This week on BioTech Nation, Dr. Cory Nicholas, Co-Founder and CEO of Neurona Therapeutics, discusses their groundbreaking success in treating drug-resistant epilepsy. With a single, targeted delivery of lab-grown brain cells, Neurona is offering not just symptom control but the possibility of long-term seizure relief. This is Part 1 of a two-part series exploring the future of regenerative medicine in neurology.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Dr. Moira Gunn (00:11):
We're talking about an experience of success
in science and biotech that wedon't often see. Usually, we're
hoping for a little betterquality of life or precious
time, even a little more time inextending a life or stopping the
progression of a medicalcondition for some relatively
(00:32):
short period of time. But today,we're talking about something
that has all the earmarks of agreat leap forward, both for
science and for biotech. I'll bespeaking with doctor Cory
Nicholas, the cofounder and CEOof Neurona Therapeutics. And
without stepping on Neurona'sgood news, let me just say that
(00:56):
they've essentially been workingon delivering to the brain
something essential it lacks,and they've been working on it
for over two decades.
In their very first treatment,they focused on the most common
type of epilepsy, temporal lobeepilepsy. While epilepsy in
general is a condition shared bysome three million Americans and
(01:20):
fifty million more worldwide,Neurona's potential is not
limited to temporal lobeepilepsy or even epilepsy alone.
There are many disorders of thenervous system, and epilepsy is
just one. Neurona's techniquemay also have potential for
other neuropsychiatricdisorders, including Alzheimer's
(01:42):
and dementia, Parkinson's, andeven brain trauma and PTSD. But
all that is looking ahead.
What we have today is clearprogress for the underlying
science and a durable two yearsuccess for Neurona's first one
and done therapy. We'll talkabout exactly where Neurona is
(02:05):
in its bio entrepreneurshipjourney, which started on that
long ago lab bench to this placetoday where it may actually be
able to help millions of peoplelive lives they simply didn't
think possible. And now, Doctor.Cory Nicholas. Doctor.
Nicholas, welcome back toBiotech Nation.
Dr. Cory Nicholas (02:26):
Thank you, Moira.
Dr. Moira Gunn (02:28):
Now we have some really good news to report in
Neurona's quest to developeffective treatments for
epilepsy. But before we get tothat, let's give everyone a view
of what the experience ofepilepsy is like for people who
have this condition and thetreatments currently available
to them.
Dr. Cory Nicholas (02:47):
Well, epilepsy is a huge unmet need
and I think most people don'trealize the severe quality of
life issue that it poses.Epilepsy affects three million
people in The United States Anddespite there being over three
dozen medications for seizures,most adults with epilepsy
(03:11):
continue to have seizures. Andit's thought that an estimated
one third to one half of peopleliving with epilepsy have their
seizures, poorly controlled bythe current medications on the
market. And so unfortunately,for about a third to a half of
the population with epilepsy,the current medications just
(03:33):
aren't good enough to controltheir seizures and to allow,
folks living with this, disorderto, do the things they want in
life. And so for this reason,you know, there's a definite
need for alternative therapies.
Dr. Moira Gunn (03:48):
Now, we certainly can say that the
seizures themselves will stopyou from doing a lot of things.
You don't want to be out andabout or driving a car or
anything like flying a plane andsuddenly have a seizure. But the
medications, any of us who takemedications, are subject to side
effects.
Dr. Cory Nicholas (04:06):
Right, and many of these medications work
by reducing activity in thebrain. And so a common adverse
effect of the anti seizuremedications is somnolence or
sedation fatigue. And a lot ofthese can be can be troubling.
And a lot of the medications canalso affect, as you as you said,
cognitive function and can,impair memory. And so,
(04:30):
absolutely.
And and many times one drug isnot enough. And so a lot of the
patients that we see are comingin on a polypharmacy cocktail of
multiple medications, and eachof them have their own
contraindications and are not sowell easily combined with one
another. And so a lot of thecombinatory effects aren't
known. And so this is a definiteconcern and risk.
Dr. Moira Gunn (04:54):
So what do you do if the current medications
don't work?
Dr. Cory Nicholas (04:57):
So people who are drug refractory, meaning
that, you know, they're notresponding to at least two or
three of the anti seizuremedications on the market, and
oftentimes they've tried manymore than that. And at this
point, if folks have access to,health care, which of course is,
not a given in our, challenginghealth care environment, then
(05:22):
people would be referred to aneurologist and then on to a
comprehensive epilepsy center.And these are accredited
epilepsy centers, that arecalled, the National Academy of
Epilepsy Centers, and they havelevels to them. And so level
three and level four are the topcenters. And there's about two
(05:43):
fifty of these centers acrossThe United States where if
people aren't responding tomedications, that's ideally
where they should go to seekadditional care.
