October 17, 2024 • 36 mins
After decades of research, gene therapy is starting to work. Shannon Boye is a professor of cellular and molecular therapeutics at the University of Florida. She is also the co-founder and chief scientific officer of Atsena Therapeutics. Shannon’s problem is this: How do you use gene therapy to cure certain forms of blindness?
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Speaker 1 (00:15):
Pushkin. Think about the basic idea of gene therapy. You
string together a gene, put the gene inside a virus,
put the virus inside a patient, and then the virus
delivers the gene to the patient, sells, and then that
new gene, if everything goes according to plan, makes the
(00:37):
patient get better. It sounds hard, it is hard, but
after decades of research, gene therapy is starting to work.
I'm Jacob Goldstein and this is What's Your Problem, the
show where I talk to people who are trying to
make technological progress. My guest today is Shannon boy She's
(00:59):
a professor of genetics at the University of Florida and
the co founder and chief scientific officer of Atsina Therapeutics.
Shannon's problem is this, how do you use gene therapy
to cure blindness, or at least certain forms of blindness.
Shannon has been working on gene therapy for twenty years,
and I wanted to talk with her about the long
(01:22):
arc of the field, from the wild optimism of the
early two thousands to the realization that developing gene therapy
would be a long, hard slog, to the recent promising
results from an experimental drug that her company has developed
that drug treats a rare disease that Sharon started studying
as a grad student back in two thousand and four.
(01:42):
The disease is called LCA one.
Speaker 2 (01:46):
So babies are born with the disease and usually within
the first few months of life, their moms or dads
notice that they're not looking at them directly, they're not
fixating on objects. Oftentimes the babies will have a roving
eye movement called nystagmus, and so they're diagnosed usually pretty
quickly with this condition, and unfortunately, it's profound visual impairment,
(02:09):
if not total blindness, and that remains with the patient
throughout the course of their life. So that's really the
reason that this lab was really interested in studying that
gene AHU.
Speaker 1 (02:20):
So it's one of the somewhat rare instances where there
is like a single gene that maps to a single
in this case, profound problem basically blindness or severe problems
with vision, which is kind of you would think would
be the first wave of gene therapy, right exactly, This
(02:41):
is what the early two thousands, when you're and so
the human genome has just been mapped, there's like a
sense of oh, now we know all the genes, right,
let's figure out how to help people with this new knowledge.
Speaker 2 (02:53):
That's exactly right. This was sort of the step one
in gene therapy was the simplest form, which is just
gene replacement. Can we take a healthy copy of a
gene and put it back into the patient's cells and
then have that gene go on to make the protein
it was supposed to make and then hopefully rett or
the function to those cells.
Speaker 1 (03:11):
And so what as a grad student are you trying
to figure out?
Speaker 2 (03:16):
The lab was studying the biochemical underpinnings of this disease,
and they were using a chicken model to do this.
That's kind of a unique thing in a lab. Usually
research labs are using mice or rats, but there was
a naturally occurring chicken model of this disease that had
profound visual impairment and blindness.
Speaker 1 (03:33):
So naturally occurring chicken model basically means this happens to
chickens too, Yes, exactly, it is. That's right.
Speaker 2 (03:41):
Yeah. So, at the same time that the lab was studying,
you know, what was going wrong in this chicken and
why it was happening, they wanted to ask the question
would gene therapy be a reasonable approach for treating these chickens.
Can we restore visions to these chickens with gene therapy.
So this was a collaborative effort with my other grad
(04:02):
students and I where we took a vector called Lenti
virus and we to the chicken embryos. I felt very
much in grad school like I was a poultry farmer,
because I would on my way into lab every day,
stop at the farm, pick up the eggs, burning them
into lab, and then my fellow grad students and I
(04:25):
we would make these tiny little holes in the chicken
egg and we would pull these glass micro needles and
use them to inject into the chicken embryo. And remember
this is a disease that you have from birth, so
we needed to treat these chickens very early. But it
was a difficult process to get that micro needle injection
into the head of the chicken embryo and then for
(04:47):
that chicken to make it all the way to hatch, right,
And that was I think one of the hardest parts
of that project. Actually, It's why I said I felt
like a poultry farmer. Is all of the machinations you know,
getting the humidity right, the temperature right, the position right,
making sure you close that egg right, just getting that
chicken to survive.
Speaker 1 (05:07):
And so you injecting the non mutated form of the gene,
the good form of the gene, if you will, encased
in this virus, into the head of the chicken embryo. Yes,
did it work?
Speaker 2 (05:25):
For a while it did not, because again, it was
difficult to manipulate a chicken embryo like that and actually
have it to survive to hatch. But my fellow grad
students and I did a lot of work to optimize
that process, and eventually it actually did work. We had
little chicks that were born, and I can distinctly remember
them walking around on the lab bench and pecking at
(05:48):
our jewelry or at Eminem's that we had laid out
on the surface of the bench. Very different from the
blind chickens. It was very clear. You know, chickens are
very visually guided creatures. It's very obvious when a chicken
can see versus Nazi.
Speaker 3 (06:03):
It was so fun. We were all so so happy.
Speaker 1 (06:07):
Okay, so that's two thousand and four as twenty years ago. Yeah, yeah,
at that time, is it like, well, we did it
in chickens, let's do it in people or what.
Speaker 2 (06:19):
So that's actually where my thesis project comes in. So
all of that chicken work was a really collaborative effort
and it was exciting, but it had its drawbacks and
it wasn't clinically translatable for a number of reasons. First
and foremost, we were never going to do an embryonic
injection and a patient. Maybe that'll happen one day, honestly,
but it certainly wasn't close to happening in two thousand
(06:41):
and four. So we needed a gene therapy that could
be injected in a patient after birth, right, And unfortunately,
the virus that we were using in the chicken experiments,
the Lenti virus, is really poor at a gene delivery
to a developed retina. So we needed to find a
more clinically relevant vector to do the gene therapy.
Speaker 1 (07:02):
Let's just pause for a moment and talk about this
idea of a vector in gene therapy. So the basic idea, right,
is like, you know what the good gene is, you
know the gene you want to get into, in this case,
the person's eye. But there's this weird question of how
do you get it there, right, Like, you can't just
put a string of genetic material randomly in someone's body, right,
(07:27):
It'll just get destroyed. And so there's this basic idea
that you put it in a virus, right, because a
virus is like, it's billions of years of evolution to
be a genetic material delivery mechanism.
Speaker 3 (07:41):
That's exactly right.
Speaker 1 (07:42):
But that's hard for a number of reasons. So like,
tell me sort of the state of vectors at this
time twenty years ago when you're figuring this out.
Speaker 2 (07:49):
So there were a number of viral vectors that were
being used to deliver genes, and each of them had
their pros and their cons One was named adnovirus. This
was a good virus because it's big, you can fit
a lot of genetic material into it, and it was
used in the early days of gene therapy and on.
Fortunately it was discovered you know later on that it
(08:12):
came with you know, some downsides. It's more immunogenic than
the other viral vectors that are out there.
Speaker 1 (08:17):
Meaning it generates an immune response. So the body's like, oh,
that's a virus. I'm going to destroy it, and you're like, no, no, no,
this is a virus that's going to help you exactly.
It's like, I don't care. I've gotten rid of it.
Speaker 3 (08:27):
Yes, yeah.
Speaker 2 (08:28):
And then of course there was lenty virus, which is
what we were using in the chickens. It is not
the vector of choice, for instance, in the eye where
I work, because it's not very good at delivering genes
to developed cells in the retina. And then in the
nineties some exciting work was going on evaluating a newer
vector called Adno associated virus or AAV. Since the nineties
(08:54):
early two thousands, AAV has become the gold standard gene
delivery vector for essentially all of gene therapy.
Speaker 1 (09:01):
And so at this time in two thousand and four, like,
what was the state of gene therapy?
Speaker 2 (09:08):
Oh, my gosh, it was the heyday. It was such
a fun time and it was so it was so exciting.
The my grad school days, my postdoc days, it was
an extremely exciting time in the field that I would
say it was filled with hope because there was so
much proof of concept work going on in animal models
of disease showing that gene therapy could restore vision, could
(09:31):
restore muscular function, could restore clotting.
