November 20, 2024 • 25 mins
This week on BioTech Nation, Dr. Peter Vanderklish, Chief Scientific Officer at Spinogenix discusses their clinical trials focused on regenerating synapses to repair brain connections and offer hope for conditions like Alzheimer's, ALS, schizophrenia and depression. Phase 2 trials are underway. Check their website for patient recruitment information.
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Dr. Moira Gunn (00:11):
It's your brain. We all pretty much know that
over time, we lose synapses.Depending on where you lose
them, it could lead to suchconditions as depression,
schizophrenia, Alzheimer's, orALS. Doctor Peter Vanderklish
from Spinogenix talks abouttheir advanced human trials in
(00:33):
synaptic generation. DoctorVanderklish, welcome to the
program.
Dr. Peter Vanderklish (00:37):
Thanks for having me.
Dr. Moira Gunn (00:38):
Now there's a whole range of medical
conditions that we are allfamiliar with and they have to
do with the loss of synapses inthe brain. That could be
depression, schizophrenia,Alzheimer's, ALS. So let me
start there. Give us a pictureof our healthy brains. What are
(00:59):
synapses?
What do they do? And how many doI have in my brain or your brain
or any brain?
Dr. Peter Vanderklish (01:06):
Well, synapses are physical
connections between neurons thatallow them to communicate with
each other. And so every neuronhas, you know, potentially
thousands of synapses and cansort of link up with many other
neurons by virtue of having thatmany contacts with other
neurons. So neurons link up intolarge networks of neurons and
(01:28):
it's a synaptic communicationbetween them that allows them to
do things like informationprocessing. So synapses are
really, an indispensable elementof yours your nervous system and
are involved in everything youdo, everything you you think,
everything you perceive,everything you say you do. And,
of course, they're involved inmemory formation, which is
perhaps, maybe, the mostimportant faculty of mine become
(01:51):
over a lifetime, together.
Dr. Moira Gunn (01:54):
Now how many do I have? You like it how it's all
about me? Yeah.
Dr. Peter Vanderklish (01:58):
Yeah. Well, you have a lot. I can
sense
Dr. Moira Gunn (02:00):
How many does the listener have?
Dr. Peter Vanderklish (02:03):
So on average, the, you know, the
human brand is about85,000,000,000 neurons. And
estimates of the number ofsynapses that you have range
from about a 150,000,000,000,000all the way up to, you know,
pushing up towards 1quadrillion. So that's an
enormous number. To give you asense of that that number, I I
actually want to refer back to apassage from a book my, my
(02:26):
postdoctoral mentor, the lateGerald Edelman wrote, where he
he tried to relate, you know,the sort of the size or the the
complexity of the number ofsynapses. And he said he had a
great quote in there, which was,if you were to start counting
each synapse 1 by 1 everysecond, it would take you
32000000 years before youfinished.
(02:47):
Now if you then went on toactually calculate how many
different ways those varioussynapses could be activated, the
it becomes what he called hyperastronomical. So the number of
potential combinations of activesynapses that you can have in
your brain is 10 followed by1,000,000 of zeros. And to give
you some perspective, theestimate of the number of atoms
(03:11):
in the known universe is about10 followed by 80 2zeros. So the
complexity embedded within yourbrain in terms of the number of
synapses and how they can beactive, and that says nothing
about sequences of activationwhich would project beyond all
balance is hyper astronomical.
Dr. Moira Gunn (03:28):
And pretty darn complex.
Dr. Peter Vanderklish (03:30):
Yes.
Dr. Moira Gunn (03:30):
I'll take that for sure. No one is gonna argue
with me about that. Now from thetime you were born to throughout
your life to the time you age,if you have a healthy brain, how
does that change?
Dr. Peter Vanderklish (03:43):
Well, that's that's a great question.
So, you know, I'm gonna paint alittle picture for you. So early
on in your life, you havebelieve it or not, you have too
many synapses. So in early braindevelopment, you have this
explosion of synaptogenesis thatcreates, you know, a template,
if you will, that the brain canwork with as you mature and
develop and learn. And once youpass that peak in early life,
(04:06):
and I think it's somewherearound 3 years old, and mature
and develop and learn, youactively prune down synaptic
contacts.
You whittle them away, the onesthat aren't used or are aren't
so important. And you resolve ata plateau. You you have a stable
number of synapses in your adultlife for a very long period of
time. Now as you age and maybegetting into maybe around 60
(04:31):
years old, somewhere aroundthere, this sort of flat line
that is synaptic number throughmost of your adult life starts
to dip a little bit, but slowly,not too much. You know?
And and that is one of thecontributors, not the only one,
but one of the contributors tonormal age related cognitive
decline. It's not the type ofprecipitous decline that you see
(04:51):
in diseases such as Alzheimer'sand other forms of dementia, But
it, you know, it's measurable.And so, you know, healthy brain
aging, normal brain aging doesinvolve at some point a
reduction of synapses from astable plateau that you have in
most of your adult life.
Dr. Moira Gunn (05:06):
Now these medical conditions, I mentioned,
depression, schizophrenia,Alzheimer's, ALS, from the
outside, they all look differentto us and yet they all share
loss of synapses. How are theydifferent from each other if we
look at it through the lens ofsynapses?
Dr. Peter Vanderklish (05:26):
At a basic level, one of the main
differences is that you'relosing synapses in in different
regions. Now a lot of thesediseases have a lot of
commonalities. So, you know,they have overlapping patterns
of synapse loss in terms of whatbrain regions you've seen
synapse loss in, but they alsohave important differences. So
for example, in Alzheimer'sdisease, you see a lot of
(05:47):
synapse loss in a region calledthe hippocampus and the neuronal
cortex are involved in memoryformation. Frontotemporal
dementia, you've seen it more onthe frontal cortices, temporal
cortices.
