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