Speaker 3 (09:34):
You know, you name it.
Speaker 2 (09:35):
It was these successes were being seen across neuromuscular disease,
CNS disease, ocular disease, but everybody was just really excited
about it, and that extended beyond the scientists in the lab.
That was true of the macro environment too, So you know,
I mean.
Speaker 1 (09:52):
Like in the media or like the industry, like the
pharmaceutical industry.
Speaker 2 (09:57):
Yeah, I'm talking more about like investors and big pharma.
So I mean investors were keen to throw their money
at gene therapy at the time because of how much
promise it was showing in these pre clinical studies, and
big Arma was keen to acquire, you know, startup companies
that were in this space because of that promise it
was showing. And I think their their reason at the
(10:17):
time was a sound one. They wanted to use. Even
if those companies were focused on rare disease, it was
like this platform for them to say, well, if I
can get gene therapy to work in this small, rare disease,
that proves that as a company, I'm capable of doing
this and that eventually I can do it in a
disease that affects millions of people. So it was a
really really exciting time, both scientifically and from kind of
(10:41):
a financial standpoint.
Speaker 1 (10:43):
And then at some point, right there are these these
strong results using gene therapy to treat a disease called
LCA two, which is similar to LCA one, the disease
you work on, and that's like a big moment in
the field, right.
Speaker 2 (10:58):
Yeah, the RP sixty five LCA two gene therapy trials
were a huge success, and then they went on to
form the basis of Luxterno, which is the first approved
ocular gene therapy, and so everybody was super excited that, Okay,
they got this approved. We're going to see this, you know,
flood of other gene therapies getting approved on the heels
(11:18):
of luxtern And I think that's I think that's when
it got hard, and you know, there was a little
bit of a reality check for the field.
Speaker 1 (11:25):
What was that like for you? So you're working on
LCA one, a very similar disease. Everybody is very excited
about l c A two, are you like, yes, we
got l c A two, I'm about to get LCA one.
Like what what was your where were you at that? Oh?
Speaker 3 (11:40):
I was I was super excited.
Speaker 1 (11:41):
I was.
Speaker 2 (11:42):
I was further behind obviously in my pursuit of l
c A one, but I had, you know, high hopes
that it would it would go, that it would work.
Speaker 1 (11:49):
Why didn't it happen as fast as you thought?
Speaker 2 (11:52):
So in twenty fourteen, I hit a stage where you know,
the technology had been developed, I had done everything that
I really could, you know, from the academic standpoint, to
get this ready to move forward. But at that stage
you hit what the NIH calls the valley of death,
which is, you know, a period of time where you
need a lot of capital and a lot of infrastructure
(12:13):
to move a gene therapy from bench to bedside, and
you can't do that in an academic lab.
Speaker 1 (12:18):
So to put it to test it in people, basically
testing it in people is obviously complicated and expensive and
very at least some extent rightly so, right you're ingesting
things into people's eyes.
Speaker 3 (12:30):
Yes.
Speaker 2 (12:31):
In twenty fourteen, my husband and I who I work with,
we were very much in a pattern of developing technologies
and then out licensing them to different companies. So in
around twenty fourteen, we partnered with Genzyme, which was a
company focused on developing gene therapies for rare disease, and
they took that technology. Shortly thereafter they were acquired by
(12:54):
Santafie and together with Genzyme Slash Santafee, we conducted all
of the studies that were what we call I and
D enabling studies, sort of like the really well documented
careful safety studies and efficacy studies, dose ranging studies that
are required to show to the FDA before.
Speaker 3 (13:13):
They let you go into people.
Speaker 1 (13:14):
I INDA is an investigational new drug's exactly. So you're
like doing all the work to say, like, look, this
should be an investigational new drug that we can test
in a very small number of people just to see
if it's safe to start out with exactly.
Speaker 3 (13:27):
Yeah.
Speaker 2 (13:27):
So, and I'll be honest, that moved a little bit
slower than I would have liked. But I mean, when
you work with Big Pharma, and I will say they
were an amazing, amazing team, excellent group of people, but
Big Pharma is very siloed, and you know, it can
take a long time for things to move. And then unfortunately,
in around twenty eighteen, Cianna FI decided to pivot away
(13:50):
from ocular gene therapy altogether, so they wanted to give
the program away, and I was heartbroken. I remember the
night that someone told me it was happening. I couldn't
believe it because you know, we were just about to
treat the first patient and everything was ready to go,
and I just couldn't believe it. But you know, companies
make decisions like this all the time. So when that happened,
(14:13):
that was really what motivated my husband and I to
co found our own company because we wanted hopefully to
get that program back so that we could make sure
that it went forward. And that was just that was
one reason that we founded at Seena Therapeutics. I would
say that the broader reason we founded the company was
out of a sense of frustration because we had developed
(14:35):
a lot of technologies and we had outlcensed them to
a variety of companies, and there was a theme emerging
that the technologies weren't getting to patients. And whether that
was because of you know, business decisions overriding science decisions,
or just you know, companies being too big and siloed,
there were a variety of reasons, but it ultimately we
(14:57):
formed the company because we were frustrated. We wanted to
have some more control over the direction that the science
was taking.
Speaker 1 (15:03):
It's like you want it more than anybody else can
want it.
Speaker 3 (15:07):
Yes, it was.
Speaker 2 (15:08):
I mean one is my baby, right, and so are
some of the other indications that I'm working on now.
But yeah, I wanted to be the one to help
usher them towards patients and keep it moving in the
right direction.
Speaker 1 (15:21):
And you mentioned your husband, So is he in the
same field as you, like, is.
Speaker 3 (15:25):
What's he doing?
Speaker 2 (15:26):
Yeah, he's an AV vectorologist. When I was a grad
student and I was tasked with my thesis project, which
was okay, come up with a clinically relevant approach for
treating this disease. So to do that, I needed to
shift away from Lenti virus and start using ad no
associated virus AAV. I needed to shift into a mouse model,
(15:47):
a mammalian model of the disease, and so to get
help on the AAV aspect of the project, I went
to Bill Houseworth, who became my post docmentor, and he
pointed me in the direction of my now husband. He
was a scientific research manager at the time. He said,
you know, he can field any questions you have about
vector design, and so I went to him and then
that you know was an excellent collaboration obviously that lossoened
(16:09):
into a nerd romance and then eventually a marriage in
two k.
Speaker 1 (16:12):
Yes, it is a very nerdy meet cute, yes.
Speaker 2 (16:17):
But yeah, we're very much in the same field. But
we have very different skill sets, I would say, so
we compliment each other.
Speaker 3 (16:24):
Which is nice.
Speaker 1 (16:26):
Obviously to get from, you know, doing this in chickens
twenty years ago to doing it in people now. There
were many, many, many things I'm sure that you had
to figure out. There is there anything in particular that
was a thing you figured out? Maybe that was a
thing that people doing gene therapy more broadly were trying
to figure out, just in the sense of, yeah, something
(16:47):
you solved along the way.
Speaker 2 (16:49):
In the early days, when I had first transitioned into
testing the AV vector in the mouse, I did it
over and over and over again, and it didn't work.
And I think one big mistake that I made was
that I was using the same gene, the same coding
sequence that we had used in the chicken experiments, and interestingly,
that gene was a bovine gene. In the early two thousands,
(17:12):
it was a lot easier to generate bovine sequences for
reasons I don't even actually remember. But what it took
was figuring out that we needed to deliver the species
specific gene. So the mouse gene worked, the human gene worked,
which was great because that was very translatable, So the
species of the gene was important. Another really important thing
(17:33):
was the foot.
Speaker 1 (17:34):
So basically the versions of the gene exist in these
different animals, but they're slightly different.
Speaker 3 (17:39):
Exactly.
Speaker 1 (17:40):
Yes, I have to say retrospectively out of my armchair ignorance.
I feel like that one seems obvious in retrospect to me.
Speaker 2 (17:50):
But it was strange to me because this bovine sequence
worked in a chicken, so.