In ALS, you've seen it in in themotor cortex. And additionally,
in ALS, you know, there are somepeople who have frontal temporal
dementia like cognitive issuesand you see synapse loss in
(06:09):
those people in the frontalcortex. And so, you know,
regionally these diseasesdiffer. In schizophrenia, for
instance, is as well you youhave loss of synapses in the
frontal cortex. So regionallythey differ but also at a
mechanistic level it's kind ofthe same picture.
There's there's a lot ofmechanisms that are involved,
pathological mechanisms involvedin synapse loss and at least to
(06:31):
some extent these diseases sharesome of those, but they also
have important differences. Sofrom an anatomical perspective
and from a mechanisticperspective, they have
overlapping but differentproperties. So in your brain and
Alzheimer's, you know, what youwould be seeing is a pattern of
synapse loss that is occurring,you know, predominantly at first
in the hippocampus and thenspreading to other regions. In a
(06:53):
disease like ALS, which is amotor neuron disease, you're
going to see synapse lossprimarily in the motor cortex.
And in disease likeschizophrenia and frontotemporal
dementia, you're going to see apattern of synapse loss that
mostly involves the the frontalpre and prefrontal cortical
regions.
Dr. Moira Gunn (07:09):
Well, what about depression? Are there many kinds
of depression?
Dr. Peter Vanderklish (07:12):
That's a great question. So, you know,
depression actually, it turnsout that you're losing synapses
to a degree, in some of thosesame regions, in the hippocampus
and the prefrontal cortex. Thoseare particularly important areas
for not just memory formationbut emotional regulation as well
and stress regulation.
Dr. Moira Gunn (07:30):
Now if you hear anything about Alzheimer's, you
often hear about a theory whichis some combination of the
presence of amyloid beta causingplaques and tau tangles within
neurons and it all, you know, tothe lay listener, it all all
kind of sounds the same. Is thistheory accepted science?
Dr. Peter Vanderklish (07:53):
Oh, that's that's a great question.
So I I think a lot of it is. Ithink, you know, you know, the
amyloid theory of Alzheimer'sdisease is core in its most
basic form just posits that thegeneration of a small protein
fragment called amyloid beta, iscausing is a central player in
the pathogenesis of the diseaseand kind of accounts for for
(08:13):
most of the the pathology yousee and the symptoms you see.
It's and it's thought that thispeptide, this short protein
fragment is is toxic to bothsynapses and neurons and
increases inflammation and doesother things. It's a decent
theory but, you know, it may be,you know, it may be wrong.
And this, you know, this youknow, a lot of people have seen,
(08:35):
you know, data in the popularpress, you know, about how the
the effects of new medicationsthat have been approved are are
very modest, and some of themcome with a nontrivial risk for
serious adverse events as well.And there's also been reports
that you've heard about, ofcourse, about allegations of
scientific misconduct by majorfigures in the field. This has
brought some doubt more doubtinto the theory. But I think
(08:58):
when you, you know, when all thesmoke clears, you know, it does
carry some weight. And I dothink, you know, it can be
safely concluded that amyloidbeta is at least a stressor on
neurons, and synapses.
It may not be the the centralplayer in the disease
processing, but it's notsomething you want a lot of in
your brain. I think probably thebigger problem with the amyloid
(09:20):
theory is that it's justinsufficient. So in Alzheimer's
disease, we know that it'stremendously heterogeneous from
a clinical perspective, and froma mechanistic perspective. So
patients will present, you know,with different profiles of
dementia. And there's also it'salso known that there are a lot
of different pathologicalprocesses going on in the
(09:40):
Alzheimer's brain that maydiffer in their relative
contribution to symptoms fromone person to another.
So I think as people go forwardin this area, trying to parse
that heterogeneity and attackthe disease from multiple
angles, you're gonna find moresuccess. And of course, we think
synaptic regeneration is gonnabe a great therapeutic value.
Dr. Moira Gunn (10:00):
Which leads us to the theory that Spine
Genetics is pursuing.
Dr. Peter Vanderklish (10:05):
Yeah. And so we're pursuing synaptic
regeneration as a therapeuticapproach to address the larger
set of what we call thesynaptopathies. So all these
diseases that you mentioned atthe outset that are you, having
common a loss of synapses. Andin particular, our compounds are
are geared towards regeneratinga subset of synapses called a
(10:27):
special type of synapses calledglutamatergic synapses. These
the amino acid glutamate is aneurotransmitter.
And these are the dominant, themost abundant type of synapses
in your brain. And so we thinkby regenerating synapses through
a mechanism that is actually, wethink to a degree, disease
agnostic, You can actuallyoffset synapse loss in these
(10:49):
different diseases in differentareas of the brain, and
hopefully slower, maybe evenpossibly reverse, the course of
symptoms in different diseases.
Dr. Moira Gunn (10:58):
What exactly, are you doing? Yeah.
Dr. Peter Vanderklish (11:01):
So we've developed, a compound which is
called SBG 302. It's a smallmolecule, which basically means
it's something that you canformulate into a pill and take
by mouth and it gets into yourbrain where it works to
regenerate synapses. And we'reusing this as a therapeutic
approach to treat a spectrum ofdiseases that are termed the
(11:22):
synaptopathies, which encompassmany of the diseases you
mentioned at the outset,Alzheimer's disease,
schizophrenia, frontotemporaldementia, ALS, on and on. There
are many synaptopathies and wethink that regenerating synapses
in these conditions has thepotential to slow or potentially
even reverse, some of thesymptoms of these diseases.