And now at these centers,patients will be evaluated, for
the nature of their seizures andthe location, in the brain at
(06:04):
where they start and how theyspread. And this is done using
the latest state of the artimaging and EEG technologies.
And unfortunately for about athird of people that undergo
these, monitoring, workup tests,they find that the seizures
can't be pinpointed to aparticular place in the brain.
(06:24):
And at this point, many peoplehave no other options. Now for
two thirds of people, generallyspeaking, they can find a point
in the brain where the seizuresstart.
And these are what's calledfocal onset epilepsy. Most times
they start in the temporal lobeof the brain, but there are many
(06:44):
others that start in other lobesof the brain. And if they can
pinpoint an epicenter forseizure onset, then some of
those folks can be eligible fora surgical procedure to either
remove that part of the brain orto destroy it with a laser. And
in well selected people, thiscan potentially be a good
(07:06):
option, but it does, due to thedestructiveness of those
surgeries, it does carry a riskof impaired brain function. And
most notable in the temporallobe is memory loss.
And this can be irreversible oncognitive function. And so for
some, it's not a good option,especially, you know, folks that
(07:31):
are younger that have, you know,their lives ahead of them,
ambitious life goals. That thatjust some, you know, it's not a
good option, for for thoseindividuals. You know, and and
for others, they're just simplynot eligible because of this
risk. And, the surgeons don'twant to touch areas of the brain
that are, quote, unquote,eloquent, areas of the brain.
(07:55):
And so the, and and for all,it's a very scary prospect,
obviously, to go in to have apart of the brain removed or
destroyed, and to potentiallycome out of the operating room
as, you know, a different personin in a way. Now for some, it
can be a good option. And sothey should be evaluated and,
(08:15):
you know, these options shouldbe thoroughly discussed. In some
cases, you know, going in soonerrather than later is highly
advised by epilepsy physicians,because the sooner you can get
evaluated, if you are a goodcandidate, to have the seizures
dealt with before the repeatedseizures can damage the brain as
well. And so you wanna get thatevaluated by, you know, a
(08:39):
neurologist and a neurosurgeonand an epilepsy center as soon
as possible.
But the point is here is thatthe current surgical options are
still, largely suboptimal,because they pose a risk of
irreversible, impairment forsome people that go through with
them. And so this is why whatwe're doing at, Neurona has so
(09:03):
much potential in that, youknow, we're developing a cell
therapy that could possibly,restore function to this part of
the brain, and and repair thatpart of the brain in a
nondestructive manner,potentially regenerative manner,
and in this way preservingcognitive function and hopefully
(09:24):
taking care of the seizures.
Dr. Moira Gunn (09:26):
Now from your last visit to biotechnician,
Doctor. Nicholas, you remindedus that we had billions of nerve
cells throughout our bodies andthat we had even more
neurotransmitters communicatingbetween all these nerve cells
operating all the time even aswe speak. And some are excitable
neurotransmitters as in getexcited, and some are inhibitory
(09:49):
as in calm down. Remind us aboutwhat neurotransmitters do,
especially in the brain, andwhat do they have to do with
epilepsy?
Dr. Cory Nicholas (09:58):
So brain cells come in a couple of main
flavors. The first are glialsupport cells and the other are
the, neurons, or neuronal cells,which the, the neuronal cells
are the cells that conductelectricity through the nervous
system. And the neurons connectto one another through synaptic
(10:21):
connections. And in thosesynaptic connections, there are
these little chemical messagescalled neurotransmitters, which
communicate from one neuron tothe next and propagate that
electrical impulse through thecircuitry. And so most of the
neurotransmitters and theneurons in the brain that are
secreting theseneurotransmitters have an
(10:43):
excitatory role in that oneneuron communicates to the next
and excites the next, whichexcites the next.
And this is which whatpropagates electricity and and,
you know, signals through thethe nervous system. And this
excitatory neurotransmitter, thethe predominant one in the, in
the forebrain is calledglutamate. Now what a lot of
(11:06):
folks don't know is that, andthat's the majority of of the
neurons in in the brain. Butwhat's not understood is that
there's a minor population ofneurons representing about 30%
of the neurons in the brain thatare inhibitory. And these
neurons secrete the keyinhibitory neurotransmitter
(11:27):
that's called GABA, which standsfor gamma aminobutyric acid.