Speaker 1 (17:54):
I think, and a mouse and a person who's more
like a cow. Yes, okay, what's another one? What's another one?
You had to figure out?
Speaker 2 (18:03):
Another one was the flavor of AAV that we needed
to use.
Speaker 1 (18:06):
So the particular nature of the vector.
Speaker 3 (18:09):
Yes, exactly.
Speaker 2 (18:10):
So AV comes in a variety of flavors, and one
flavor of AV might be good at infecting neurons, and
another flavor of AV might be good at infecting skin cells,
for instance.
Speaker 1 (18:19):
Yes, and interestingly, in this point, you want it to infect, right,
Infecting is delivering the gene exactly. Huh.
Speaker 2 (18:27):
So we tested for the first time in non human
primates a certain flavor of AV called AAV five, and
we really for the first time showed that that flavor
of AV was really useful in the rod and the
cone foto receptors of the human of a primate retina rather,
so that was the flavor of AV that we needed
to figure out. And then I would say the third
(18:48):
thing that we figured out was a specific regulatory sequence
that we used to drive expression of the gene. So
it's called a promoter, and specifically it's the adoptin kinase promoter,
which drives expression exclusively in photo receptors.
Speaker 1 (19:03):
And so just to be clear, just to unpack that
a little bit, so the idea is, you don't just
need to have the gene itself in this vector. You
need to have the genetic information that tells it in
what kinds of cells should this gene be expressed exactly,
and in what kinds of cells should it not be
(19:23):
expressed exactly.
Speaker 2 (19:24):
And that's important from a safety standpoint, because ideally you
don't want this gene expressing a protein in cells where
it's not supposed to be.
Speaker 1 (19:32):
In potent harm in your heart right exactly in a minute.
What happened when Shannon's drug finally made its way out
of the lab and into the eyes of patience. I
(19:54):
asked Shannon how she got from figuring everything out in
the lab and in animals to actually doing a clinical
trial to actually testing her drug in patience.
Speaker 2 (20:05):
So I will say that, fortunately, before Santafie let the
program go, they did dose a couple of patients, so
we did get them to start the trial thankfully, and
they were absolutely critical and getting that off the ground.
But when they handed it back to at Sina, obviously
we had to build a clinical team and we worked
closely with Santa fe during that transition period to make
(20:27):
sure there were no bumps in the road, and then
we just continued with the trial. We had some amazing
clinical investigators at the University of Pennsylvania and OHSU, which
is Oregon Health Sciences University at the CACI Institute, and
so the surgeons there did the injections. We also had
a surgeon at Will's I Institute, and just excellent teams
(20:49):
of physicians focused on inherited retinal disease that we worked
closely with to monitor these patients over time.
Speaker 1 (20:55):
So you have this virus that you have engineered to
have this gene and this promoter, you inject it into
the back of somebody's eye.
Speaker 2 (21:08):
Then what happens, So the virus infects the photo receptors,
it unloads the DNA inside, and then that DNA remains
inside that cell over the lifetime of that living cell.
So the gene will persistently remain inside that cell and
express that protein that it needs to express. It does
(21:30):
not integrate into the genome. It remains outside the genome.
We call that episomal, but it leads to persistent expression
of that gene and continuous production of that therapeutic protein.
And when the cell dies that when the cell dies,
the gene dies with it. So in order for gene
therapy to be successful, those cells need to be retained.
(21:51):
If the cells degenerate, then that therapeutic effect can be lost.
Speaker 1 (21:54):
And do cells Do those cells last forever?
Speaker 2 (21:57):
It depends on the indication. So that's why LCA one
with such an attractive target is because those patients retain
their photoreceptor structure over their lifetime, So theoretically we could
at persistent rescue over their lifetime.
Speaker 1 (22:11):
So photoreceptor celves just stay there, they develop, and then
they just hang out receiving photons forever.
Speaker 3 (22:18):
Yes, in the syndication yep.
Speaker 1 (22:20):
So like how many people are in this in this trial?
Speaker 3 (22:23):
So we had.
Speaker 2 (22:23):
Fifteen people total enrolled in this trial.
Speaker 1 (22:26):
Okay, And how long does it take to find out
if it works?
Speaker 2 (22:32):
So with this condition, typically we saw responses by about
four weeks post injection, and those responses get a little
bit better up until about two or three months post injection,
at which time the response is plateau. So it's a
very quick, very quick readout.
Speaker 1 (22:48):
And the patients are they completely blind? Like what is
there before when they're coming to you? What is the
state of their vision?
Speaker 2 (22:57):
That's a good question. So there's a range, but we
would consider all LCA one patients to be profoundly visually impaired,
so ranging from twenty two hundred all the way to
light perception only, so legally blind to folks that can
only see light.
Speaker 1 (23:16):
And so when do you first hear about the results,
Like how do the results come into you?
Speaker 2 (23:23):
Well, you have to be very careful as a you know,
co founder and CSO of a company, I you know,
don't have any direct interaction with the patients. That would
be it's kind of a conflict of interest, right, But
you know we do the data starts pouring in into
the you know, the software that we use to collect
that data as a company, and you start to see
(23:45):
the numbers, and on occasion, you know, a patient will
anecdotally tell the physician something and that physician will report
it back to the company, like wow, this this person
was able to see the lines and the crosswalk for
the first time outside last night. Or this woman was
really excited because this Halloween was the first time that
(24:06):
she could read the labels on her kids Halloween. So
you hear, you hear little stories like that, and it's
like they make you cry, right, Like you just can't
believe that it's happening. It's one thing to see a
mouse regain vision and be able to, you know, swim
through a maze. But to hear that a patient can
read something for the first time or navigate outside their
(24:28):
home for the first time, that's something else.
Speaker 1 (24:30):
Yeah, So you're not spending your career trying to cure
blindness in mice.
Speaker 3 (24:34):
Nope, Nope.
Speaker 1 (24:36):
So what was the outcome of that trial?
Speaker 2 (24:40):
Sure, so it was a very positive outcome. We just
published the results in the Lancet a few weeks ago,
looking at all all fifteen of the Phase one two
patients out to one year post treatment, and we showed
that the gene therapy had a very very good safety profile.
There were no you know, serious adverse events related to
the medicine itself, and we showed a very profound efficacy.
(25:04):
So we used a test called FST, which is just
a measure of retinal sensitivity, and we saw, for instance,
in one patient there was a ten thousandfold improvement in
retinal sensitivity. And what that means is it's akin to
someone being able to navigate under bright sunlight versus someone
(25:24):
being able to navigate in the light of the full moon.
So a huge improvement in retinal sensitivity.
Speaker 1 (25:30):
And what is there like a median improvement.
Speaker 2 (25:33):
Yeah, so the median improvement was about one hundredfold improvement,
so really exciting and significant. And then you know, of
course the anecdotes come in. We have one video of
a little girl who saw snowflakes for the first time,
so you know, it's more than the cold hard numbers
like one hundredfold improvement in retal sensitivity. It's you're seeing
(25:53):
a genuine improvement in the patient's quality of life, which
is amazing.
Speaker 1 (25:58):
So what's next?
Speaker 2 (26:00):
So next will be phase three. Before you can get
anything commercialized for broader use, you have to do a
phase three trial. So we're fortunate because our LCA one
program has received what's called an ARMAT designation, and put simply,
that is a designation given to programs that cause a
profound illness at birth and for which you have promising
(26:22):
proof of concept data showing that you might have a cure.
So we receive that designation and we need to align
on a path forward with the FDA. So, in other words,
what does our phase three trial design need to be?
And once we decide on that, then we will execute
that Phase three trial and then hopefully after that we'll
seek approval from the FDA to commercialize it for broader
patient access.
Speaker 1 (26:44):
How many people more or less have LCA one.
Speaker 2 (26:49):
So there's about three thousand patients I would say in
the US and the EU that have they indication.
Speaker 1 (26:56):
So I mean a lot on a human level, but
on a kind of population level, not a lot. It's
very rare, that's correct. And so what does that mean? Well,
what does that mean. I guess on the on the
business side. Right on the science side, it sort of
doesn't matter. It's the same science whether a million people
have it or people have it. But what does it
mean on the business side.