Dr. Moira Gunn (11:45):
I think what strikes me is that I've always
heard about synapses dying, butI haven't heard about synapses
regenerating. Can you give usany examples of that?
Dr. Peter Vanderklish (11:58):
Yeah. So in your adult life, you're you
do have synaptogenesis. Youknow, it's not just a as we
talked about earlier, it's notjust a a downward curve the
whole time. You're things are ata stable plateau for quite a
while. You know, you're losingsynapses, you're generating
synapses and they're roughlyoffsetting in most brain regions
for a long period of time.
Dr. Moira Gunn (12:16):
So that's the flat line.
Dr. Peter Vanderklish (12:18):
Exactly. Yeah. So, you know, regeneration
and gen synaptogenesis andregeneration are alive and well
for a lot of your your lifetime.But as you age, a lot of these
diseases are have too manycomponents to them. They have
degenerative processes,obviously, which are very
multifactorial.
But with age, you also lose theability to regenerate. And we
(12:42):
think our compound is coming inand coaxing a particular
molecular process that isallowing synapses to, you know,
or neurons to sort of wake up,if you will, and and to be able
to regenerate synapses wherethey're needed. And, you know, a
good example of where this thishappens in nature is, you know,
under conditions of stress, isin in hibernating animals. You
(13:05):
know, there are there arestudies that were done on
hibernating ground squirrels,for instance, where, you know,
they do because of a scarcity offood, these animals, you know,
evolved to go into a state wherethey they use less energy
because they don't have as muchfood. And so and then you get to
survive the winter as well.
So they they hibernate. They gointo a state of torpor, low body
(13:28):
temperature. They lower theirmetabolic rate all in an effort
to sort of survive the stressesof winter and and and low intake
of food. Now this is a bigchallenge for the brain, which
is very metabolically active, toto weather this. And and one of
the things that the brain doesis to retract some of its
(13:49):
synapses.
Now these studies in groundsquirrels are very interesting
because when they go intohibernation, it turns out that
their brains actually, showevidence of, Alzheimer's like
changes. They, they develop, youknow, tangles of tau, the
hyperphosphorylated tau proteinthat you see in the Alzheimer's
brain. They lose some of theirsynapses. But by the time, you
(14:11):
know, within hours after themcoming out of the hibernating
state, their synaptic density,comes back to normal. Now the
the the percentage of synapsesthat they've lost has returned
to a normal state.
And also some of the theAlzheimer's like changes that
you see in their brains arereversed. So there is this
(14:33):
ability to have the brain torebound and regenerate after,
states of severe metabolicstress, which is a component to
neurodegenerative disease, andto do so in short order and in
an appropriate way.Interestingly as well is the
fact that in hibernation, youknow, the additional studies
(14:54):
were showing that memories thatwere encoded in ground scrolls
shortly before hibernationactually, remained intact after
hibernation. There could be alot to explain that. One of the
explanations could be that eventhough some of the synapses have
been lost, when synapses wereregenerated, they were
regenerated at the right leveland in the right places.
Dr. Moira Gunn (15:16):
Wow. That's all I gotta say. Hey. I remember
where my acorn is that that Iburied over here in the fall.
Dr. Peter Vanderklish (15:24):
It's important. Yeah.
Dr. Moira Gunn (15:26):
It's very important. And I think what's so
important here is is not justthat they can be regenerated,
but that we naturally have aregeneration process that may be
what was affecting and it's notso much the decline in synapses,
which we all have, but the factthat we're unable to regenerate
them. You know, there's anynumber of combinations here
(15:48):
again because it's very complex,but it's it's a it's a much
different way, I think, of ofthinking about how to go
forward. Now, you, of course,are already in phase 2 with
this, but I wanna, talk aboutwhat did you do in phase 1, that
first study to make sure thatit's safe? But, you know, we
(16:11):
always learn things in phase 1.
What did you do in phase 1 thatwhen you started studying it in
humans? And what did you learn?
Dr. Peter Vanderklish (16:19):
Yeah. So phase 1, involved healthy
volunteers, over 80. And what wedo in those studies is we test
our our drug at a single dose ofour drug at multiple dose
levels, and they called a asingle ascending dose, portion
of the trial. And we tested, youknow, what we think would be low
(16:41):
levels to give people and andand levels that we think exceed
what you need to achievetherapeutic value. And then we
also have a cohort of peoplewhere, they receive multiple
doses, either multiple low dosesover days or multiple high
doses.
And we found that that the drugis very safe and well tolerated.
It doesn't seem to induce anysevere adverse events. And we
(17:03):
also found that at relativelymodest doses, we achieved blood
levels of the compound that areassociated with, efficacy and
regenerating synapses andimproving symptoms in animal
models of neurodegenerativedisease.
Dr. Moira Gunn (17:17):
So in fact, you're seeing that it's it's at
some point is something is beingdelivered here.
Dr. Peter Vanderklish (17:23):
Yeah. Yeah. So it's it's it was doing
everything you would want for adrug of this nature. It's
getting it quickly. It'sachieving plasma blood levels
that are associated with thebiological the intended
biological effect in preclinicalmodels.
And it's not it appears to benot causing any harm.
Dr. Moira Gunn (17:40):
Now now let's go to phase 2 because now now
you're starting to separate outwhich disease are we working on.
They're different arms of phase2 here. Let's start with the
Alzheimer's. How many people areyou studying? Who are they?
What are they doing? How how howis everything being measured?