And its role is to inhibit theother cells from firing. And so
it's a very delicate balancebetween the inhibitory cells and
the excitatory cells that allowsour brain and our neural
networks to function in a normalstate. And there's this optimal
(11:49):
set point of activity that'svery important to maintain, in
order to have a healthyfunctioning nervous system. And
what can happen in epilepsy andin other diseases is that these
two, signals can becomeimbalanced And you can have too
much of the glutamate, too muchof the activity, and not enough
(12:13):
of the GABA, which leads to thishyperexcitable imbalanced state
that is essentially thedefinition of an epileptic
seizure.
Dr. Moira Gunn (12:23):
I'm speaking with Doctor. Corey Nicholas, the
co founder and CEO of NeuronaTherapeutics, a former member of
the faculty and postdoc in thedepartment of neurology at UC
San Francisco, his research workin part evaluated the
therapeutic potential ofinterneuron cell therapy in
(12:44):
neurological disease. Now Iremember you telling us before
that you are born with all theinhibitory brain cells for life.
They're created pre birth.
Dr. Cory Nicholas (12:59):
Yes. And that's true for most of the
neurons in our brains is thatthey are generated during the
peak period of neurogenesisbefore birth in utero in the
second and third trimester. Andas far as we know, for most of
the neurons in our brains, thereis no stem cell after birth in
(13:20):
our adult brains that canreplenish aging or dying
neurons, either through aging orthrough different types of
traumas from the environment orfrom genetic predisposition. And
this is why disorders of thenervous system are so, so
difficult to treat.
Dr. Moira Gunn (13:40):
Now let me ask you this before we get on to
Neurona's big idea, and that isthat we can certainly observe
epileptic seizures, but can wedo we actually have a test to
ensure that's what we're lookingat? Do we have a technology or a
set of technologies to tell us?
Dr. Cory Nicholas (14:00):
Yes. So seizures come in different
flavors as well, and it dependson where the seizure starts and
how it spreads through thenetwork. Epilepsy is truly a
neural network disease. Anddepending on where in the brain
that electrical hyperactivity isoccurring, it can have different
(14:21):
physical manifestations onbehavior. And seizures can
start, and by the way, areusually not predictable.
In other words, they'respontaneous, They can strike at
any moment, and this is why theycan be so scary. And oftentimes,
they start as a an aura or ahyperintense feeling of euphoria
(14:44):
or confusion. And this can thenevolve as the electrical
activity starts to spread aroundthe brain into more disabling
phenotypic manifestations suchas twitching of the hands or lip
smacking, impairment of vision.These can then evolve further
(15:08):
into complete loss ofconsciousness events where
someone can freeze for quite along period, and this can result
in crashing a car or, you know,walking into the street. And
then of course, as the seizureengages both sides of the brain
more fully, this can result intothe most severe type of seizure,
(15:29):
which is, the grand mal atoniccolonic seizure, which often
involves, you know, fullconvulsing and, falling to the
ground.
And, you know, these, seizuresoftentimes, you know, people
think that, if you're onlyhaving, you know, one seizure
every month or one seizure ayear, it's not a big deal. Well,
(15:49):
it is a huge deal because youhave just one or two of these in
a year or ever in life, and thatcan damage the brain from a
single event. It often sets thebrain up for future events that
can strike. And so it's verycommon for people with epilepsy
to have had their first seizureduring childhood, oftentimes
(16:10):
after a fever called a febrileseizure, and then not have a
seizure for decades. And thensuddenly later in life start to
have spontaneous, chronicrecurrent seizures, to then be
formally diagnosed with epilepsylater in life.
And so just having a singlesevere seizure can be very, just
(16:33):
devastating. And not to mentionthat, you know, a seizure can
can result in a in a fall andcan result in having to go to
the ER. Burns are very common.And then, of course, there's
always a risk of SUDEP, whichstands for sudden unexpected
(16:53):
death from epilepsy. And that isobviously just not acceptable.
The thing about epilepsy that isso hard is that you never know
when a seizure's gonna strike,as I said, but you also never
know when it's gonna spread. Andso these can strike and stay
mild and never evolve, but theycan also continue to spread
(17:17):
around the brain and evolve intoa very serious event.
Dr. Moira Gunn (17:23):
So in one sense, they they create damage and
extensive damage go onthemselves.