Speaker 2 (27:17):
It's you know, the pendulum has swung back since the
early two thousands where investors in big pharma were all
very eager to throw money into this space, and they're
less excited about rare disease obviously, But you know, as
a scientist who sees the obvious impact it's having on
these patients, I'm going to push it forward with full force.
(27:41):
We've successfully raised money at SENA to keep this program going.
We have plans for it moving forward, and I think
our ability to continue to raise money is increased or
strengthened by the fact that we have other ongoing clinical
programs that are also showing success. So you know, if
you have one rare disease that you have in clinic,
you might be only quasi interesting to investors are big pharma.
(28:03):
But we have a bunch of things going on at
SENA that I think will improve the chances that this
program is forward.
Speaker 1 (28:09):
What else are you working on?
Speaker 2 (28:10):
So we are working actively on another inherited retinal disease
called X linked retinoskeesis or XLRS. We're also in a
phase one two clinical trial and already showing structural and
functional improvements in those patients using a novel flavor of AV,
which has been interesting. So really excited.
Speaker 1 (28:31):
So you have a separate indication where you're in clinical trials, yep,
and anything else. I feel like remember seeing a couple
more on the website.
Speaker 3 (28:41):
Now, yeah, else.
Speaker 1 (28:43):
Yeah.
Speaker 2 (28:43):
So we're also working on a dual vector technology. So
there are some indications caused by mutations in large genes
that don't fit inside a standard AAV vector. So we've
developed a technology wherein we split that large gene in half.
We deliver the front half via one AAV in the
back half via a second AV.
Speaker 3 (29:02):
Those two. Yeah, it's really cool.
Speaker 1 (29:05):
Say one gene, it's one gene and you're putting it
into two different yes suitcases.
Speaker 3 (29:10):
That's very sically Yeah, and.
Speaker 1 (29:12):
Then dumb question, how does it get put back together?
Speaker 2 (29:15):
So there's a complimentary sequence shared between the front and
the back half. So when the two suitcases unpack their
their respective front and back half genes, they find each
other via that complementary sequence and then they recombine to
form a full length gene.
Speaker 1 (29:32):
That is wild. Have people done that technique in other
other you know, indications of gene therapy and other domains
they have.
Speaker 2 (29:41):
Yes, there's a company recently that it is in the
hearing space actually, but they use dual vectors to deliver
a certain gene to patients that had hearing loss and
restored hearing to these children.
Speaker 1 (29:53):
So, and is the issue the gene is just too long,
like it physically just doesn't fit inside. That's correct.
Speaker 2 (30:00):
Yeah, So standard AV can only fit about five thousand
base pairs of DNA, and some of these genes are
are just too big to fit.
Speaker 1 (30:09):
That is so clever. I love it when people are
so clever. So let's let's zoom out. And you know,
you've been working on gene therapy for twenty years ish,
which is close to the life of gene therapy. Right
of the field you got in or early, you've been
there a long time. A lot has happened. Like when
(30:31):
you zoom out, what do you see? Like where is
the field now? You know? Yeah, where is it now?
What's the big picture for gene therapy right now?
Speaker 2 (30:40):
I think the big picture for gene therapy right now
is we're a little bit bruised, right. You know, we
have the success of Luxterna getting approved. Then you know
you've got zulgensimo, which is a huge success story. And
those were the successes. But we entered a period around
that same time where I think, unfortunately, folks were taking
(31:01):
a one size fits all approach to gene therapy. In
other words, like, Okay, if this flavor of av or
this regulatory region or this dose worked for lucerna, then
it's going to work for this other indication, right, And
I think that hasn't That hasn't played out right. It's
not a one size fits all approach. Every indication needs
a treatment tailored to that indication. What cell type is impacted,
(31:25):
you know, does the gene expression need to be restricted,
what dose needs to be used, what's the underlying immune
status of that patient's retina for instance. So it's not
a one size fits all approach, and I think I
think people have realized that.
Speaker 1 (31:38):
So like, so does that mean it's going to be
hard every time? I mean it's going to be hard forever,
And it's not like great, we figured it out and
we can just put any gene into this vector and
will cure everything.
Speaker 2 (31:51):
Yeah, I mean I think it's somewhere in the middle, right,
It's it's it's never going to be like just plug
and play, right, But there are certainly tools that are
being developed along the way that can be you know,
used in one trial and used in another trial. But
I think you always have to put a lot of
thought into it. It can't just simply be Okay, if
this worked for l c A two, then it's going
(32:12):
to work for disease X, right. There always has to
be a thoughtful process.
Speaker 1 (32:17):
I mean, is it harder than you thought it was
going to be?
Speaker 3 (32:23):
Yes?
Speaker 2 (32:24):
You know, in my grad school days it was hope, hope, hope,
you know, excitement, excitement, excitement, and then forming my own
company and being in charge of kind of the fundraising
behind keeping these programs going. It's been it's been a
lot of work, but I believe strongly in what I
do and that it's having a positive impact on patient lives,
(32:45):
and so it's it's worth that effort.
Speaker 1 (32:50):
We'll be back in a minute with the lightning round.
M hm hm. Let's finish with the lightning round. Okay,
what's the best thing about working with your husband.
Speaker 2 (33:13):
Oh, let's see. I think that at the end of
the day, we can understand each other's stresses. You know,
It's not like coming home and you know he has
no idea what I'm talking about. It's like, if I
have a problem, he can think through it very clearly
because he understands it at its core and give me
advice on how to navigate the situation and vice versa.
Speaker 1 (33:36):
What's the worst thing about working with your husband?
Speaker 2 (33:41):
Sometimes there's you know, evenings where I'm done talking about
a vy. You know, I've done it all day long,
and we're sitting over the dinner table with our kids
and he's still talking about, you know, designing a vector
to do whatever, and I'm like, Okay, we're done here,
We're done for the night. But I mean it's with
us all the time, and I think that's what makes
us better scientists for it.
Speaker 1 (34:02):
What's one interesting or surprising thing you've learned about the
human eye?
Speaker 2 (34:08):
The human eye, I would say most of all that
you can be seventy years old and have had a
congenital form of blindness since you were a baby and
still benefit from gene therapy. And that's wild to me, Like,
you know, I got my PhD and neuroscience, so I'm
always thinking about you know, so what if we restore
(34:29):
function to the retina, what's that going to mean in
the brain? Is the brain going to be able to
be receptive to that message if it's been turned off
from that message input its entire life?
Speaker 3 (34:39):
Right?
Speaker 2 (34:40):
But we had a seventy year old patient in our
LCA one clinical trial that showed some benefit following gene therapy,
and that tells me that the brain is, you know,
extremely plastic, more plastic than I gave it credit for before.
Speaker 1 (34:53):
Huh, So it's not the eye but the brain. Like
we're not really seeing with our eye. Our eye is
just like the window and the brain is really where
the seeing is happening.
Speaker 3 (35:02):
That's right.
Speaker 1 (35:04):
I read that you have a boat called wet Lab
we do. H What was the runner up name? Oh?
Speaker 2 (35:13):
I don't think we had a runner up. We've planned
that one for years.
Speaker 1 (35:20):
What's the biggest fish you ever caught? Oh?
Speaker 2 (35:23):
My goodness. We go all the time and we catch
big fish so often. I don't remember the biggest one
that you catch.
Speaker 1 (35:30):
So many big things to tell a first story. Thank
you so much, for your time. It was very interesting
to talk to you. I learned.
Speaker 2 (35:40):
Thank you, Thank you. You're a great interviewer. This was
a pleasure.
Speaker 1 (35:46):
Jennon boy is a professor of genetics at the University
of Florida and the co founder and chief scientific officer
of Atsina Therapeutics. Just a quick note, the show is
going to take a break. We'll be back with new
episodes in a couple of weeks. In the meantime, please
let us know who you'd like to hear on the show,
who I should interview, were, just how we can make
(36:06):
the show better. You can email us at at pushkin
dot fm. Today's show was produced by Gabriel Hunter Chang.