Dr. Peter Vanderklish (18:03):
So we have an ongoing phase 2 trial in
Alzheimer's disease. It'senrolling patients with mild to
moderate Alzheimer's disease upto 24 patients. And, you know,
the trial is designed asfollows. So there's an initial
period that is placebocontrolled, meaning that some
will get the drug and some willget a placebo. And that period
(18:24):
is followed by a longer periodafter that and during which
patients can elect to stay onthe drug if they'd like to and
know they're getting the drug.
And in the trial, we're we'remeasuring 2 general things. So
one, we're measuring we're usingmultiple tests to get a gauge of
their patient's cognitivestatus, the same tests that are
used by many others, testingother types of candidate
(18:47):
Alzheimer's therapies. Inaddition to that, we're using,
we're doing measures of ofproteins in the blood that are,
you know, biomarkers of thedisease process. One of them's a
measure of neurodegeneration ingeneral. And then there are
other biomarkers that are aredecent measures of of
(19:08):
degenerative processes that aremore specific to Alzheimer's
disease.
And then on top of that, we areadding, neurophysiological
measures, you know, actual EEGrecordings, different types of
measures that allow us to get asense of whether or not our
compound is actually changing,the number of synapses in the
(19:28):
brain. And there there's sortof, you know, ensemble activity
that you can record, from theoutside of the brain, from the
skull.
Dr. Moira Gunn (19:36):
How about the ALS trial? Is that very
different?
Dr. Peter Vanderklish (19:41):
It's it's different in some ways. So and
that has some similarities. So,it's fully enrolled for one
thing. And, we had our, youknow, last patient enrolled very
recently. It also has in thebeginning a placebo controlled
phase where, you know, somepatients will get drug and
others will get placebo.
And then after that, it also hasthat extension phase where
(20:01):
patients can elect to to stay ondrug and and know they're
they're on the drug. Now, inthis trial, you know, again,
we're using some of the standardoutcome measures that are used
by people testing othercandidate therapeutics for ALS.
But in addition here, again,we're using neurophysiological
techniques that we view asobjective, quantitative outcome
(20:25):
measures of neural function. Inthis case, we have not only are
we using EEG like we did inAlzheimer's disease, but we also
have the the added benefit ofbeing able to use a technique
called transcranial magneticstimulation or TMS. And what's
interesting about this thistechnique is it allows you to
position a magnet basicallyright over the skull, right over
(20:49):
an area of the cortex called themotor cortex that's degenerating
in ALS.
And it's the region of yourbrain that's con you know, it's
kind of one of the mastercontrol areas of movement. And
you can apply a magnetic fieldand evoke a motor response. Now
in ALS patients they find that alot of patients even early on in
a disease they can measure thesort of excitability of the
(21:12):
motor cortex with this measureand the patients have what's
called a hyperexcitable motorcortex, and you can quantify
that. And so we will be able andthis and this is linked to, we
believe, the density of synapseson the motor neurons that are
degenerating in the condition.And so we can measure this
degree of hyperexcitability andand see if we're having a
(21:35):
benefit at theneurophysiological level and the
neuro level in the brain in ALSpatients.
At the same time, we'remeasuring basically function
with other outcome measures andand blood biomarkers of
neurodegeneration.
Dr. Moira Gunn (21:49):
Well, again you're going into many areas
here, but I think some of thetakeaways for me is that you're
able to see changes, and you'reable to do it pretty quickly,
non invasively. And, we can thenhope to follow those down as we
(22:11):
go forward. But that's quitedifferent than having to say, do
you feel better? Do you get alittle more? How many months
from now?
I mean, you're able to seechanges pretty quickly in the
body.
Dr. Peter Vanderklish (22:23):
Yeah. It's it's you know, we're
fortunate to be able to leveragethese measures, you know, these
neurophysiological measures asobjective readouts of a
therapeutic phenomenon that wethink will have a rapid, you
know, has the potential to havea rapid onset. We're not just
relying on patient reports andother measures of functionality.
Dr. Moira Gunn (22:43):
And earlier we were speaking of this, not just
the synapses but the ability toregenerate them. Do we know if
the ability to regenerate themmay in fact be kicked in? And
I'll tell you exactly where I'mgoing here. Do we know if people
would have to take thismedication for the rest of their
lives or that possibly someportion of their own body might
(23:07):
just restart?
Dr. Peter Vanderklish (23:08):
Yeah. That's a really good question. I
I it could be completely,forthcoming. I I don't think we
have the answer to that. So,it's interesting a couple ways.
So, yes, the intent is thatpeople would take this as a once
a day pill that you would justsimply swallow. It's not, you
know, it's not hard toadminister. But is it is that
(23:31):
going to be needed in everydisease for every patient? And
there's a question mark there.And the question mark comes from
the fact that we have dataspeaking to the fact that when
we regenerate synapses in theabsence of any underlying
disease process in preclinicalmodels, we see that they
persist.
They can actually persist forweeks or more. Now it's
(23:53):
anybody's guess, you know, howthat persistence is going to
change in the context of, youknow, one Alzheimer's patient
versus another, Alzheimer'sversus ALS, frontotemporal
dementia versus those, etcetera,etcetera, etcetera. And that's
not something you can reallyadequately model in preclinical
studies. And it's we're justgoing to have to find out in the
(24:14):
clinic. But for right now, wethink we can do benefit without
doing harm with once once dailydosing.
We may find out later that youdon't have to take it all the
time.
Dr. Moira Gunn (24:23):
Well, doctor Vanderklish, this is
fascinating. I hope you'll comeback and see us again.
Dr. Peter Vanderklish (24:28):
Oh, that'd be great. Yeah. Thanks
for having me, Maura.
Dr. Moira Gunn (24:31):
Doctor Peter Vanderklish is the chief
scientific officer ofSpinogenix. Spinogenix is
currently recruitingparticipants for clinical trials
in Alzheimer's, fragile xsyndrome, and schizophrenia.
