AI transcript
0:00:17 think about the basic idea of gene therapy. you string together a gene, put the gene inside
0:00:23 a virus, put the virus inside a patient, and then the virus delivers the gene to the patient’s cells,
0:00:29 and then that new gene, if everything goes according to plan, makes the patient get better.
0:00:35 It sounds hard, it is hard, but after decades of research, gene therapy is starting to work.
0:00:45 I’m Jacob Goldstein, and this is What’s Your Problem, the show where I talk to people who
0:00:51 are trying to make technological progress. My guest today is Shannon Boyd. She’s a professor
0:00:56 of genetics at the University of Florida and the co-founder and chief scientific officer
0:01:04 of Athena Therapeutics. Shannon’s problem is this. How do you use gene therapy to cure blindness,
0:01:10 or at least certain forms of blindness? Shannon has been working on gene therapy for 20 years,
0:01:15 and I wanted to talk with her about the long arc of the field, from the wild optimism of the early
0:01:22 2000s, to the realization that developing gene therapy would be a long hard slog, to the recent
0:01:28 promising results from an experimental drug that her company has developed. That drug treats a rare
0:01:36 disease that Sharon started studying as a grad student back in 2004. The disease is called LCA1.
0:01:41 So babies are born with the disease, and usually within the first few months of life,
0:01:47 their moms or dads notice that they’re not looking at them directly, they’re not fixating on objects.
0:01:53 Oftentimes, the babies will have a roving eye movement called nystagmus, and so they’re diagnosed
0:01:59 usually pretty quickly with this condition. And unfortunately, it’s profound visual impairment,
0:02:04 if not total blindness, and that remains with the patient throughout the course of their life.
0:02:09 So that’s really the reason that this lab was really interested in studying that gene.
0:02:19 So it’s one of the somewhat rare instances where there is a single gene that maps to a single,
0:02:25 in this case, profound problem, basically blindness or severe problems with vision,
0:02:32 which is kind of, you would think would be the first wave of gene therapy. This is what,
0:02:39 the early 2000s when you’re, and so the human genome has just been mapped. There’s a sense of,
0:02:44 oh, now we know all the genes. Let’s figure out how to help people with this new knowledge.
0:02:49 That’s exactly right. This was sort of the step one in gene therapy was the simplest form, which is
0:02:55 just gene replacement. Can we take a healthy copy of a gene and put it back into the patient’s cells
0:03:00 and then have that gene go on to make the protein it was supposed to make, and then hopefully restore
0:03:06 the function to those cells? And so what, as a grad student, are you trying to figure out?
0:03:12 The lab was studying the biochemical underpinnings of this disease, and they were using a chicken
0:03:18 model to do this. That’s kind of a unique thing in a lab. Usually research labs are using mice or
0:03:23 rats, but there was a naturally occurring chicken model of this disease that had profound visual
0:03:28 impairment and blindness. So naturally occurring chicken model basically means this happens to
0:03:35 chickens too. Yes, exactly. That’s right. Yeah. So at the same time that the lab was studying,
0:03:39 you know, what was going wrong in this chicken and why it was happening,
0:03:45 they wanted to ask the question, would gene therapy be a reasonable approach for treating
0:03:51 these chickens? Can we restore vision to these chickens with gene therapy? So this was a collaborative
0:04:00 effort with my other grad students and I, where we took a vector called lentivirus and we delivered
0:04:05 it to the chicken embryos. I felt very much in grad school like I was a poultry farmer.
0:04:11 Because I would, on my way into lab every day, stop at the farm, pick up the eggs,
0:04:17 bring them into lab. And then my fellow grad students and I, we would make these tiny little
0:04:23 holes in the chicken egg and we would pull these glass micro needles and use them to inject
0:04:28 into the chicken embryo. And remember, this is a disease that you have from birth. So we
0:04:33 needed to treat these chickens very early. But it was a difficult process to get that
0:04:38 micro needle injection into the head of the chicken embryo and then for that chicken to
0:04:43 make it all the way to hatch, right? And that was, I think, one of the hardest parts of that
0:04:49 project actually. It’s why I said I felt like a poultry farmer is all the machinations, you know,
0:04:53 getting the humidity right, the temperature right, the position right, making sure you
0:05:01 close that egg right, just getting that chicken to survive. And so you are injecting the
0:05:10 non-mutated form of the gene, the good form of the gene, if you will, encased in this virus
0:05:18 into the head of the chicken embryo. Yes. Did it work? For a while it did not, because again,
0:05:24 it was difficult to manipulate a chicken embryo like that and actually have it to survive to
0:05:29 hatch. But my fellow grad students and I did a lot of work to optimize that process. And eventually,
0:05:35 it actually did work. We had little chicks that were born and I can distinctly remember them
0:05:41 walking around on the lab bench and pecking at our jewelry or at M&Ms that we had laid out on
0:05:47 the surface of the bench. Very different from the blind chickens. It was very clear, you know,
0:05:53 chickens are very visually guided creatures. It’s very obvious when a chicken can see versus
0:06:04 not see. It was so fun. We were all so, so happy. So that’s 2004, that’s 20 years ago. Yeah. At that
0:06:11 time, is it like, well, we did it in chickens, let’s do it in people or what? So that’s actually
0:06:16 where my thesis project comes in. So all of that chicken work was a really collaborative effort and
0:06:21 it was exciting, but it had its drawbacks and it wasn’t clinically translatable for a number of
0:06:27 reasons. First and foremost, we were never going to do an embryonic injection in a patient. Maybe
0:06:34 that’ll happen one day, honestly, but it certainly wasn’t close to happening in 2004. So we needed
0:06:40 a gene therapy that could be injected in a patient after birth, right? And unfortunately,
0:06:47 the virus that we were using in the chicken experiments, the lentivirus, is really poor at
0:06:52 gene delivery to a developed retina. So we needed to find a more clinically relevant vector to do
0:07:00 the gene therapy. Let’s just pause for a moment and talk about this idea of a vector in gene therapy.