It was edited by Lyddy Jean Kott and engineered by
Sarah Buguer. You can email us at Problem at pushkin
dot fm. I'm Jacob Goldstein and we'll be back next
week with another episode of What's Your Problem.
Pushkin. Think about the basic idea of gene therapy. You
string together a gene, put the gene inside a virus,
put the virus inside a patient, and then the virus
delivers the gene to the patient, sells, and then that
new gene, if everything goes according to plan, makes the
(00:37):
patient get better. It sounds hard, it is hard, but
after decades of research, gene therapy is starting to work.
I'm Jacob Goldstein and this is What's Your Problem, the
show where I talk to people who are trying to
make technological progress. My guest today is Shannon boy She's
(00:59):
a professor of genetics at the University of Florida and
the co founder and chief scientific officer of Atsina Therapeutics.
Shannon's problem is this, how do you use gene therapy
to cure blindness, or at least certain forms of blindness.
Shannon has been working on gene therapy for twenty years,
and I wanted to talk with her about the long
(01:22):
arc of the field, from the wild optimism of the
early two thousands to the realization that developing gene therapy
would be a long, hard slog, to the recent promising
results from an experimental drug that her company has developed
that drug treats a rare disease that Sharon started studying
as a grad student back in two thousand and four.
(01:42):
The disease is called LCA one.
Speaker 2 (01:46):
So babies are born with the disease and usually within
the first few months of life, their moms or dads
notice that they're not looking at them directly, they're not
fixating on objects. Oftentimes the babies will have a roving
eye movement called nystagmus, and so they're diagnosed usually pretty
quickly with this condition, and unfortunately, it's profound visual impairment,
(02:09):
if not total blindness, and that remains with the patient
throughout the course of their life. So that's really the
reason that this lab was really interested in studying that
gene AHU.
Speaker 1 (02:20):
So it's one of the somewhat rare instances where there
is like a single gene that maps to a single
in this case, profound problem basically blindness or severe problems
with vision, which is kind of you would think would
be the first wave of gene therapy, right exactly, This
(02:41):
is what the early two thousands, when you're and so
the human genome has just been mapped, there's like a
sense of oh, now we know all the genes, right,
let's figure out how to help people with this new knowledge.
Speaker 2 (02:53):
That's exactly right. This was sort of the step one
in gene therapy was the simplest form, which is just
gene replacement. Can we take a healthy copy of a
gene and put it back into the patient's cells and
then have that gene go on to make the protein
it was supposed to make and then hopefully rett or
the function to those cells.
Speaker 1 (03:11):
And so what as a grad student are you trying
to figure out?
Speaker 2 (03:16):
The lab was studying the biochemical underpinnings of this disease,
and they were using a chicken model to do this.
That's kind of a unique thing in a lab. Usually
research labs are using mice or rats, but there was
a naturally occurring chicken model of this disease that had
profound visual impairment and blindness.
Speaker 1 (03:33):
So naturally occurring chicken model basically means this happens to
chickens too, Yes, exactly, it is. That's right.
Speaker 2 (03:41):
Yeah. So, at the same time that the lab was studying,
you know, what was going wrong in this chicken and
why it was happening, they wanted to ask the question
would gene therapy be a reasonable approach for treating these chickens.
Can we restore visions to these chickens with gene therapy.
So this was a collaborative effort with my other grad
(04:02):
students and I where we took a vector called Lenti
virus and we to the chicken embryos. I felt very
much in grad school like I was a poultry farmer,
because I would on my way into lab every day,
stop at the farm, pick up the eggs, burning them
into lab, and then my fellow grad students and I
(04:25):
we would make these tiny little holes in the chicken
egg and we would pull these glass micro needles and
use them to inject into the chicken embryo. And remember
this is a disease that you have from birth, so
we needed to treat these chickens very early. But it
was a difficult process to get that micro needle injection
into the head of the chicken embryo and then for
(04:47):
that chicken to make it all the way to hatch, right,
And that was I think one of the hardest parts
of that project. Actually, It's why I said I felt
like a poultry farmer. Is all of the machinations you know,
getting the humidity right, the temperature right, the position right,
making sure you close that egg right, just getting that
chicken to survive.
Speaker 1 (05:07):
And so you injecting the non mutated form of the gene,
the good form of the gene, if you will, encased
in this virus, into the head of the chicken embryo. Yes,
did it work?
Speaker 2 (05:25):
For a while it did not, because again, it was
difficult to manipulate a chicken embryo like that and actually
have it to survive to hatch. But my fellow grad
students and I did a lot of work to optimize
that process, and eventually it actually did work. We had
little chicks that were born, and I can distinctly remember
them walking around on the lab bench and pecking at
(05:48):
our jewelry or at Eminem's that we had laid out
on the surface of the bench. Very different from the
blind chickens. It was very clear. You know, chickens are
very visually guided creatures. It's very obvious when a chicken
can see versus Nazi.
Speaker 3 (06:03):
It was so fun. We were all so so happy.
Speaker 1 (06:07):
Okay, so that's two thousand and four as twenty years ago. Yeah, yeah,
at that time, is it like, well, we did it
in chickens, let's do it in people or what.
Speaker 2 (06:19):
So that's actually where my thesis project comes in. So
all of that chicken work was a really collaborative effort
and it was exciting, but it had its drawbacks and
it wasn't clinically translatable for a number of reasons. First
and foremost, we were never going to do an embryonic
injection and a patient. Maybe that'll happen one day, honestly,
but it certainly wasn't close to happening in two thousand
(06:41):
and four. So we needed a gene therapy that could
be injected in a patient after birth, right, And unfortunately,
the virus that we were using in the chicken experiments,
the Lenti virus, is really poor at a gene delivery
to a developed retina. So we needed to find a
more clinically relevant vector to do the gene therapy.
Speaker 1 (07:02):
Let's just pause for a moment and talk about this
idea of a vector in gene therapy. So the basic idea, right,
is like, you know what the good gene is, you
know the gene you want to get into, in this case,
the person's eye. But there's this weird question of how
do you get it there, right, Like, you can't just
put a string of genetic material randomly in someone's body, right,
(07:27):
It'll just get destroyed. And so there's this basic idea
that you put it in a virus, right, because a
virus is like, it's billions of years of evolution to
be a genetic material delivery mechanism.
Speaker 3 (07:41):
That's exactly right.
Speaker 1 (07:42):
But that's hard for a number of reasons. So like,
tell me sort of the state of vectors at this
time twenty years ago when you're figuring this out.
Speaker 2 (07:49):
So there were a number of viral vectors that were
being used to deliver genes, and each of them had
their pros and their cons One was named adnovirus. This
was a good virus because it's big, you can fit
a lot of genetic material into it, and it was
used in the early days of gene therapy and on.
Fortunately it was discovered you know later on that it
(08:12):
came with you know, some downsides. It's more immunogenic than
the other viral vectors that are out there.
Speaker 1 (08:17):
Meaning it generates an immune response. So the body's like, oh,
that's a virus. I'm going to destroy it, and you're like, no, no, no,
this is a virus that's going to help you exactly.
It's like, I don't care. I've gotten rid of it.
Speaker 3 (08:27):
Yes, yeah.
Speaker 2 (08:28):
And then of course there was lenty virus, which is
what we were using in the chickens. It is not
the vector of choice, for instance, in the eye where
I work, because it's not very good at delivering genes
to developed cells in the retina. And then in the
nineties some exciting work was going on evaluating a newer
vector called Adno associated virus or AAV. Since the nineties
(08:54):
early two thousands, AAV has become the gold standard gene
delivery vector for essentially all of gene therapy.
Speaker 1 (09:01):
And so at this time in two thousand and four, like,
what was the state of gene therapy?
Speaker 2 (09:08):
Oh, my gosh, it was the heyday. It was such
a fun time and it was so it was so exciting.
The my grad school days, my postdoc days, it was
an extremely exciting time in the field that I would
say it was filled with hope because there was so
much proof of concept work going on in animal models
of disease showing that gene therapy could restore vision, could
(09:31):
restore muscular function, could restore clotting.
Speaker 3 (09:34):
You know, you name it.