Dr. Cory Nicholas (17:28):
That's exactly right. And it's thought
that the more seizures you have,the easier it is to hit that
threshold where the brain cancontinue to cease. And so it can
be very progressive in this way.
Dr. Moira Gunn (17:40):
Okay, so what was Neurona's big idea?
Dr. Cory Nicholas (17:42):
Well, our idea at Neurona was to develop a
regenerative cell therapy thatcould provide balance to the
brain in a nondestructive way.And so rather than the current
surgical paradigm of having theseizure prone part or parts of
(18:03):
the brain removed or ablatedwith a laser, we wanted to put
the missing cells and themissing inhibitory tone back
into those parts of the brain.And so to regenerate the cells
that are missing and to thendeliver that cell material
(18:23):
precisely where it is where itbelongs and to in this way
regenerate and restore andrepair the nervous system.
Dr. Moira Gunn (18:32):
So you're talking about those GABA cells,
the the the GABA inhibitoryneurotransmitters. You're saying
if we can put those in, the onesthat say calm down in a
sufficient balance, so itbalances the excitability
transmitters, then you'reactually you can stay in balance
(18:55):
and avoid the seizures.
Dr. Cory Nicholas (18:56):
That's precisely right. And so we are
delivering neurons that arethose inhibitory, GABA secreting
neurons, and these are calledinterneurons. And we're putting
these neurons, precisely at thisepicenter of where seizures
start and allowing these cellsto bring that GABA inhibitory
(19:21):
signal that's been missing inthis part of the brain and to
reconstitute that using thiscell therapy approach so that we
can re achieve that balance andthat set point and quiet the
seizure storm.
Dr. Moira Gunn (19:35):
Now two questions here. First of all,
how do we get these GABA cellsand do I need my own? And the
second question, I realized Iasked two questions there, but
the second question is how doyou get them into my brain?
Dr. Cory Nicholas (19:51):
Right. So there are a couple of different
approaches for accomplishingthis goal. One is to use stem
cells that are patient specific,but the other is to use stem
cells that are what's called offthe shelf or one cell line for
all recipients. We've chosen thelatter path so that it's an off
(20:14):
the shelf therapy, meaning thatthe cells are ready on demand.
They don't have to bemanufactured separately for each
person.
And because of that, they are,the therapy is actually frozen
and it's ready when patientsenter our studies. And it's
(20:36):
suitable for all essentially.There is no matching
immunologically or conditioning.We do give a short course of
what's called immunosuppressionin the early phase of the
therapy to facilitate long termsurvival of the cells because we
do intend for this to be a oneand done procedure. So we think,
(21:00):
and to the best of our abilityin all of the preclinical
testing that we've done, thatone administration of this
procedure will be sufficient,hopefully for a lifetime, and
that these cells are intendedto, migrate into that neural
network in the brain and becomepart of that network, and they
make those synaptic connections.
(21:21):
And once they do that, we thinkthat they will be a permanent
resident and that they will be,you know, part of the brain in
the recipient, for for alifetime. And so the cells are
delivered in an image guidedprocedure. And so I mentioned
earlier that when patients cometo a comprehensive NAEC,
(21:42):
National Academy of EpilepsyCenter, for a workup, EEG and
MRI imaging are performed. Thisis where the surgeon and the
neurologist can triangulate theseizure onset zone good
candidates for this type oftherapy. And so they can see by
(22:02):
MRI and are some other imagingmodalities such as PET and or by
EEG as to where the seizures arestarting.
And it gives them a target forwhere to put the cells. And then
the cells are then the thefrozen product, which contains
(22:25):
these inhibitory cells, is,thawed and then it's, loaded
into a MRI compatible, cannulaor needle essentially. And then
that is carefully guided usingintraoperative MRI or CT into
the part of the brain where theseizures are coming from. And
(22:46):
then these cells are carefullyand slowly infused into that
part of the brain. And theinfusion process takes one to
two hours depending on the dosewe're using.
And so it's a relatively it's avery small volume, but it's
infused at a very slow andcareful rate. And then the
delivery cannula is removed andthe patients have all come out
(23:12):
of the procedure just fine. Thenthey stay overnight in the
hospital for observation. But tomy knowledge, everybody has gone
home the next day and, has beendoing very well.