0:07:05 So the basic idea, right, is like, you know what the good gene is, you know the gene you want to get
0:07:11 into, in this case, the person’s eye. But there’s this weird question of, how do you get it there,
0:07:18 right? You can’t just put a string of genetic material randomly in someone’s body, right? It’ll
0:07:25 just get destroyed. And so there’s this basic idea that you put it in a virus, right? Because
0:07:31 a virus is like, it’s billions of years of evolution to be a genetic material delivery
0:07:36 mechanism, right? But that’s hard for a number of reasons. So like, tell me sort of the state of
0:07:42 vectors at this time 20 years ago when you’re figuring this out. So there were a number of
0:07:47 viral vectors that were being used to deliver genes and each of them had their pros and their cons.
0:07:54 One was named adenovirus. This was a good virus because it’s big. You can fit a lot of genetic
0:08:01 material into it. And it was used in the early days of gene therapy. And unfortunately, it was
0:08:06 discovered, you know, later on that it came with, you know, some downsides, it’s more immunogenic
0:08:10 than the other viral vectors that are out there. Meaning it generates an immune response. So the
0:08:14 body’s like, oh, that’s a virus. I’m going to destroy it. And you’re like, no, no, no, this
0:08:18 is a virus that’s going to help you. Exactly. The body’s like, I don’t care. I’m getting rid of it.
0:08:23 Yes. Yeah. And then of course, there was lentivirus, which is what we were using in the chickens.
0:08:28 It is not the vector of choice for, for instance, in the eye where I work, because it’s not very
0:08:37 good at delivering genes to developed cells in the retina. And then in the 90s, some exciting work
0:08:44 was going on evaluating a newer vector called adeno associated virus or AAV. Since the 90s,
0:08:51 early 2000s, AAV has become the gold standard gene delivery vector for essentially all of gene
0:08:59 therapy. And so at this time in 2004, like what was the state of gene therapy? Oh my gosh, it was
0:09:06 the heyday. It was such a fun time. And it was so, it was so exciting. The my grad school days,
0:09:12 my postdoc days, it was an extremely exciting time in the field that I would say it was filled
0:09:18 with hope because there was so much proof of concept work going on in animal models of disease,
0:09:24 showing that gene therapy could restore vision, could restore muscular function, could restore
0:09:30 clotting. You name it, it was these successes were being seen across neuromuscular disease,
0:09:36 CNS disease, ocular disease, but everybody was just really excited about it. And that
0:09:42 extended beyond the scientists in the lab. That was true of the macro environment too. So, you know.
0:09:47 Meaning like in the media or like the industry, like the pharmaceutical industry?
0:09:53 Yeah, I’m talking more about investors and big pharma. So, I mean, investors were keen to throw
0:09:58 their money at gene therapy at the time because of how much promise it was showing in these pre-clinical
0:10:04 studies. And big pharma was keen to acquire startup companies that were in this space because of that
0:10:10 promise it was showing. And I think their reason at the time was a sound one. They wanted to use,
0:10:16 even if those companies were focused on rare disease, it was like this platform for them to
0:10:21 say, “Well, if I can get gene therapy to work in this small rare disease, that proves that as a
0:10:25 company, I’m capable of doing this and that eventually I can do it in a disease that affects
0:10:31 millions of people.” So, it was a really, really exciting time both scientifically and from kind
0:10:38 of a financial standpoint. And then at some point, right, there are these strong results
0:10:45 using gene therapy to treat a disease called LCA2, which is similar to LCA1, the disease you work on.
0:10:53 And that’s like a big moment in the field, right? Yeah, the RP65 LCA2 gene therapy trials were a
0:10:58 huge success. And then they went on to form the basis of Luxterna, which is the first approved
0:11:04 ocular gene therapy. And so everybody was super excited that, okay, they got this approved. We’re
0:11:10 going to see this flood of other gene therapies getting approved on the heels of Luxterna. And I
0:11:16 think that’s when it got hard. And there was a little bit of a reality check for the field.
0:11:22 What was that like for you? So, you’re working on LCA1, a very similar disease. Everybody is very
0:11:29 excited about LCA2. Are you like, “Yes, we got LCA2. I’m about to get LCA1.” Like, what was your,
0:11:34 where were you at that point? Oh, I was super excited. I was further behind,
0:11:40 obviously, in my pursuit of LCA1. But I had high hopes that it would go, that it would work.