Speaker 2 (09:35):
It was these successes were being seen across neuromuscular disease,
CNS disease, ocular disease, but everybody was just really excited
about it, and that extended beyond the scientists in the lab.
That was true of the macro environment too, So you know,
I mean.
Speaker 1 (09:52):
Like in the media or like the industry, like the
pharmaceutical industry.
Speaker 2 (09:57):
Yeah, I'm talking more about like investors and big pharma.
So I mean investors were keen to throw their money
at gene therapy at the time because of how much
promise it was showing in these pre clinical studies, and
big Arma was keen to acquire, you know, startup companies
that were in this space because of that promise it
was showing. And I think their their reason at the
(10:17):
time was a sound one. They wanted to use. Even
if those companies were focused on rare disease, it was
like this platform for them to say, well, if I
can get gene therapy to work in this small, rare disease,
that proves that as a company, I'm capable of doing
this and that eventually I can do it in a
disease that affects millions of people. So it was a
really really exciting time, both scientifically and from kind of
(10:41):
a financial standpoint.
Speaker 1 (10:43):
And then at some point, right there are these these
strong results using gene therapy to treat a disease called
LCA two, which is similar to LCA one, the disease
you work on, and that's like a big moment in
the field, right.
Speaker 2 (10:58):
Yeah, the RP sixty five LCA two gene therapy trials
were a huge success, and then they went on to
form the basis of Luxterno, which is the first approved
ocular gene therapy, and so everybody was super excited that, Okay,
they got this approved. We're going to see this, you know,
flood of other gene therapies getting approved on the heels
(11:18):
of luxtern And I think that's I think that's when
it got hard, and you know, there was a little
bit of a reality check for the field.
Speaker 1 (11:25):
What was that like for you? So you're working on
LCA one, a very similar disease. Everybody is very excited
about l c A two, are you like, yes, we
got l c A two, I'm about to get LCA one.
Like what what was your where were you at that? Oh?
Speaker 3 (11:40):
I was I was super excited.
Speaker 1 (11:41):
I was.
Speaker 2 (11:42):
I was further behind obviously in my pursuit of l
c A one, but I had, you know, high hopes
that it would it would go, that it would work.
Speaker 1 (11:49):
Why didn't it happen as fast as you thought?
Speaker 2 (11:52):
So in twenty fourteen, I hit a stage where you know,
the technology had been developed, I had done everything that
I really could, you know, from the academic standpoint, to
get this ready to move forward. But at that stage
you hit what the NIH calls the valley of death,
which is, you know, a period of time where you
need a lot of capital and a lot of infrastructure
(12:13):
to move a gene therapy from bench to bedside, and
you can't do that in an academic lab.
Speaker 1 (12:18):
So to put it to test it in people, basically
testing it in people is obviously complicated and expensive and
very at least some extent rightly so, right you're ingesting
things into people's eyes.
Speaker 3 (12:30):
Yes.
Speaker 2 (12:31):
In twenty fourteen, my husband and I who I work with,
we were very much in a pattern of developing technologies
and then out licensing them to different companies. So in
around twenty fourteen, we partnered with Genzyme, which was a
company focused on developing gene therapies for rare disease, and
they took that technology. Shortly thereafter they were acquired by
(12:54):
Santafie and together with Genzyme Slash Santafee, we conducted all
of the studies that were what we call I and
D enabling studies, sort of like the really well documented
careful safety studies and efficacy studies, dose ranging studies that
are required to show to the FDA before.
Speaker 3 (13:13):
They let you go into people.
Speaker 1 (13:14):
I INDA is an investigational new drug's exactly. So you're
like doing all the work to say, like, look, this
should be an investigational new drug that we can test
in a very small number of people just to see
if it's safe to start out with exactly.
Speaker 3 (13:27):
Yeah.
Speaker 2 (13:27):
So, and I'll be honest, that moved a little bit
slower than I would have liked. But I mean, when
you work with Big Pharma, and I will say they
were an amazing, amazing team, excellent group of people, but
Big Pharma is very siloed, and you know, it can
take a long time for things to move. And then unfortunately,
in around twenty eighteen, Cianna FI decided to pivot away
(13:50):
from ocular gene therapy altogether, so they wanted to give
the program away, and I was heartbroken. I remember the
night that someone told me it was happening. I couldn't
believe it because you know, we were just about to
treat the first patient and everything was ready to go,
and I just couldn't believe it. But you know, companies
make decisions like this all the time. So when that happened,
(14:13):
that was really what motivated my husband and I to
co found our own company because we wanted hopefully to
get that program back so that we could make sure
that it went forward. And that was just that was
one reason that we founded at Seena Therapeutics. I would
say that the broader reason we founded the company was
out of a sense of frustration because we had developed
(14:35):
a lot of technologies and we had outlcensed them to
a variety of companies, and there was a theme emerging
that the technologies weren't getting to patients. And whether that
was because of you know, business decisions overriding science decisions,
or just you know, companies being too big and siloed,
there were a variety of reasons, but it ultimately we
(14:57):
formed the company because we were frustrated. We wanted to
have some more control over the direction that the science
was taking.
Speaker 1 (15:03):
It's like you want it more than anybody else can
want it.
Speaker 3 (15:07):
Yes, it was.
Speaker 2 (15:08):
I mean one is my baby, right, and so are
some of the other indications that I'm working on now.
But yeah, I wanted to be the one to help
usher them towards patients and keep it moving in the
right direction.
Speaker 1 (15:21):
And you mentioned your husband, So is he in the
same field as you, like, is.
Speaker 3 (15:25):
What's he doing?
Speaker 2 (15:26):
Yeah, he's an AV vectorologist. When I was a grad
student and I was tasked with my thesis project, which
was okay, come up with a clinically relevant approach for
treating this disease. So to do that, I needed to
shift away from Lenti virus and start using ad no
associated virus AAV. I needed to shift into a mouse model,
(15:47):
a mammalian model of the disease, and so to get
help on the AAV aspect of the project, I went
to Bill Houseworth, who became my post docmentor, and he
pointed me in the direction of my now husband. He
was a scientific research manager at the time. He said,
you know, he can field any questions you have about
vector design, and so I went to him and then
that you know was an excellent collaboration obviously that lossoened
(16:09):
into a nerd romance and then eventually a marriage in
two k.
Speaker 1 (16:12):
Yes, it is a very nerdy meet cute, yes.
Speaker 2 (16:17):
But yeah, we're very much in the same field. But
we have very different skill sets, I would say, so
we compliment each other.
Speaker 3 (16:24):
Which is nice.
Speaker 1 (16:26):
Obviously to get from, you know, doing this in chickens
twenty years ago to doing it in people now. There
were many, many, many things I'm sure that you had
to figure out. There is there anything in particular that
was a thing you figured out? Maybe that was a
thing that people doing gene therapy more broadly were trying
to figure out, just in the sense of, yeah, something
(16:47):
you solved along the way.
Speaker 2 (16:49):
In the early days, when I had first transitioned into
testing the AV vector in the mouse, I did it
over and over and over again, and it didn't work.
And I think one big mistake that I made was
that I was using the same gene, the same coding
sequence that we had used in the chicken experiments, and interestingly,
that gene was a bovine gene. In the early two thousands,
(17:12):
it was a lot easier to generate bovine sequences for
reasons I don't even actually remember. But what it took
was figuring out that we needed to deliver the species
specific gene. So the mouse gene worked, the human gene worked,
which was great because that was very translatable, So the
species of the gene was important. Another really important thing
(17:33):
was the foot.
Speaker 1 (17:34):
So basically the versions of the gene exist in these
different animals, but they're slightly different.
Speaker 3 (17:39):
Exactly.
Speaker 1 (17:40):
Yes, I have to say retrospectively out of my armchair ignorance.
I feel like that one seems obvious in retrospect to me.
Speaker 2 (17:50):
But it was strange to me because this bovine sequence
worked in a chicken, so.
Speaker 1 (17:54):
I think, and a mouse and a person who's more
like a cow. Yes, okay, what's another one? What's another one?
You had to figure out?