Dr. Moira Gunn (23:26):
You've just listened to part one of a two
part interview with doctor CoryNicholas, the cofounder and CEO
of Neurona Therapeutics. In parttwo, we will hear about the
unprecedented interim results ofthis important phase onetwo
study. More information aboutNeurona Therapeutics is
(23:47):
available on the web atneuronatx.com. That's Neurona, n
e u r o n a, neurona t x dotcom.
We're talking about an experience of success
in science and biotech that wedon't often see. Usually, we're
hoping for a little betterquality of life or precious
time, even a little more time inextending a life or stopping the
progression of a medicalcondition for some relatively
(00:32):
short period of time. But today,we're talking about something
that has all the earmarks of agreat leap forward, both for
science and for biotech. I'll bespeaking with doctor Cory
Nicholas, the cofounder and CEOof Neurona Therapeutics. And
without stepping on Neurona'sgood news, let me just say that
(00:56):
they've essentially been workingon delivering to the brain
something essential it lacks,and they've been working on it
for over two decades.
In their very first treatment,they focused on the most common
type of epilepsy, temporal lobeepilepsy. While epilepsy in
general is a condition shared bysome three million Americans and
(01:20):
fifty million more worldwide,Neurona's potential is not
limited to temporal lobeepilepsy or even epilepsy alone.
There are many disorders of thenervous system, and epilepsy is
just one. Neurona's techniquemay also have potential for
other neuropsychiatricdisorders, including Alzheimer's
(01:42):
and dementia, Parkinson's, andeven brain trauma and PTSD. But
all that is looking ahead.
What we have today is clearprogress for the underlying
science and a durable two yearsuccess for Neurona's first one
and done therapy. We'll talkabout exactly where Neurona is
(02:05):
in its bio entrepreneurshipjourney, which started on that
long ago lab bench to this placetoday where it may actually be
able to help millions of peoplelive lives they simply didn't
think possible. And now, Doctor.Cory Nicholas. Doctor.
Nicholas, welcome back toBiotech Nation.
Dr. Cory Nicholas (02:26):
Thank you, Moira.
Dr. Moira Gunn (02:28):
Now we have some really good news to report in
Neurona's quest to developeffective treatments for
epilepsy. But before we get tothat, let's give everyone a view
of what the experience ofepilepsy is like for people who
have this condition and thetreatments currently available
to them.
Dr. Cory Nicholas (02:47):
Well, epilepsy is a huge unmet need
and I think most people don'trealize the severe quality of
life issue that it poses.Epilepsy affects three million
people in The United States Anddespite there being over three
dozen medications for seizures,most adults with epilepsy
(03:11):
continue to have seizures. Andit's thought that an estimated
one third to one half of peopleliving with epilepsy have their
seizures, poorly controlled bythe current medications on the
market. And so unfortunately,for about a third to a half of
the population with epilepsy,the current medications just
(03:33):
aren't good enough to controltheir seizures and to allow,
folks living with this, disorderto, do the things they want in
life. And so for this reason,you know, there's a definite
need for alternative therapies.
Dr. Moira Gunn (03:48):
Now, we certainly can say that the
seizures themselves will stopyou from doing a lot of things.
You don't want to be out andabout or driving a car or
anything like flying a plane andsuddenly have a seizure. But the
medications, any of us who takemedications, are subject to side
effects.
Dr. Cory Nicholas (04:06):
Right, and many of these medications work
by reducing activity in thebrain. And so a common adverse
effect of the anti seizuremedications is somnolence or
sedation fatigue. And a lot ofthese can be can be troubling.
And a lot of the medications canalso affect, as you as you said,
cognitive function and can,impair memory. And so,
(04:30):
absolutely.
And and many times one drug isnot enough. And so a lot of the
patients that we see are comingin on a polypharmacy cocktail of
multiple medications, and eachof them have their own
contraindications and are not sowell easily combined with one
another. And so a lot of thecombinatory effects aren't
known. And so this is a definiteconcern and risk.
Dr. Moira Gunn (04:54):
So what do you do if the current medications
don't work?
Dr. Cory Nicholas (04:57):
So people who are drug refractory, meaning
that, you know, they're notresponding to at least two or
three of the anti seizuremedications on the market, and
oftentimes they've tried manymore than that. And at this
point, if folks have access to,health care, which of course is,
not a given in our, challenginghealth care environment, then
(05:22):
people would be referred to aneurologist and then on to a
comprehensive epilepsy center.And these are accredited
epilepsy centers, that arecalled, the National Academy of
Epilepsy Centers, and they havelevels to them. And so level
three and level four are the topcenters. And there's about two
(05:43):
fifty of these centers acrossThe United States where if
people aren't responding tomedications, that's ideally
where they should go to seekadditional care.