More information is available onthe web at spinogenix.com.
(24:51):
That's spinogenix spinogenix.com.
It's your brain. We all pretty much know that
over time, we lose synapses.Depending on where you lose
them, it could lead to suchconditions as depression,
schizophrenia, Alzheimer's, orALS. Doctor Peter Vanderklish
from Spinogenix talks abouttheir advanced human trials in
(00:33):
synaptic generation. DoctorVanderklish, welcome to the
program.
Dr. Peter Vanderklish (00:37):
Thanks for having me.
Dr. Moira Gunn (00:38):
Now there's a whole range of medical
conditions that we are allfamiliar with and they have to
do with the loss of synapses inthe brain. That could be
depression, schizophrenia,Alzheimer's, ALS. So let me
start there. Give us a pictureof our healthy brains. What are
(00:59):
synapses?
What do they do? And how many doI have in my brain or your brain
or any brain?
Dr. Peter Vanderklish (01:06):
Well, synapses are physical
connections between neurons thatallow them to communicate with
each other. And so every neuronhas, you know, potentially
thousands of synapses and cansort of link up with many other
neurons by virtue of having thatmany contacts with other
neurons. So neurons link up intolarge networks of neurons and
(01:28):
it's a synaptic communicationbetween them that allows them to
do things like informationprocessing. So synapses are
really, an indispensable elementof yours your nervous system and
are involved in everything youdo, everything you you think,
everything you perceive,everything you say you do. And,
of course, they're involved inmemory formation, which is
perhaps, maybe, the mostimportant faculty of mine become
(01:51):
over a lifetime, together.
Dr. Moira Gunn (01:54):
Now how many do I have? You like it how it's all
about me? Yeah.
Dr. Peter Vanderklish (01:58):
Yeah. Well, you have a lot. I can
sense
Dr. Moira Gunn (02:00):
How many does the listener have?
Dr. Peter Vanderklish (02:03):
So on average, the, you know, the
human brand is about85,000,000,000 neurons. And
estimates of the number ofsynapses that you have range
from about a 150,000,000,000,000all the way up to, you know,
pushing up towards 1quadrillion. So that's an
enormous number. To give you asense of that that number, I I
actually want to refer back to apassage from a book my, my
(02:26):
postdoctoral mentor, the lateGerald Edelman wrote, where he
he tried to relate, you know,the sort of the size or the the
complexity of the number ofsynapses. And he said he had a
great quote in there, which was,if you were to start counting
each synapse 1 by 1 everysecond, it would take you
32000000 years before youfinished.
(02:47):
Now if you then went on toactually calculate how many
different ways those varioussynapses could be activated, the
it becomes what he called hyperastronomical. So the number of
potential combinations of activesynapses that you can have in
your brain is 10 followed by1,000,000 of zeros. And to give
you some perspective, theestimate of the number of atoms
(03:11):
in the known universe is about10 followed by 80 2zeros. So the
complexity embedded within yourbrain in terms of the number of
synapses and how they can beactive, and that says nothing
about sequences of activationwhich would project beyond all
balance is hyper astronomical.
Dr. Moira Gunn (03:28):
And pretty darn complex.
Dr. Peter Vanderklish (03:30):
Yes.
Dr. Moira Gunn (03:30):
I'll take that for sure. No one is gonna argue
with me about that. Now from thetime you were born to throughout
your life to the time you age,if you have a healthy brain, how
does that change?
Dr. Peter Vanderklish (03:43):
Well, that's that's a great question.
So, you know, I'm gonna paint alittle picture for you. So early
on in your life, you havebelieve it or not, you have too
many synapses. So in early braindevelopment, you have this
explosion of synaptogenesis thatcreates, you know, a template,
if you will, that the brain canwork with as you mature and
develop and learn. And once youpass that peak in early life,
(04:06):
and I think it's somewherearound 3 years old, and mature
and develop and learn, youactively prune down synaptic
contacts.
You whittle them away, the onesthat aren't used or are aren't
so important. And you resolve ata plateau. You you have a stable
number of synapses in your adultlife for a very long period of
time. Now as you age and maybegetting into maybe around 60
(04:31):
years old, somewhere aroundthere, this sort of flat line
that is synaptic number throughmost of your adult life starts
to dip a little bit, but slowly,not too much. You know?
And and that is one of thecontributors, not the only one,
but one of the contributors tonormal age related cognitive
decline. It's not the type ofprecipitous decline that you see
(04:51):
in diseases such as Alzheimer'sand other forms of dementia, But
it, you know, it's measurable.And so, you know, healthy brain
aging, normal brain aging doesinvolve at some point a
reduction of synapses from astable plateau that you have in
most of your adult life.
Dr. Moira Gunn (05:06):
Now these medical conditions, I mentioned,
depression, schizophrenia,Alzheimer's, ALS, from the
outside, they all look differentto us and yet they all share
loss of synapses. How are theydifferent from each other if we
look at it through the lens ofsynapses?
Dr. Peter Vanderklish (05:26):
At a basic level, one of the main
differences is that you'relosing synapses in in different
regions. Now a lot of thesediseases have a lot of
commonalities. So, you know,they have overlapping patterns
of synapse loss in terms of whatbrain regions you've seen
synapse loss in, but they alsohave important differences. So
for example, in Alzheimer'sdisease, you see a lot of
(05:47):
synapse loss in a region calledthe hippocampus and the neuronal
cortex are involved in memoryformation. Frontotemporal
dementia, you've seen it more onthe frontal cortices, temporal
cortices.