Speaker 2 (18:03):
Another one was the flavor of AAV that we needed
to use.
Speaker 1 (18:06):
So the particular nature of the vector.
Speaker 3 (18:09):
Yes, exactly.
Speaker 2 (18:10):
So AV comes in a variety of flavors, and one
flavor of AV might be good at infecting neurons, and
another flavor of AV might be good at infecting skin cells,
for instance.
Speaker 1 (18:19):
Yes, and interestingly, in this point, you want it to infect, right,
Infecting is delivering the gene exactly. Huh.
Speaker 2 (18:27):
So we tested for the first time in non human
primates a certain flavor of AV called AAV five, and
we really for the first time showed that that flavor
of AV was really useful in the rod and the
cone foto receptors of the human of a primate retina rather,
so that was the flavor of AV that we needed
to figure out. And then I would say the third
(18:48):
thing that we figured out was a specific regulatory sequence
that we used to drive expression of the gene. So
it's called a promoter, and specifically it's the adoptin kinase promoter,
which drives expression exclusively in photo receptors.
Speaker 1 (19:03):
And so just to be clear, just to unpack that
a little bit, so the idea is, you don't just
need to have the gene itself in this vector. You
need to have the genetic information that tells it in
what kinds of cells should this gene be expressed exactly,
and in what kinds of cells should it not be
(19:23):
expressed exactly.
Speaker 2 (19:24):
And that's important from a safety standpoint, because ideally you
don't want this gene expressing a protein in cells where
it's not supposed to be.
Speaker 1 (19:32):
In potent harm in your heart right exactly in a minute.
What happened when Shannon's drug finally made its way out
of the lab and into the eyes of patience. I
(19:54):
asked Shannon how she got from figuring everything out in
the lab and in animals to actually doing a clinical
trial to actually testing her drug in patience.
Speaker 2 (20:05):
So I will say that, fortunately, before Santafie let the
program go, they did dose a couple of patients, so
we did get them to start the trial thankfully, and
they were absolutely critical and getting that off the ground.
But when they handed it back to at Sina, obviously
we had to build a clinical team and we worked
closely with Santa fe during that transition period to make
(20:27):
sure there were no bumps in the road, and then
we just continued with the trial. We had some amazing
clinical investigators at the University of Pennsylvania and OHSU, which
is Oregon Health Sciences University at the CACI Institute, and
so the surgeons there did the injections. We also had
a surgeon at Will's I Institute, and just excellent teams
(20:49):
of physicians focused on inherited retinal disease that we worked
closely with to monitor these patients over time.
Speaker 1 (20:55):
So you have this virus that you have engineered to
have this gene and this promoter, you inject it into
the back of somebody's eye.
Speaker 2 (21:08):
Then what happens, So the virus infects the photo receptors,
it unloads the DNA inside, and then that DNA remains
inside that cell over the lifetime of that living cell.
So the gene will persistently remain inside that cell and
express that protein that it needs to express. It does
(21:30):
not integrate into the genome. It remains outside the genome.
We call that episomal, but it leads to persistent expression
of that gene and continuous production of that therapeutic protein.
And when the cell dies that when the cell dies,
the gene dies with it. So in order for gene
therapy to be successful, those cells need to be retained.
(21:51):
If the cells degenerate, then that therapeutic effect can be lost.
Speaker 1 (21:54):
And do cells Do those cells last forever?
Speaker 2 (21:57):
It depends on the indication. So that's why LCA one
with such an attractive target is because those patients retain
their photoreceptor structure over their lifetime, So theoretically we could
at persistent rescue over their lifetime.
Speaker 1 (22:11):
So photoreceptor celves just stay there, they develop, and then
they just hang out receiving photons forever.
Speaker 3 (22:18):
Yes, in the syndication yep.
Speaker 1 (22:20):
So like how many people are in this in this trial?
Speaker 3 (22:23):
So we had.
Speaker 2 (22:23):
Fifteen people total enrolled in this trial.
Speaker 1 (22:26):
Okay, And how long does it take to find out
if it works?
Speaker 2 (22:32):
So with this condition, typically we saw responses by about
four weeks post injection, and those responses get a little
bit better up until about two or three months post injection,
at which time the response is plateau. So it's a
very quick, very quick readout.
Speaker 1 (22:48):
And the patients are they completely blind? Like what is
there before when they're coming to you? What is the
state of their vision?
Speaker 2 (22:57):
That's a good question. So there's a range, but we
would consider all LCA one patients to be profoundly visually impaired,
so ranging from twenty two hundred all the way to
light perception only, so legally blind to folks that can
only see light.
Speaker 1 (23:16):
And so when do you first hear about the results,
Like how do the results come into you?
Speaker 2 (23:23):
Well, you have to be very careful as a you know,
co founder and CSO of a company, I you know,
don't have any direct interaction with the patients. That would
be it's kind of a conflict of interest, right, But
you know we do the data starts pouring in into
the you know, the software that we use to collect
that data as a company, and you start to see
(23:45):
the numbers, and on occasion, you know, a patient will
anecdotally tell the physician something and that physician will report
it back to the company, like wow, this this person
was able to see the lines and the crosswalk for
the first time outside last night. Or this woman was
really excited because this Halloween was the first time that
(24:06):
she could read the labels on her kids Halloween. So
you hear, you hear little stories like that, and it's
like they make you cry, right, Like you just can't
believe that it's happening. It's one thing to see a
mouse regain vision and be able to, you know, swim
through a maze. But to hear that a patient can
read something for the first time or navigate outside their
(24:28):
home for the first time, that's something else.
Speaker 1 (24:30):
Yeah, So you're not spending your career trying to cure
blindness in mice.
Speaker 3 (24:34):
Nope, Nope.
Speaker 1 (24:36):
So what was the outcome of that trial?
Speaker 2 (24:40):
Sure, so it was a very positive outcome. We just
published the results in the Lancet a few weeks ago,
looking at all all fifteen of the Phase one two
patients out to one year post treatment, and we showed
that the gene therapy had a very very good safety profile.
There were no you know, serious adverse events related to
the medicine itself, and we showed a very profound efficacy.
(25:04):
So we used a test called FST, which is just
a measure of retinal sensitivity, and we saw, for instance,
in one patient there was a ten thousandfold improvement in
retinal sensitivity. And what that means is it's akin to
someone being able to navigate under bright sunlight versus someone
(25:24):
being able to navigate in the light of the full moon.
So a huge improvement in retinal sensitivity.
Speaker 1 (25:30):
And what is there like a median improvement.
Speaker 2 (25:33):
Yeah, so the median improvement was about one hundredfold improvement,
so really exciting and significant. And then you know, of
course the anecdotes come in. We have one video of
a little girl who saw snowflakes for the first time,
so you know, it's more than the cold hard numbers
like one hundredfold improvement in retal sensitivity. It's you're seeing
(25:53):
a genuine improvement in the patient's quality of life, which
is amazing.
Speaker 1 (25:58):
So what's next?
Speaker 2 (26:00):
So next will be phase three. Before you can get
anything commercialized for broader use, you have to do a
phase three trial. So we're fortunate because our LCA one
program has received what's called an ARMAT designation, and put simply,
that is a designation given to programs that cause a
profound illness at birth and for which you have promising
(26:22):
proof of concept data showing that you might have a cure.
So we receive that designation and we need to align
on a path forward with the FDA. So, in other words,
what does our phase three trial design need to be?
And once we decide on that, then we will execute
that Phase three trial and then hopefully after that we'll
seek approval from the FDA to commercialize it for broader
patient access.
Speaker 1 (26:44):
How many people more or less have LCA one.
Speaker 2 (26:49):
So there's about three thousand patients I would say in
the US and the EU that have they indication.
Speaker 1 (26:56):
So I mean a lot on a human level, but
on a kind of population level, not a lot. It's
very rare, that's correct. And so what does that mean? Well,
what does that mean. I guess on the on the
business side. Right on the science side, it sort of
doesn't matter. It's the same science whether a million people
have it or people have it. But what does it
mean on the business side.