0:11:48 Why didn’t it happen as fast as you thought? So, in 2014, I hit a stage where the technology
0:11:53 had been developed. I had done everything that I really could from the academic standpoint to get
0:11:59 this ready to move forward. But at that stage, you hit what the NIH calls the Valley of Death,
0:12:05 which is a period of time where you need a lot of capital and a lot of infrastructure to move
0:12:09 a gene therapy from bench to bedside. And you can’t do that in an academic lab.
0:12:15 To put it, to test it in people, basically. Testing it in people is obviously complicated
0:12:20 and expensive. And to at least some extent, rightly so, right? You’re injecting things into
0:12:28 people’s eyes. Yes. In 2014, my husband and I, who I work with, we were very much in a pattern of
0:12:35 developing technologies and then out licensing them to different companies. So, in around 2014,
0:12:40 we partnered with Genzyme, which was a company focused on developing gene therapies for rare
0:12:47 disease. And they took that technology. Shortly thereafter, they were acquired by Sanofi. And
0:12:53 together with Genzyme/Sanofi, we conducted all of the studies that were what we call
0:12:59 IND enabling studies, sort of like the really well-documented careful safety studies and efficacy
0:13:05 studies, dose-ranging studies that are required to show to the FDA before they let you go into people.
0:13:10 IND is an Investigational New Drug. That’s correct. So, you’re like doing all the work to say like,
0:13:14 look, this should be an Investigational New Drug that we can test in a very small number of people
0:13:20 just to see if it’s safe to start out with. Exactly. Yeah. So, and I’ll be honest, that moved
0:13:26 a little bit slower than I would have liked. But I mean, when you work with Big Pharma,
0:13:30 and I will say they were an amazing, amazing team, excellent group of people. But
0:13:35 Big Pharma is very siloed and it can take a long time for things to move. And then,
0:13:43 unfortunately, in around 2018, Sanofi decided to pivot away from ocular gene therapy altogether. So,
0:13:50 they wanted to give the program away. And I was heartbroken. I remember the night that someone
0:13:56 told me it was happening. I couldn’t believe it because we were just about to treat the first
0:14:01 patient and everything was ready to go and I just couldn’t believe it. But companies make
0:14:06 decisions like this all the time. So, when that happened, that was really what motivated my husband
0:14:12 and I to co-found our own company because we wanted, hopefully, to get that program back
0:14:18 so that we could make sure that it went forward. And that was just, that was one reason that we
0:14:23 founded Atcena Therapeutics. I would say that the broader reason we founded the company was
0:14:28 out of a sense of frustration because we had developed a lot of technologies and we had
0:14:34 out licensed them to a variety of companies. And there was a theme emerging that the technologies
0:14:39 weren’t getting to patients. And whether that was because of, you know, business decisions,
0:14:44 overriding science decisions, or just, you know, companies being too big and siloed,
0:14:49 there were a variety of reasons. But ultimately, we formed the company because we were frustrated.
0:14:54 We wanted to have some more control over the direction that the science was taking.
0:14:58 It’s like you want it more than anybody else can want it.
0:15:03 Yes. It was, I mean, LCA1 is my baby, right? And so are some of the other indications that
0:15:09 I’m working on now. But yeah, I wanted to be the one to help usher them towards patients and
0:15:15 keep it moving in the right direction. And you mentioned your husband. So is he in the same
0:15:22 field as you? Like what is, what do you do? Yeah, he’s an AV Vectorologist. When I was a grad student
0:15:27 and I was tasked with my thesis project, which was, okay, come up with a clinically relevant
0:15:33 approach for treating this disease. So to do that, I needed to shift away from Lenti virus
0:15:38 and start using Adno Associated Virus, AAV. I needed to shift into a mouse model,
0:15:44 a mammalian model of the disease. And so to get help on the AAV aspect of the project,
0:15:48 I went to Bill Houseworth, who became my post-doc mentor. And he pointed me in the direction of
0:15:52 my now husband. He was a scientific research manager at the time. He said, you know, he can
0:15:57 field any questions you have about vector design. And so I went to him and then that, you know,
0:16:02 was an excellent collaboration, obviously, that blossomed into a nerd romance and then
0:16:09 eventually a marriage in two kids. Yes, it is a very nerdy meek cute. Yes. But yeah, we’re very
0:16:14 much in the same field, but we have very different skill sets, I would say. So we compliment each
0:16:21 other, which is nice. Obviously, to get from, you know, doing this in chickens 20 years ago
0:16:25 to doing it in people now, there were many, many, many things I’m sure that you had to figure out.
0:16:30 Is there, is there anything in particular that was a thing you figured out?
0:16:34 Maybe that was a thing that people doing gene therapy more broadly were trying to figure out,
0:16:39 just in the sense of, yeah, something, something you solved along the way.
0:16:44 In the early days, when I had first transitioned into testing the AAV vector in the mouse,
0:16:51 I did it over and over and over again, and it didn’t work. And I think one big mistake that I made
0:16:56 was that I was using the same gene, the same coding sequence that we had used in the chicken
0:17:03 experiment. And interestingly, that, that gene was a bovine gene. In the early 2000s, it was a
0:17:07 lot easier to generate bovine sequences for reasons I don’t even actually remember. But
0:17:12 what it took was figuring out that we needed to deliver the species specific gene. So
0:17:19 the mouse gene worked, the human gene worked, which was great, because that was very translatable.