In ALS, you've seen it in in themotor cortex. And additionally,
in ALS, you know, there are somepeople who have frontal temporal
dementia like cognitive issuesand you see synapse loss in
(06:09):
those people in the frontalcortex. And so, you know,
regionally these diseasesdiffer. In schizophrenia, for
instance, is as well you youhave loss of synapses in the
frontal cortex. So regionallythey differ but also at a
mechanistic level it's kind ofthe same picture.
There's there's a lot ofmechanisms that are involved,
pathological mechanisms involvedin synapse loss and at least to
(06:31):
some extent these diseases sharesome of those, but they also
have important differences. Sofrom an anatomical perspective
and from a mechanisticperspective, they have
overlapping but differentproperties. So in your brain and
Alzheimer's, you know, what youwould be seeing is a pattern of
synapse loss that is occurring,you know, predominantly at first
in the hippocampus and thenspreading to other regions. In a
(06:53):
disease like ALS, which is amotor neuron disease, you're
going to see synapse lossprimarily in the motor cortex.
And in disease likeschizophrenia and frontotemporal
dementia, you're going to see apattern of synapse loss that
mostly involves the the frontalpre and prefrontal cortical
regions.
Dr. Moira Gunn (07:09):
Well, what about depression? Are there many kinds
of depression?
Dr. Peter Vanderklish (07:12):
That's a great question. So, you know,
depression actually, it turnsout that you're losing synapses
to a degree, in some of thosesame regions, in the hippocampus
and the prefrontal cortex. Thoseare particularly important areas
for not just memory formationbut emotional regulation as well
and stress regulation.
Dr. Moira Gunn (07:30):
Now if you hear anything about Alzheimer's, you
often hear about a theory whichis some combination of the
presence of amyloid beta causingplaques and tau tangles within
neurons and it all, you know, tothe lay listener, it all all
kind of sounds the same. Is thistheory accepted science?
Dr. Peter Vanderklish (07:53):
Oh, that's that's a great question.
So I I think a lot of it is. Ithink, you know, you know, the
amyloid theory of Alzheimer'sdisease is core in its most
basic form just posits that thegeneration of a small protein
fragment called amyloid beta, iscausing is a central player in
the pathogenesis of the diseaseand kind of accounts for for
(08:13):
most of the the pathology yousee and the symptoms you see.
It's and it's thought that thispeptide, this short protein
fragment is is toxic to bothsynapses and neurons and
increases inflammation and doesother things. It's a decent
theory but, you know, it may be,you know, it may be wrong.
And this, you know, this youknow, a lot of people have seen,
(08:35):
you know, data in the popularpress, you know, about how the
the effects of new medicationsthat have been approved are are
very modest, and some of themcome with a nontrivial risk for
serious adverse events as well.And there's also been reports
that you've heard about, ofcourse, about allegations of
scientific misconduct by majorfigures in the field. This has
brought some doubt more doubtinto the theory. But I think
(08:58):
when you, you know, when all thesmoke clears, you know, it does
carry some weight. And I dothink, you know, it can be
safely concluded that amyloidbeta is at least a stressor on
neurons, and synapses.
It may not be the the centralplayer in the disease
processing, but it's notsomething you want a lot of in
your brain. I think probably thebigger problem with the amyloid
(09:20):
theory is that it's justinsufficient. So in Alzheimer's
disease, we know that it'stremendously heterogeneous from
a clinical perspective, and froma mechanistic perspective. So
patients will present, you know,with different profiles of
dementia. And there's also it'salso known that there are a lot
of different pathologicalprocesses going on in the
(09:40):
Alzheimer's brain that maydiffer in their relative
contribution to symptoms fromone person to another.
So I think as people go forwardin this area, trying to parse
that heterogeneity and attackthe disease from multiple
angles, you're gonna find moresuccess. And of course, we think
synaptic regeneration is gonnabe a great therapeutic value.
Dr. Moira Gunn (10:00):
Which leads us to the theory that Spine
Genetics is pursuing.
Dr. Peter Vanderklish (10:05):
Yeah. And so we're pursuing synaptic
regeneration as a therapeuticapproach to address the larger
set of what we call thesynaptopathies. So all these
diseases that you mentioned atthe outset that are you, having
common a loss of synapses. Andin particular, our compounds are
are geared towards regeneratinga subset of synapses called a
(10:27):
special type of synapses calledglutamatergic synapses. These
the amino acid glutamate is aneurotransmitter.
And these are the dominant, themost abundant type of synapses
in your brain. And so we thinkby regenerating synapses through
a mechanism that is actually, wethink to a degree, disease
agnostic, You can actuallyoffset synapse loss in these
(10:49):
different diseases in differentareas of the brain, and
hopefully slower, maybe evenpossibly reverse, the course of
symptoms in different diseases.
Dr. Moira Gunn (10:58):
What exactly, are you doing? Yeah.
Dr. Peter Vanderklish (11:01):
So we've developed, a compound which is
called SBG 302. It's a smallmolecule, which basically means
it's something that you canformulate into a pill and take
by mouth and it gets into yourbrain where it works to
regenerate synapses. And we'reusing this as a therapeutic
approach to treat a spectrum ofdiseases that are termed the
(11:22):
synaptopathies, which encompassmany of the diseases you
mentioned at the outset,Alzheimer's disease,
schizophrenia, frontotemporaldementia, ALS, on and on. There
are many synaptopathies and wethink that regenerating synapses
in these conditions has thepotential to slow or potentially
even reverse, some of thesymptoms of these diseases.
Dr. Moira Gunn (11:45):
I think what strikes me is that I've always
heard about synapses dying, butI haven't heard about synapses
regenerating. Can you give usany examples of that?