And now at these centers,patients will be evaluated, for
the nature of their seizures andthe location, in the brain at
(06:04):
where they start and how theyspread. And this is done using
the latest state of the artimaging and EEG technologies.
And unfortunately for about athird of people that undergo
these, monitoring, workup tests,they find that the seizures
can't be pinpointed to aparticular place in the brain.
(06:24):
And at this point, many peoplehave no other options. Now for
two thirds of people, generallyspeaking, they can find a point
in the brain where the seizuresstart.
And these are what's calledfocal onset epilepsy. Most times
they start in the temporal lobeof the brain, but there are many
(06:44):
others that start in other lobesof the brain. And if they can
pinpoint an epicenter forseizure onset, then some of
those folks can be eligible fora surgical procedure to either
remove that part of the brain orto destroy it with a laser. And
in well selected people, thiscan potentially be a good
(07:06):
option, but it does, due to thedestructiveness of those
surgeries, it does carry a riskof impaired brain function. And
most notable in the temporallobe is memory loss.
And this can be irreversible oncognitive function. And so for
some, it's not a good option,especially, you know, folks that
(07:31):
are younger that have, you know,their lives ahead of them,
ambitious life goals. That thatjust some, you know, it's not a
good option, for for thoseindividuals. You know, and and
for others, they're just simplynot eligible because of this
risk. And, the surgeons don'twant to touch areas of the brain
that are, quote, unquote,eloquent, areas of the brain.
(07:55):
And so the, and and for all,it's a very scary prospect,
obviously, to go in to have apart of the brain removed or
destroyed, and to potentiallycome out of the operating room
as, you know, a different personin in a way. Now for some, it
can be a good option. And sothey should be evaluated and,
(08:15):
you know, these options shouldbe thoroughly discussed. In some
cases, you know, going in soonerrather than later is highly
advised by epilepsy physicians,because the sooner you can get
evaluated, if you are a goodcandidate, to have the seizures
dealt with before the repeatedseizures can damage the brain as
well. And so you wanna get thatevaluated by, you know, a
(08:39):
neurologist and a neurosurgeonand an epilepsy center as soon
as possible.
But the point is here is thatthe current surgical options are
still, largely suboptimal,because they pose a risk of
irreversible, impairment forsome people that go through with
them. And so this is why whatwe're doing at, Neurona has so
(09:03):
much potential in that, youknow, we're developing a cell
therapy that could possibly,restore function to this part of
the brain, and and repair thatpart of the brain in a
nondestructive manner,potentially regenerative manner,
and in this way preservingcognitive function and hopefully
(09:24):
taking care of the seizures.
Dr. Moira Gunn (09:26):
Now from your last visit to biotechnician,
Doctor. Nicholas, you remindedus that we had billions of nerve
cells throughout our bodies andthat we had even more
neurotransmitters communicatingbetween all these nerve cells
operating all the time even aswe speak. And some are excitable
neurotransmitters as in getexcited, and some are inhibitory
(09:49):
as in calm down. Remind us aboutwhat neurotransmitters do,
especially in the brain, andwhat do they have to do with
epilepsy?
Dr. Cory Nicholas (09:58):
So brain cells come in a couple of main
flavors. The first are glialsupport cells and the other are
the, neurons, or neuronal cells,which the, the neuronal cells
are the cells that conductelectricity through the nervous
system. And the neurons connectto one another through synaptic
(10:21):
connections. And in thosesynaptic connections, there are
these little chemical messagescalled neurotransmitters, which
communicate from one neuron tothe next and propagate that
electrical impulse through thecircuitry. And so most of the
neurotransmitters and theneurons in the brain that are
secreting theseneurotransmitters have an
(10:43):
excitatory role in that oneneuron communicates to the next
and excites the next, whichexcites the next.
And this is which whatpropagates electricity and and,
you know, signals through thethe nervous system. And this
excitatory neurotransmitter, thethe predominant one in the, in
the forebrain is calledglutamate. Now what a lot of
(11:06):
folks don't know is that, andthat's the majority of of the
neurons in in the brain. Butwhat's not understood is that
there's a minor population ofneurons representing about 30%
of the neurons in the brain thatare inhibitory. And these
neurons secrete the keyinhibitory neurotransmitter
(11:27):
that's called GABA, which standsfor gamma aminobutyric acid.