0:17:24 So the, the, the species of the gene was important. Another really important thing
0:17:28 was the flame. So basically the versions of the gene exist in these different animals,
0:17:33 but they’re slightly different. Exactly. Yes. I have to say retrospectively,
0:17:40 out of my armchair ignorance, I feel like that one seems obvious in retrospect to me who doesn’t
0:17:45 know anything. But it was strange to me because this bovine sequence worked in a chicken. So I
0:17:50 figured. Yeah, and a mouse and a person is more like a cow, right? We’re all mammals. Yes, yeah.
0:17:54 Okay. What’s another one? What’s another one you had to figure out?
0:18:00 Another one was the flavor of AAV that we needed to use. So the particular nature of the vector?
0:18:05 Yes, exactly. So AAV comes in a variety of flavors and one flavor of AAV might be good at
0:18:10 infecting neurons and another flavor of AAV might be good at infecting skin cells, for instance.
0:18:16 Yes. And interestingly, in this point, you want it to infect, right? Infecting is delivering the
0:18:23 gene. Exactly. So we tested for the first time in non-human primates, a certain flavor of AAV
0:18:30 called AAV5. And we really, for the first time, showed that that flavor of AAV was really useful
0:18:36 in the rod and the cone photoreceptors of a primate retina, rather. So that was the flavor
0:18:40 of AAV that we needed to figure out. And then I would say the third thing that we figured out was
0:18:47 a specific regulatory sequence that we used to drive expression of the gene. So it’s called a
0:18:53 promoter. And specifically, it’s the redox and kinase promoter, which drives expression exclusively
0:19:00 in photoreceptors. And so just to be clear, just to unpack that a little bit, so the idea is you
0:19:08 don’t just need to have the gene itself in this vector. You need to have the genetic information
0:19:13 that tells it in what kinds of cells should this gene be expressed. Exactly. And in what kinds of
0:19:18 cells should it not be expressed. Exactly. And that’s important from a safety standpoint, because
0:19:23 ideally, you don’t want this gene expressing a protein in cells where it’s not supposed to be
0:19:26 and potentially… In your arm, in your heart. Right, exactly.
0:19:33 In a minute, what happened when Shannon’s drug finally made its way out of the lab
0:19:36 and into the eyes of patients?
0:19:50 I asked Shannon how she got from figuring everything out in the lab and in animals
0:19:55 to actually doing a clinical trial, to actually testing her drug in patients.
0:20:02 So I will say that, fortunately, before Sanofi let the program go, they did dose a couple of
0:20:07 patients. So we did get them to start the trial, thankfully. And they were absolutely critical
0:20:13 in getting that off the ground. But when they handed it back to Atstina, obviously we had to
0:20:18 build a clinical team. And we worked closely with Sanofi during that transition period to
0:20:23 make sure there were no bumps in the road. And then we just continued with the trial.
0:20:28 We had some amazing clinical investigators at the University of Pennsylvania and OHSU,
0:20:34 which is Oregon Health Sciences University, at the KCI Institute. And so the surgeons there
0:20:40 did the injections. We also had a surgeon at Will’s Eye Institute. And just excellent teams of
0:20:45 physicians focused on inherited retinal disease that we worked closely with to monitor these
0:20:52 patients over time. So you have this virus that you have engineered to have this gene and this
0:21:03 promoter. You inject it into the back of somebody’s eye. Then what happens? So the virus infects the
0:21:11 photoreceptors. It unloads the DNA inside. And then that DNA remains inside that cell over the
0:21:18 lifetime of that living cell. So the gene will persistently remain inside that cell and express
0:21:24 that protein that it needs to express. It does not integrate into the genome. It remains outside
0:21:29 the genome. We call that epizomal. But it leads to persistent expression of that gene and continuous
0:21:36 production of that therapeutic protein. And when the cell dies? When the cell dies, the gene dies
0:21:41 with it. So in order for gene therapy to be successful, those cells need to be retained.
0:21:47 If the cells degenerate, then that therapeutic effect can be lost. And do cells, do those cells
0:21:53 last forever? It depends on the indication. So that’s why LCA1 was such an attractive target,
0:21:59 is because those patients retain their photoreceptor structure over their lifetime. So theoretically,
0:22:04 we could get persistent rescue over their lifetime. So photoreceptor cells just stay there. They
0:22:10 develop and then they just hang out receiving photons forever. Yes, in this indication. Yep.
0:22:17 So how many people are in this trial? So we had 15 people total enrolled in this trial.
0:22:26 And how long does it take to find out if it works? So with this condition, typically we saw responses
0:22:33 by about four weeks post-injection. And those responses get a little bit better up until about
0:22:38 two or three months post-injection at which time the response is plateau. So it’s a very quick,
0:22:44 very quick readout. And the patients, are they completely blind? Like what is there before,
0:22:48 before when they’re coming to you? What is the state of their vision? That’s a good question.