Speaker 2 (27:17):
It's you know, the pendulum has swung back since the
early two thousands where investors in big pharma were all
very eager to throw money into this space, and they're
less excited about rare disease obviously, But you know, as
a scientist who sees the obvious impact it's having on
these patients, I'm going to push it forward with full force.
(27:41):
We've successfully raised money at SENA to keep this program going.
We have plans for it moving forward, and I think
our ability to continue to raise money is increased or
strengthened by the fact that we have other ongoing clinical
programs that are also showing success. So you know, if
you have one rare disease that you have in clinic,
you might be only quasi interesting to investors are big pharma.
(28:03):
But we have a bunch of things going on at
SENA that I think will improve the chances that this
program is forward.
Speaker 1 (28:09):
What else are you working on?
Speaker 2 (28:10):
So we are working actively on another inherited retinal disease
called X linked retinoskeesis or XLRS. We're also in a
phase one two clinical trial and already showing structural and
functional improvements in those patients using a novel flavor of AV,
which has been interesting. So really excited.
Speaker 1 (28:31):
So you have a separate indication where you're in clinical trials, yep,
and anything else. I feel like remember seeing a couple
more on the website.
Speaker 3 (28:41):
Now, yeah, else.
Speaker 1 (28:43):
Yeah.
Speaker 2 (28:43):
So we're also working on a dual vector technology. So
there are some indications caused by mutations in large genes
that don't fit inside a standard AAV vector. So we've
developed a technology wherein we split that large gene in half.
We deliver the front half via one AAV in the
back half via a second AV.
Speaker 3 (29:02):
Those two. Yeah, it's really cool.
Speaker 1 (29:05):
Say one gene, it's one gene and you're putting it
into two different yes suitcases.
Speaker 3 (29:10):
That's very sically Yeah, and.
Speaker 1 (29:12):
Then dumb question, how does it get put back together?
Speaker 2 (29:15):
So there's a complimentary sequence shared between the front and
the back half. So when the two suitcases unpack their
their respective front and back half genes, they find each
other via that complementary sequence and then they recombine to
form a full length gene.
Speaker 1 (29:32):
That is wild. Have people done that technique in other
other you know, indications of gene therapy and other domains
they have.
Speaker 2 (29:41):
Yes, there's a company recently that it is in the
hearing space actually, but they use dual vectors to deliver
a certain gene to patients that had hearing loss and
restored hearing to these children.
Speaker 1 (29:53):
So, and is the issue the gene is just too long,
like it physically just doesn't fit inside. That's correct.
Speaker 2 (30:00):
Yeah, So standard AV can only fit about five thousand
base pairs of DNA, and some of these genes are
are just too big to fit.
Speaker 1 (30:09):
That is so clever. I love it when people are
so clever. So let's let's zoom out. And you know,
you've been working on gene therapy for twenty years ish,
which is close to the life of gene therapy. Right
of the field you got in or early, you've been
there a long time. A lot has happened. Like when
(30:31):
you zoom out, what do you see? Like where is
the field now? You know? Yeah, where is it now?
What's the big picture for gene therapy right now?
Speaker 2 (30:40):
I think the big picture for gene therapy right now
is we're a little bit bruised, right. You know, we
have the success of Luxterna getting approved. Then you know
you've got zulgensimo, which is a huge success story. And
those were the successes. But we entered a period around
that same time where I think, unfortunately, folks were taking
(31:01):
a one size fits all approach to gene therapy. In
other words, like, Okay, if this flavor of av or
this regulatory region or this dose worked for lucerna, then
it's going to work for this other indication, right, And
I think that hasn't That hasn't played out right. It's
not a one size fits all approach. Every indication needs
a treatment tailored to that indication. What cell type is impacted,
(31:25):
you know, does the gene expression need to be restricted,
what dose needs to be used, what's the underlying immune
status of that patient's retina for instance. So it's not
a one size fits all approach, and I think I
think people have realized that.
Speaker 1 (31:38):
So like, so does that mean it's going to be
hard every time? I mean it's going to be hard forever,
And it's not like great, we figured it out and
we can just put any gene into this vector and
will cure everything.
Speaker 2 (31:51):
Yeah, I mean I think it's somewhere in the middle, right,
It's it's it's never going to be like just plug
and play, right, But there are certainly tools that are
being developed along the way that can be you know,
used in one trial and used in another trial. But
I think you always have to put a lot of
thought into it. It can't just simply be Okay, if
this worked for l c A two, then it's going
(32:12):
to work for disease X, right. There always has to
be a thoughtful process.
Speaker 1 (32:17):
I mean, is it harder than you thought it was
going to be?
Speaker 3 (32:23):
Yes?
Speaker 2 (32:24):
You know, in my grad school days it was hope, hope, hope,
you know, excitement, excitement, excitement, and then forming my own
company and being in charge of kind of the fundraising
behind keeping these programs going. It's been it's been a
lot of work, but I believe strongly in what I
do and that it's having a positive impact on patient lives,
(32:45):
and so it's it's worth that effort.
Speaker 1 (32:50):
We'll be back in a minute with the lightning round.
M hm hm. Let's finish with the lightning round. Okay,
what's the best thing about working with your husband.
Speaker 2 (33:13):
Oh, let's see. I think that at the end of
the day, we can understand each other's stresses. You know,
It's not like coming home and you know he has
no idea what I'm talking about. It's like, if I
have a problem, he can think through it very clearly
because he understands it at its core and give me
advice on how to navigate the situation and vice versa.
Speaker 1 (33:36):
What's the worst thing about working with your husband?
Speaker 2 (33:41):
Sometimes there's you know, evenings where I'm done talking about
a vy. You know, I've done it all day long,
and we're sitting over the dinner table with our kids
and he's still talking about, you know, designing a vector
to do whatever, and I'm like, Okay, we're done here,
We're done for the night. But I mean it's with
us all the time, and I think that's what makes
us better scientists for it.
Speaker 1 (34:02):
What's one interesting or surprising thing you've learned about the
human eye?
Speaker 2 (34:08):
The human eye, I would say most of all that
you can be seventy years old and have had a
congenital form of blindness since you were a baby and
still benefit from gene therapy. And that's wild to me, Like,
you know, I got my PhD and neuroscience, so I'm
always thinking about you know, so what if we restore
(34:29):
function to the retina, what's that going to mean in
the brain? Is the brain going to be able to
be receptive to that message if it's been turned off
from that message input its entire life?
Speaker 3 (34:39):
Right?
Speaker 2 (34:40):
But we had a seventy year old patient in our
LCA one clinical trial that showed some benefit following gene therapy,
and that tells me that the brain is, you know,
extremely plastic, more plastic than I gave it credit for before.
Speaker 1 (34:53):
Huh, So it's not the eye but the brain. Like
we're not really seeing with our eye. Our eye is
just like the window and the brain is really where
the seeing is happening.
Speaker 3 (35:02):
That's right.
Speaker 1 (35:04):
I read that you have a boat called wet Lab
we do. H What was the runner up name? Oh?
Speaker 2 (35:13):
I don't think we had a runner up. We've planned
that one for years.
Speaker 1 (35:20):
What's the biggest fish you ever caught? Oh?
Speaker 2 (35:23):
My goodness. We go all the time and we catch
big fish so often. I don't remember the biggest one
that you catch.
Speaker 1 (35:30):
So many big things to tell a first story. Thank
you so much, for your time. It was very interesting
to talk to you. I learned.
Speaker 2 (35:40):
Thank you, Thank you. You're a great interviewer. This was
a pleasure.
Speaker 1 (35:46):
Jennon boy is a professor of genetics at the University
of Florida and the co founder and chief scientific officer
of Atsina Therapeutics. Just a quick note, the show is
going to take a break. We'll be back with new
episodes in a couple of weeks. In the meantime, please
let us know who you'd like to hear on the show,
who I should interview, were, just how we can make
(36:06):
the show better. You can email us at at pushkin
dot fm. Today's show was produced by Gabriel Hunter Chang.
It was edited by Lyddy Jean Kott and engineered by
Sarah Buguer. You can email us at Problem at pushkin
dot fm. I'm Jacob Goldstein and we'll be back next
week with another episode of What's Your Problem.
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