And its role is to inhibit theother cells from firing. And so
it's a very delicate balancebetween the inhibitory cells and
the excitatory cells that allowsour brain and our neural
networks to function in a normalstate. And there's this optimal
(11:49):
set point of activity that'svery important to maintain, in
order to have a healthyfunctioning nervous system. And
what can happen in epilepsy andin other diseases is that these
two, signals can becomeimbalanced And you can have too
much of the glutamate, too muchof the activity, and not enough
(12:13):
of the GABA, which leads to thishyperexcitable imbalanced state
that is essentially thedefinition of an epileptic
seizure.
Dr. Moira Gunn (12:23):
I'm speaking with Doctor. Corey Nicholas, the
co founder and CEO of NeuronaTherapeutics, a former member of
the faculty and postdoc in thedepartment of neurology at UC
San Francisco, his research workin part evaluated the
therapeutic potential ofinterneuron cell therapy in
(12:44):
neurological disease. Now Iremember you telling us before
that you are born with all theinhibitory brain cells for life.
They're created pre birth.
Dr. Cory Nicholas (12:59):
Yes. And that's true for most of the
neurons in our brains is thatthey are generated during the
peak period of neurogenesisbefore birth in utero in the
second and third trimester. Andas far as we know, for most of
the neurons in our brains, thereis no stem cell after birth in
(13:20):
our adult brains that canreplenish aging or dying
neurons, either through aging orthrough different types of
traumas from the environment orfrom genetic predisposition. And
this is why disorders of thenervous system are so, so
difficult to treat.
Dr. Moira Gunn (13:40):
Now let me ask you this before we get on to
Neurona's big idea, and that isthat we can certainly observe
epileptic seizures, but can wedo we actually have a test to
ensure that's what we're lookingat? Do we have a technology or a
set of technologies to tell us?
Dr. Cory Nicholas (14:00):
Yes. So seizures come in different
flavors as well, and it dependson where the seizure starts and
how it spreads through thenetwork. Epilepsy is truly a
neural network disease. Anddepending on where in the brain
that electrical hyperactivity isoccurring, it can have different
(14:21):
physical manifestations onbehavior. And seizures can
start, and by the way, areusually not predictable.
In other words, they'respontaneous, They can strike at
any moment, and this is why theycan be so scary. And oftentimes,
they start as a an aura or ahyperintense feeling of euphoria
(14:44):
or confusion. And this can thenevolve as the electrical
activity starts to spread aroundthe brain into more disabling
phenotypic manifestations suchas twitching of the hands or lip
smacking, impairment of vision.These can then evolve further
(15:08):
into complete loss ofconsciousness events where
someone can freeze for quite along period, and this can result
in crashing a car or, you know,walking into the street. And
then of course, as the seizureengages both sides of the brain
more fully, this can result intothe most severe type of seizure,
(15:29):
which is, the grand mal atoniccolonic seizure, which often
involves, you know, fullconvulsing and, falling to the
ground.
And, you know, these, seizuresoftentimes, you know, people
think that, if you're onlyhaving, you know, one seizure
every month or one seizure ayear, it's not a big deal. Well,
(15:49):
it is a huge deal because youhave just one or two of these in
a year or ever in life, and thatcan damage the brain from a
single event. It often sets thebrain up for future events that
can strike. And so it's verycommon for people with epilepsy
to have had their first seizureduring childhood, oftentimes
(16:10):
after a fever called a febrileseizure, and then not have a
seizure for decades. And thensuddenly later in life start to
have spontaneous, chronicrecurrent seizures, to then be
formally diagnosed with epilepsylater in life.
And so just having a singlesevere seizure can be very, just
(16:33):
devastating. And not to mentionthat, you know, a seizure can
can result in a in a fall andcan result in having to go to
the ER. Burns are very common.And then, of course, there's
always a risk of SUDEP, whichstands for sudden unexpected
(16:53):
death from epilepsy. And that isobviously just not acceptable.
The thing about epilepsy that isso hard is that you never know
when a seizure's gonna strike,as I said, but you also never
know when it's gonna spread. Andso these can strike and stay
mild and never evolve, but theycan also continue to spread
(17:17):
around the brain and evolve intoa very serious event.
Dr. Moira Gunn (17:23):
So in one sense, they they create damage and
extensive damage go onthemselves.
Dr. Cory Nicholas (17:28):
That's exactly right. And it's thought
that the more seizures you have,the easier it is to hit that
threshold where the brain cancontinue to cease. And so it can
be very progressive in this way.