0:22:55 So there’s a range, but we would consider all LCA1 patients to be profoundly visually impaired. So
0:23:04 ranging from 20 to 100 all the way to light perception only. So legally blind to folks
0:23:12 that can only see light. And so when do you first hear about the results? Like how do the results
0:23:21 come into you? Well, you have to be very careful as a co-founder and CSO of a company. I don’t
0:23:26 have any direct interaction with the patients. It’s kind of a conflict of interest, right? But
0:23:34 we do, the data starts pouring in into the software that we use to collect that data as a company.
0:23:42 And you start to see the numbers. And on occasion, a patient will anecdotally tell the physician
0:23:47 something. And that physician will report it back to the company like, wow, this person was able to
0:23:54 see the lines in the crosswalk for the first time outside last night. Or this woman was really
0:23:59 excited because this Halloween was the first time that she could read the labels on her kids’
0:24:06 Halloween candy. So you hear little stories like that. And it’s like, they make you cry, right?
0:24:11 Like you just can’t believe that it’s happening. It’s one thing to see a mouse regain vision and
0:24:17 be able to, you know, swim through a maze, but to hear that a patient can read something for
0:24:20 the first time or navigate outside their home for the first time, that’s something else.
0:24:25 Yes, you’re not spending your career trying to cure blindness in mice.
0:24:25 No, no.
0:24:30 So what was the outcome of that trial?
0:24:37 Sure. So it was a very positive outcome. We just published the results in the Lancet a few weeks
0:24:43 ago looking at all 15 of the Phase 1-2 patients out to one-year post-treatment. And we showed that
0:24:49 the gene therapy had a very, very good safety profile. There were no, you know, serious adverse
0:24:57 events related to the medicine itself. And we showed very profound efficacy. So we used a test
0:25:02 called FST, which is just a measure of retinal sensitivity. And we saw, for instance, in one
0:25:08 patient, there was a 10,000-fold improvement in retinal sensitivity. And what that means is
0:25:15 it’s akin to someone being able to navigate under bright sunlight versus someone being
0:25:21 able to navigate in the light of the full moon. So a huge improvement in retinal sensitivity.
0:25:24 And what is there like a median improvement?
0:25:28 Yeah, so the median improvement was about 100-fold improvement.
0:25:34 So really exciting and significant. And then, of course, the anecdotes come in. We have one video
0:25:40 of a little girl who saw snowflakes for the first time. So it’s more than the cold hard numbers,
0:25:46 like 100-fold improvement in retinal sensitivity. You’re seeing a genuine improvement in the patient’s
0:25:55 quality of life, which is amazing. So what’s next? So next will be Phase 3. Before you can get
0:26:00 anything commercialized for broader use, you have to do a Phase 3 trial. So we’re fortunate
0:26:04 because our LCA1 program has received what’s called an RMAT designation and put simply that
0:26:12 is a designation given to programs that cause a profound illness at birth and for which you have
0:26:17 promising proof of concept data showing that you might have a cure. So we receive that designation
0:26:22 and we need to align on a path forward with the FDA. So in other words, what is our Phase 3 trial
0:26:28 design need to be? And once we decide on that, then we will execute that Phase 3 trial and then
0:26:34 hopefully after that we’ll seek approval from the FDA to commercialize it for broader patient access.
0:26:43 How many people, more or less, have LCA1? So there’s about 3,000 patients, I would say,
0:26:50 in the US and the EU that have this indication? So, I mean, a lot on a human level, but on a
0:26:56 kind of population level, not a lot. It’s very rare. That’s correct. And so what does that mean?
0:27:01 Well, what does that mean? I guess on the business side, right? On the science side,
0:27:05 it sort of doesn’t matter. It’s the same science whether a million people have it or
0:27:09 10 people have it. But what does it mean on the business side? It’s, you know,
0:27:15 the pendulum has swung back since the early 2000s where investors and Big Pharma were all
0:27:22 very eager to throw money into the space. And they’re less excited about rare disease, obviously.
0:27:28 But, you know, as a scientist who sees the obvious impact it’s having on these patients,
0:27:34 I’m going to push it forward with full force. We’ve successfully raised money at Outsina to
0:27:40 keep this program going. We have plans for it moving forward. And I think our ability to continue
0:27:46 to raise money is increased or strengthened by the fact that we have other ongoing clinical
0:27:50 programs that are also showing success. So, you know, if you have one rare disease that you have
0:27:55 in clinic, you might be only quasi-interesting to investors or Big Pharma, but we have a bunch
0:27:59 of things going on at Outsina that I think will improve the chances that this program moves forward.
