of huddle out in the hallway and says
what are you gonna tell her?
What are we gonna tell her?
Oh, well, tell her that
she's got emphysema
and she's gotta go home and rest,
and then she'll just die and never know.
Think about that, I mean,
we actually really used to do that,
which just blows my mind, but I saw,
and actually the handling
of my grandmother
who had Parkinson's just
tell her what you have to
don't tell her everything,
don't tell her that's bad news.
Like bad news is, is the
only, it's only detrimental
and bad news is bad news, but
it also empowers the patient
to be able to deal with
it and deal with it
in a way that's meaningful for them.
That's like the speed version of that,
I've never done it that fast.
I wanna thank again,
thanks to the physicians
and scientists that work in this building,
or they're working at the
Stanford Consortium building
and Torrey Pines.
And if anybody here has any questions
about how their taxpayers
monies are being used, hopefully
let me know, I'd be happy
to talk about that with you,
thank you.
- Thank you so much David, you know,
it's clear that with your own advocacy
at the California Institute
for Regenerative Medicine,
great strides have been
made in terms of developing
new therapies and potentially
new diagnostic techniques
as Dr. Litvan was alluding
to, with a prodromal version
of Parkinson's disease,
the earlier we treat
the better it may be.
And as we heard from Don
Cleveland, DNA is not destiny
because there's designer
DNA in a way that we can use
in for drugs.
So there are a number of questions here.
One of the questions is
I think this is for Don,
when you suppress PTB, is
it cell cycle specific,
for example, what if you were
suppressing PTB in neurons,
as opposed to other cell types.
So is the cell type
and context specificity
of PTB suppression is the question.
- It is not cell type selected,
but within the nervous system
PTB is barely expressed in the neurons.
So suppressing it further
doesn't we think is,
has no effect on the neurons.
The cell type that's most
effected is the astrocyte,
but other cells would also see that.
So far, these are all issues
as you get more sophisticated
that, of course we need
to determine whether
what's the fate of other
cells as PTB is suppressed.
But what we know is that in those animals
with chemically induced
Parkinson's disease,
we got disease reversal.
So there are and I get asked frequently,
don't those astrocytes
do important things.
And so now aren't you going
to deplete the astrocytes
and I'm thinking, well, actually
in one direct experiment,
the answer is no, we didn't
deplete the astrocytes,
whatever, whichever ones
converted told their friends
that they needed to make more astrocytes.
So we, right now we have, we only see
if we've only observed
effects in the astrocytes.
Of course, we need to
look more carefully at
the cells that make the
myelin that coats these axons,
the oligodendrocytes
microglia, but the neurons,
they don't make PTB anyway.
- So then one just short
question for you as well Don.
When would you estimate
design or DNA therapy
will be available for Parkinson's disease?
- Yeah, so those are
really hard to estimate,
but we do know that at the end of 2021,
we'll see the outcome from the first,
the first clinical trial.
We hope that we've been
able to demonstrate that we,
that we can indeed deliver the drug safely
and that we can hit the
target and lower the target.
And the first one will be LRRK2,
and then we can lower alpha-synuclein.
Then then there will be the
big trial, efficacy trial,
which we hope would initiate in 2022.
And that would be the way
these go to two year trial.
So there will be an efficacy
trial in 2020 two-ish I hope.
And I should, but I should
make it absolutely clear
I am not a representative
of Ionis or Biogen or Roche
and so I am not making
predictions for those companies.
I'm a cheerleader for the approach.
And, but I think in
the, you know, 2023, 24
will be the efficacy trial.
The outcome of those will be 2025.
And if we were successful,
that that's the timeframe
that would be required
for an FDA approval.
- Right, well, thanks very much.
One question for Dr. Litvan,
how often do people have
multicopy of the synuclein gene driven,
idiopathic Parkinson'sdisease?
How common is that?
- It's a rare disease.
- It's hyper rare.
- Okay and then that's good to know.
And although there may
be a way to target it
and I'm sure you'll be
doing the clinical trials.
Dr. Litvan.
The final question goes to David Higgins.
Do you have advice on how
to communicate the need
for patient advocate to a patient
who is reluctant to include
one or admit they need help?
- If you have a physician
that is resisting the role
of a patient advocate,
get a new physician.
As, if you need something
like that, let me know.
- Okay, well, I know that
David and Irene and Don
are always available.
They're incredible mentors
for other scientists
and physicians and patient advocates.
And I, you know, we
will be able to respond
to some of your questions via email.
This has been a spectacular
first WebEx first Closer Look,
and you can see we worked
very closely together.
We all get along rather well
because we're pretty excited
about what we're doing,
and we really appreciate
you joining us for this
special Closer Look
on Parkinson's disease, thanks again.
(soft music)