Dr. Peter Vanderklish (11:58):
Yeah. So in your adult life, you're you
do have synaptogenesis. Youknow, it's not just a as we
talked about earlier, it's notjust a a downward curve the
whole time. You're things are ata stable plateau for quite a
while. You know, you're losingsynapses, you're generating
synapses and they're roughlyoffsetting in most brain regions
for a long period of time.
Dr. Moira Gunn (12:16):
So that's the flat line.
Dr. Peter Vanderklish (12:18):
Exactly. Yeah. So, you know, regeneration
and gen synaptogenesis andregeneration are alive and well
for a lot of your your lifetime.But as you age, a lot of these
diseases are have too manycomponents to them. They have
degenerative processes,obviously, which are very
multifactorial.
But with age, you also lose theability to regenerate. And we
(12:42):
think our compound is coming inand coaxing a particular
molecular process that isallowing synapses to, you know,
or neurons to sort of wake up,if you will, and and to be able
to regenerate synapses wherethey're needed. And, you know, a
good example of where this thishappens in nature is, you know,
under conditions of stress, isin in hibernating animals. You
(13:05):
know, there are there arestudies that were done on
hibernating ground squirrels,for instance, where, you know,
they do because of a scarcity offood, these animals, you know,
evolved to go into a state wherethey they use less energy
because they don't have as muchfood. And so and then you get to
survive the winter as well.
So they they hibernate. They gointo a state of torpor, low body
(13:28):
temperature. They lower theirmetabolic rate all in an effort
to sort of survive the stressesof winter and and and low intake
of food. Now this is a bigchallenge for the brain, which
is very metabolically active, toto weather this. And and one of
the things that the brain doesis to retract some of its
(13:49):
synapses.
Now these studies in groundsquirrels are very interesting
because when they go intohibernation, it turns out that
their brains actually, showevidence of, Alzheimer's like
changes. They, they develop, youknow, tangles of tau, the
hyperphosphorylated tau proteinthat you see in the Alzheimer's
brain. They lose some of theirsynapses. But by the time, you
(14:11):
know, within hours after themcoming out of the hibernating
state, their synaptic density,comes back to normal. Now the
the the percentage of synapsesthat they've lost has returned
to a normal state.
And also some of the theAlzheimer's like changes that
you see in their brains arereversed. So there is this
(14:33):
ability to have the brain torebound and regenerate after,
states of severe metabolicstress, which is a component to
neurodegenerative disease, andto do so in short order and in
an appropriate way.Interestingly as well is the
fact that in hibernation, youknow, the additional studies
(14:54):
were showing that memories thatwere encoded in ground scrolls
shortly before hibernationactually, remained intact after
hibernation. There could be alot to explain that. One of the
explanations could be that eventhough some of the synapses have
been lost, when synapses wereregenerated, they were
regenerated at the right leveland in the right places.
Dr. Moira Gunn (15:16):
Wow. That's all I gotta say. Hey. I remember
where my acorn is that that Iburied over here in the fall.
Dr. Peter Vanderklish (15:24):
It's important. Yeah.
Dr. Moira Gunn (15:26):
It's very important. And I think what's so
important here is is not justthat they can be regenerated,
but that we naturally have aregeneration process that may be
what was affecting and it's notso much the decline in synapses,
which we all have, but the factthat we're unable to regenerate
them. You know, there's anynumber of combinations here
(15:48):
again because it's very complex,but it's it's a it's a much
different way, I think, of ofthinking about how to go
forward. Now, you, of course,are already in phase 2 with
this, but I wanna, talk aboutwhat did you do in phase 1, that
first study to make sure thatit's safe? But, you know, we
(16:11):
always learn things in phase 1.
What did you do in phase 1 thatwhen you started studying it in
humans? And what did you learn?
Dr. Peter Vanderklish (16:19):
Yeah. So phase 1, involved healthy
volunteers, over 80. And what wedo in those studies is we test
our our drug at a single dose ofour drug at multiple dose
levels, and they called a asingle ascending dose, portion
of the trial. And we tested, youknow, what we think would be low
(16:41):
levels to give people and andand levels that we think exceed
what you need to achievetherapeutic value. And then we
also have a cohort of peoplewhere, they receive multiple
doses, either multiple low dosesover days or multiple high
doses.
And we found that that the drugis very safe and well tolerated.
It doesn't seem to induce anysevere adverse events. And we
(17:03):
also found that at relativelymodest doses, we achieved blood
levels of the compound that areassociated with, efficacy and
regenerating synapses andimproving symptoms in animal
models of neurodegenerativedisease.
Dr. Moira Gunn (17:17):
So in fact, you're seeing that it's it's at
some point is something is beingdelivered here.
Dr. Peter Vanderklish (17:23):
Yeah. Yeah. So it's it's it was doing
everything you would want for adrug of this nature. It's
getting it quickly. It'sachieving plasma blood levels
that are associated with thebiological the intended
biological effect in preclinicalmodels.
And it's not it appears to benot causing any harm.
Dr. Moira Gunn (17:40):
Now now let's go to phase 2 because now now
you're starting to separate outwhich disease are we working on.
They're different arms of phase2 here. Let's start with the
Alzheimer's. How many people areyou studying? Who are they?
What are they doing? How how howis everything being measured?
Dr. Peter Vanderklish (18:03):
So we have an ongoing phase 2 trial in
Alzheimer's disease. It'senrolling patients with mild to
moderate Alzheimer's disease upto 24 patients. And, you know,
the trial is designed asfollows. So there's an initial
period that is placebocontrolled, meaning that some
will get the drug and some willget a placebo. And that period
(18:24):
is followed by a longer periodafter that and during which
patients can elect to stay onthe drug if they'd like to and
know they're getting the drug.