0:28:05 What else are you working on? So, we are working actively on another inherited retinal disease
0:28:11 called X-linked retinoskesis or XLRS. We’re also in a phase one-two clinical trial and already
0:28:18 showing structural and functional improvements in those patients using a novel flavor of AAV,
0:28:24 which has been interesting. So, really excited. So, you have a separate indication where you’re
0:28:32 in clinical trials. Yeah. And anything else? I feel like remember seeing a couple more on
0:28:37 the website now. Yes. Anything else? Yeah. So, we’re also working on a dual vector technology. So,
0:28:43 there are some indications caused by mutations in large genes that don’t fit inside a standard AAV
0:28:49 vector. So, we’ve developed a technology wherein we split that large gene in half. We deliver the
0:28:55 front half via one AAV and the back half via a second AAV. Those two. Whoa. Yeah. That’s really
0:29:01 cool. It’s one gene. It’s one gene and you’re putting it into two different suitcases. That’s
0:29:07 right. Basically. Yeah. And then, dumb question, how does it get put back together? So, there’s a
0:29:13 complementary sequence shared between the front and the back half. So, when the two suitcases unpack
0:29:19 their respective front and back half genes, they find each other via that complementary
0:29:24 sequence and then they recombine to form a full-length gene. That is wild. Have people
0:29:32 done that technique in other indications of gene therapy in other domains? They have. Yes.
0:29:38 There’s a company recently that is in the hearing space, actually, but they use dual vectors to
0:29:44 deliver a certain gene to patients that had hearing loss and restored hearing to these children.
0:29:50 So. And is the issue the gene is just too long? Like it physically just doesn’t fit inside the
0:29:56 virus? That’s correct. Yeah. So, standard AAV can only fit about 5,000 base pairs of DNA. And some
0:30:03 of these genes are just too big to fit. That is so clever. I love it when people are so clever.
0:30:15 So, let’s zoom out. And you’ve been working on gene therapy for 20 years-ish, which is close
0:30:20 to the life of gene therapy, right, of the field. You got in early. You’ve been there a long time.
0:30:26 A lot has happened. Like when you zoom out, what do you see? Like where is the field now?
0:30:31 Where is it now? What’s the big picture for gene therapy right now?
0:30:36 I think the big picture for gene therapy right now is we’re a little bit bruised, right?
0:30:42 We had the success of Luxterna getting approved. Then you’ve got Zolgensimo,
0:30:48 which is a huge success story. And those were the successes, but we entered a period
0:30:54 around that same time where I think, unfortunately, folks were taking a one-size-fits-all approach to
0:30:58 gene therapy. In other words, like, okay, if this flavor of AAV or this regulatory region
0:31:03 or this dose worked for Luxterna, then it’s going to work for this other indication, right?
0:31:10 And I think that hasn’t played out, right? It’s not a one-size-fits-all approach. Every indication
0:31:17 needs a treatment tailored to that indication. What cell type is impacted? Does the gene expression
0:31:22 need to be restricted? What dose needs to be used? What’s the underlying immune status of
0:31:27 that patient’s retina, for instance? So it’s not a one-size-fits-all approach, and I think people
0:31:34 have realized that. So does that mean it’s going to be hard every time? I mean, it’s going to be
0:31:39 hard forever, and it’s not like, great, we figured it out, and we can just put any gene into this
0:31:45 vector and we’ll cure everything. Yeah, I mean, I think it’s somewhere in the middle, right? It’s
0:31:50 never going to be just plug-and-play, right? But there are certainly tools that are being developed
0:31:57 along the way that can be used in one trial and used in another trial. But I think you always have
0:32:02 to put a lot of thought into it. It can’t just simply be, okay, if this worked for LCA2, then
0:32:07 it’s going to work for disease X, right? There always has to be a thoughtful process.
0:32:18 I mean, is it harder than you thought it was going to be? Yes. In my grad school days, it was hope,
0:32:24 hope, hope, excitement, excitement, excitement, and then forming my own company and being in charge
0:32:32 of the fundraising behind keeping these programs going. It’s been a lot of work, but I believe
0:32:36 strongly in what I do and that it’s having a positive impact on patient lives, and so it’s
0:32:43 worth that effort. We’ll be back in a minute with the lightning round.
0:33:01 Let’s finish with the lightning round. Okay. What’s the best thing about working with your husband?
0:33:11 Oh, let’s see. I think that at the end of the day, we can understand each other’s stresses. It’s
0:33:17 not like coming home and he has no idea what I’m talking about. It’s like, if I have a problem,
0:33:23 he can think through it very clearly because he understands it at its core and give me advice
0:33:28 on how to navigate the situation and vice versa. What’s the worst thing about working with your
0:33:38 husband? Sometimes there’s evenings where I’m done talking about AAV. I’ve done it all day long,
0:33:42 and we’re sitting over the dinner table with our kids, and he’s still talking about designing a
0:33:47 vector to do whatever, and I’m like, okay, we’re done here. We’re done for the night, but I mean,
0:33:51 it’s with us all the time, and I think that’s what makes us better scientists for it.
0:33:57 What’s one interesting or surprising thing you’ve learned about the human eye?
0:34:09 The human eye. I would say most of all that you can be 70 years old and have had a congenital
0:34:13 form of blindness since you were a baby and still benefit from gene therapy,
0:34:18 and that’s wild to me. I got my PhD in neuroscience, so I’m always thinking about,
0:34:23 so what if we restore function to the retina? What’s that going to mean in the brain? Is the
0:34:28 brain going to be able to be receptive to that message if it’s been turned off from that message
0:34:35 input its entire life, right? But we had a 70-year-old patient in our LCA1 clinical trial that
0:34:41 showed some benefit following gene therapy, and that tells me that the brain is extremely plastic,
0:34:48 more plastic than I gave it credit for before. It’s not the eye but the brain. We’re not really
0:34:52 seeing with our eye. The eye is just like the window, and the brain is really where the seeing
0:35:01 is happening. That’s right. I read that you have a boat called Wet Lab. We do. What was the runner-up
0:35:07 name? Oh, I don’t think we had a runner-up. We planned that one for years.