Dr. Moira Gunn (17:40):
Okay, so what was Neurona's big idea?
Dr. Cory Nicholas (17:42):
Well, our idea at Neurona was to develop a
regenerative cell therapy thatcould provide balance to the
brain in a nondestructive way.And so rather than the current
surgical paradigm of having theseizure prone part or parts of
(18:03):
the brain removed or ablatedwith a laser, we wanted to put
the missing cells and themissing inhibitory tone back
into those parts of the brain.And so to regenerate the cells
that are missing and to thendeliver that cell material
(18:23):
precisely where it is where itbelongs and to in this way
regenerate and restore andrepair the nervous system.
Dr. Moira Gunn (18:32):
So you're talking about those GABA cells,
the the the GABA inhibitoryneurotransmitters. You're saying
if we can put those in, the onesthat say calm down in a
sufficient balance, so itbalances the excitability
transmitters, then you'reactually you can stay in balance
(18:55):
and avoid the seizures.
Dr. Cory Nicholas (18:56):
That's precisely right. And so we are
delivering neurons that arethose inhibitory, GABA secreting
neurons, and these are calledinterneurons. And we're putting
these neurons, precisely at thisepicenter of where seizures
start and allowing these cellsto bring that GABA inhibitory
(19:21):
signal that's been missing inthis part of the brain and to
reconstitute that using thiscell therapy approach so that we
can re achieve that balance andthat set point and quiet the
seizure storm.
Dr. Moira Gunn (19:35):
Now two questions here. First of all,
how do we get these GABA cellsand do I need my own? And the
second question, I realized Iasked two questions there, but
the second question is how doyou get them into my brain?
Dr. Cory Nicholas (19:51):
Right. So there are a couple of different
approaches for accomplishingthis goal. One is to use stem
cells that are patient specific,but the other is to use stem
cells that are what's called offthe shelf or one cell line for
all recipients. We've chosen thelatter path so that it's an off
(20:14):
the shelf therapy, meaning thatthe cells are ready on demand.
They don't have to bemanufactured separately for each
person.
And because of that, they are,the therapy is actually frozen
and it's ready when patientsenter our studies. And it's
(20:36):
suitable for all essentially.There is no matching
immunologically or conditioning.We do give a short course of
what's called immunosuppressionin the early phase of the
therapy to facilitate long termsurvival of the cells because we
do intend for this to be a oneand done procedure. So we think,
(21:00):
and to the best of our abilityin all of the preclinical
testing that we've done, thatone administration of this
procedure will be sufficient,hopefully for a lifetime, and
that these cells are intendedto, migrate into that neural
network in the brain and becomepart of that network, and they
make those synaptic connections.
(21:21):
And once they do that, we thinkthat they will be a permanent
resident and that they will be,you know, part of the brain in
the recipient, for for alifetime. And so the cells are
delivered in an image guidedprocedure. And so I mentioned
earlier that when patients cometo a comprehensive NAEC,
(21:42):
National Academy of EpilepsyCenter, for a workup, EEG and
MRI imaging are performed. Thisis where the surgeon and the
neurologist can triangulate theseizure onset zone good
candidates for this type oftherapy. And so they can see by
(22:02):
MRI and are some other imagingmodalities such as PET and or by
EEG as to where the seizures arestarting.
And it gives them a target forwhere to put the cells. And then
the cells are then the thefrozen product, which contains
(22:25):
these inhibitory cells, is,thawed and then it's, loaded
into a MRI compatible, cannulaor needle essentially. And then
that is carefully guided usingintraoperative MRI or CT into
the part of the brain where theseizures are coming from. And
(22:46):
then these cells are carefullyand slowly infused into that
part of the brain. And theinfusion process takes one to
two hours depending on the dosewe're using.
And so it's a relatively it's avery small volume, but it's
infused at a very slow andcareful rate. And then the
delivery cannula is removed andthe patients have all come out
(23:12):
of the procedure just fine. Thenthey stay overnight in the
hospital for observation. But tomy knowledge, everybody has gone
home the next day and, has beendoing very well.
Dr. Moira Gunn (23:26):
You've just listened to part one of a two
part interview with doctor CoryNicholas, the cofounder and CEO
of Neurona Therapeutics. In parttwo, we will hear about the
unprecedented interim results ofthis important phase onetwo
study. More information aboutNeurona Therapeutics is
(23:47):
available on the web atneuronatx.com. That's Neurona, n
e u r o n a, neurona t x dotcom.
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