And in the trial, we're we'remeasuring 2 general things. So
one, we're measuring we're usingmultiple tests to get a gauge of
their patient's cognitivestatus, the same tests that are
used by many others, testingother types of candidate
(18:47):
Alzheimer's therapies. Inaddition to that, we're using,
we're doing measures of ofproteins in the blood that are,
you know, biomarkers of thedisease process. One of them's a
measure of neurodegeneration ingeneral. And then there are
other biomarkers that are aredecent measures of of
(19:08):
degenerative processes that aremore specific to Alzheimer's
disease.
And then on top of that, we areadding, neurophysiological
measures, you know, actual EEGrecordings, different types of
measures that allow us to get asense of whether or not our
compound is actually changing,the number of synapses in the
(19:28):
brain. And there there's sortof, you know, ensemble activity
that you can record, from theoutside of the brain, from the
skull.
Dr. Moira Gunn (19:36):
How about the ALS trial? Is that very
different?
Dr. Peter Vanderklish (19:41):
It's it's different in some ways. So and
that has some similarities. So,it's fully enrolled for one
thing. And, we had our, youknow, last patient enrolled very
recently. It also has in thebeginning a placebo controlled
phase where, you know, somepatients will get drug and
others will get placebo.
And then after that, it also hasthat extension phase where
(20:01):
patients can elect to to stay ondrug and and know they're
they're on the drug. Now, inthis trial, you know, again,
we're using some of the standardoutcome measures that are used
by people testing othercandidate therapeutics for ALS.
But in addition here, again,we're using neurophysiological
techniques that we view asobjective, quantitative outcome
(20:25):
measures of neural function. Inthis case, we have not only are
we using EEG like we did inAlzheimer's disease, but we also
have the the added benefit ofbeing able to use a technique
called transcranial magneticstimulation or TMS. And what's
interesting about this thistechnique is it allows you to
position a magnet basicallyright over the skull, right over
(20:49):
an area of the cortex called themotor cortex that's degenerating
in ALS.
And it's the region of yourbrain that's con you know, it's
kind of one of the mastercontrol areas of movement. And
you can apply a magnetic fieldand evoke a motor response. Now
in ALS patients they find that alot of patients even early on in
a disease they can measure thesort of excitability of the
(21:12):
motor cortex with this measureand the patients have what's
called a hyperexcitable motorcortex, and you can quantify
that. And so we will be able andthis and this is linked to, we
believe, the density of synapseson the motor neurons that are
degenerating in the condition.And so we can measure this
degree of hyperexcitability andand see if we're having a
(21:35):
benefit at theneurophysiological level and the
neuro level in the brain in ALSpatients.
At the same time, we'remeasuring basically function
with other outcome measures andand blood biomarkers of
neurodegeneration.
Dr. Moira Gunn (21:49):
Well, again you're going into many areas
here, but I think some of thetakeaways for me is that you're
able to see changes, and you'reable to do it pretty quickly,
non invasively. And, we can thenhope to follow those down as we
(22:11):
go forward. But that's quitedifferent than having to say, do
you feel better? Do you get alittle more? How many months
from now?
I mean, you're able to seechanges pretty quickly in the
body.
Dr. Peter Vanderklish (22:23):
Yeah. It's it's you know, we're
fortunate to be able to leveragethese measures, you know, these
neurophysiological measures asobjective readouts of a
therapeutic phenomenon that wethink will have a rapid, you
know, has the potential to havea rapid onset. We're not just
relying on patient reports andother measures of functionality.
Dr. Moira Gunn (22:43):
And earlier we were speaking of this, not just
the synapses but the ability toregenerate them. Do we know if
the ability to regenerate themmay in fact be kicked in? And
I'll tell you exactly where I'mgoing here. Do we know if people
would have to take thismedication for the rest of their
lives or that possibly someportion of their own body might
(23:07):
just restart?
Dr. Peter Vanderklish (23:08):
Yeah. That's a really good question. I
I it could be completely,forthcoming. I I don't think we
have the answer to that. So,it's interesting a couple ways.
So, yes, the intent is thatpeople would take this as a once
a day pill that you would justsimply swallow. It's not, you
know, it's not hard toadminister. But is it is that
(23:31):
going to be needed in everydisease for every patient? And
there's a question mark there.And the question mark comes from
the fact that we have dataspeaking to the fact that when
we regenerate synapses in theabsence of any underlying
disease process in preclinicalmodels, we see that they
persist.
They can actually persist forweeks or more. Now it's
(23:53):
anybody's guess, you know, howthat persistence is going to
change in the context of, youknow, one Alzheimer's patient
versus another, Alzheimer'sversus ALS, frontotemporal
dementia versus those, etcetera,etcetera, etcetera. And that's
not something you can reallyadequately model in preclinical
studies. And it's we're justgoing to have to find out in the
(24:14):
clinic. But for right now, wethink we can do benefit without
doing harm with once once dailydosing.
We may find out later that youdon't have to take it all the
time.
Dr. Moira Gunn (24:23):
Well, doctor Vanderklish, this is
fascinating. I hope you'll comeback and see us again.
Dr. Peter Vanderklish (24:28):
Oh, that'd be great. Yeah. Thanks
for having me, Maura.
Dr. Moira Gunn (24:31):
Doctor Peter Vanderklish is the chief
scientific officer ofSpinogenix. Spinogenix is
currently recruitingparticipants for clinical trials
in Alzheimer's, fragile xsyndrome, and schizophrenia.
More information is available onthe web at spinogenix.com.
(24:51):
That's spinogenix spinogenix.com.
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