0:35:17 What’s the biggest fish you ever caught? Oh, my goodness. We go all the time, and we catch
0:35:22 big fish so often. I don’t remember the biggest one. Look at that. You catch so many big fish.
0:35:29 You don’t even need to tell a fish story. Thank you so much for your time. It was
0:35:32 very interesting to talk to you. I learned a lot. Thank you. Thank you. You’re a great
0:35:33 interviewer. This was a pleasure.
0:35:42 Shannon Boy is a professor of genetics at the University of Florida and the co-founder and
0:35:47 chief scientific officer of Acena Therapeutics. Just a quick note, the show is going to take
0:35:53 a break. We’ll be back with new episodes in a couple weeks. In the meantime, please let us know
0:35:58 who you’d like to hear on the show, who I should interview, or just how we can make the show better.
0:36:05 You can email us at problem@pushkin.fm. Today’s show was produced by Gabriel Hunter Chang.
0:36:10 It was edited by Lydia Jean Cotte and engineered by Sarah Bouguere.
0:36:16 You can email us at problem@pushkin.fm. I’m Jacob Goldstein, and we’ll be back next week
0:36:24 with another episode of What’s Your Problem?
0:36:34 [BLANK_AUDIO]
0:00:23 a virus, put the virus inside a patient, and then the virus delivers the gene to the patient’s cells,
0:00:29 and then that new gene, if everything goes according to plan, makes the patient get better.
0:00:35 It sounds hard, it is hard, but after decades of research, gene therapy is starting to work.
0:00:45 I’m Jacob Goldstein, and this is What’s Your Problem, the show where I talk to people who
0:00:51 are trying to make technological progress. My guest today is Shannon Boyd. She’s a professor
0:00:56 of genetics at the University of Florida and the co-founder and chief scientific officer
0:01:04 of Athena Therapeutics. Shannon’s problem is this. How do you use gene therapy to cure blindness,
0:01:10 or at least certain forms of blindness? Shannon has been working on gene therapy for 20 years,
0:01:15 and I wanted to talk with her about the long arc of the field, from the wild optimism of the early
0:01:22 2000s, to the realization that developing gene therapy would be a long hard slog, to the recent
0:01:28 promising results from an experimental drug that her company has developed. That drug treats a rare
0:01:36 disease that Sharon started studying as a grad student back in 2004. The disease is called LCA1.
0:01:41 So babies are born with the disease, and usually within the first few months of life,
0:01:47 their moms or dads notice that they’re not looking at them directly, they’re not fixating on objects.
0:01:53 Oftentimes, the babies will have a roving eye movement called nystagmus, and so they’re diagnosed
0:01:59 usually pretty quickly with this condition. And unfortunately, it’s profound visual impairment,
0:02:04 if not total blindness, and that remains with the patient throughout the course of their life.
0:02:09 So that’s really the reason that this lab was really interested in studying that gene.
0:02:19 So it’s one of the somewhat rare instances where there is a single gene that maps to a single,
0:02:25 in this case, profound problem, basically blindness or severe problems with vision,
0:02:32 which is kind of, you would think would be the first wave of gene therapy. This is what,
0:02:39 the early 2000s when you’re, and so the human genome has just been mapped. There’s a sense of,
0:02:44 oh, now we know all the genes. Let’s figure out how to help people with this new knowledge.
0:02:49 That’s exactly right. This was sort of the step one in gene therapy was the simplest form, which is
0:02:55 just gene replacement. Can we take a healthy copy of a gene and put it back into the patient’s cells
0:03:00 and then have that gene go on to make the protein it was supposed to make, and then hopefully restore
0:03:06 the function to those cells? And so what, as a grad student, are you trying to figure out?
0:03:12 The lab was studying the biochemical underpinnings of this disease, and they were using a chicken
0:03:18 model to do this. That’s kind of a unique thing in a lab. Usually research labs are using mice or
0:03:23 rats, but there was a naturally occurring chicken model of this disease that had profound visual
0:03:28 impairment and blindness. So naturally occurring chicken model basically means this happens to
0:03:35 chickens too. Yes, exactly. That’s right. Yeah. So at the same time that the lab was studying,
0:03:39 you know, what was going wrong in this chicken and why it was happening,
0:03:45 they wanted to ask the question, would gene therapy be a reasonable approach for treating
0:03:51 these chickens? Can we restore vision to these chickens with gene therapy? So this was a collaborative
0:04:00 effort with my other grad students and I, where we took a vector called lentivirus and we delivered
0:04:05 it to the chicken embryos. I felt very much in grad school like I was a poultry farmer.
0:04:11 Because I would, on my way into lab every day, stop at the farm, pick up the eggs,
0:04:17 bring them into lab. And then my fellow grad students and I, we would make these tiny little
0:04:23 holes in the chicken egg and we would pull these glass micro needles and use them to inject
0:04:28 into the chicken embryo. And remember, this is a disease that you have from birth. So we
0:04:33 needed to treat these chickens very early. But it was a difficult process to get that
0:04:38 micro needle injection into the head of the chicken embryo and then for that chicken to
0:04:43 make it all the way to hatch, right? And that was, I think, one of the hardest parts of that
0:04:49 project actually. It’s why I said I felt like a poultry farmer is all the machinations, you know,
0:04:53 getting the humidity right, the temperature right, the position right, making sure you
0:05:01 close that egg right, just getting that chicken to survive. And so you are injecting the
0:05:10 non-mutated form of the gene, the good form of the gene, if you will, encased in this virus
0:05:18 into the head of the chicken embryo. Yes. Did it work? For a while it did not, because again,
0:05:24 it was difficult to manipulate a chicken embryo like that and actually have it to survive to
0:05:29 hatch. But my fellow grad students and I did a lot of work to optimize that process. And eventually,
0:05:35 it actually did work. We had little chicks that were born and I can distinctly remember them
0:05:41 walking around on the lab bench and pecking at our jewelry or at M&Ms that we had laid out on
0:05:47 the surface of the bench. Very different from the blind chickens. It was very clear, you know,
0:05:53 chickens are very visually guided creatures. It’s very obvious when a chicken can see versus
0:06:04 not see. It was so fun. We were all so, so happy. So that’s 2004, that’s 20 years ago. Yeah. At that
0:06:11 time, is it like, well, we did it in chickens, let’s do it in people or what? So that’s actually
0:06:16 where my thesis project comes in. So all of that chicken work was a really collaborative effort and
0:06:21 it was exciting, but it had its drawbacks and it wasn’t clinically translatable for a number of
0:06:27 reasons. First and foremost, we were never going to do an embryonic injection in a patient. Maybe
0:06:34 that’ll happen one day, honestly, but it certainly wasn’t close to happening in 2004. So we needed
0:06:40 a gene therapy that could be injected in a patient after birth, right? And unfortunately,
0:06:47 the virus that we were using in the chicken experiments, the lentivirus, is really poor at
0:06:52 gene delivery to a developed retina. So we needed to find a more clinically relevant vector to do
0:07:00 the gene therapy. Let’s just pause for a moment and talk about this idea of a vector in gene therapy.
0:07:05 So the basic idea, right, is like, you know what the good gene is, you know the gene you want to get
0:07:11 into, in this case, the person’s eye. But there’s this weird question of, how do you get it there,
0:07:18 right? You can’t just put a string of genetic material randomly in someone’s body, right? It’ll
0:07:25 just get destroyed. And so there’s this basic idea that you put it in a virus, right? Because
0:07:31 a virus is like, it’s billions of years of evolution to be a genetic material delivery
0:07:36 mechanism, right? But that’s hard for a number of reasons. So like, tell me sort of the state of
0:07:42 vectors at this time 20 years ago when you’re figuring this out. So there were a number of
0:07:47 viral vectors that were being used to deliver genes and each of them had their pros and their cons.
0:07:54 One was named adenovirus. This was a good virus because it’s big. You can fit a lot of genetic
0:08:01 material into it. And it was used in the early days of gene therapy. And unfortunately, it was
0:08:06 discovered, you know, later on that it came with, you know, some downsides, it’s more immunogenic
0:08:10 than the other viral vectors that are out there. Meaning it generates an immune response. So the
0:08:14 body’s like, oh, that’s a virus. I’m going to destroy it. And you’re like, no, no, no, this
0:08:18 is a virus that’s going to help you. Exactly. The body’s like, I don’t care. I’m getting rid of it.
0:08:23 Yes. Yeah. And then of course, there was lentivirus, which is what we were using in the chickens.
0:08:28 It is not the vector of choice for, for instance, in the eye where I work, because it’s not very
0:08:37 good at delivering genes to developed cells in the retina. And then in the 90s, some exciting work
0:08:44 was going on evaluating a newer vector called adeno associated virus or AAV. Since the 90s,
0:08:51 early 2000s, AAV has become the gold standard gene delivery vector for essentially all of gene
0:08:59 therapy. And so at this time in 2004, like what was the state of gene therapy? Oh my gosh, it was
0:09:06 the heyday. It was such a fun time. And it was so, it was so exciting. The my grad school days,
0:09:12 my postdoc days, it was an extremely exciting time in the field that I would say it was filled
0:09:18 with hope because there was so much proof of concept work going on in animal models of disease,
0:09:24 showing that gene therapy could restore vision, could restore muscular function, could restore
0:09:30 clotting. You name it, it was these successes were being seen across neuromuscular disease,
0:09:36 CNS disease, ocular disease, but everybody was just really excited about it. And that
0:09:42 extended beyond the scientists in the lab. That was true of the macro environment too. So, you know.
0:09:47 Meaning like in the media or like the industry, like the pharmaceutical industry?
0:09:53 Yeah, I’m talking more about investors and big pharma. So, I mean, investors were keen to throw
0:09:58 their money at gene therapy at the time because of how much promise it was showing in these pre-clinical
0:10:04 studies. And big pharma was keen to acquire startup companies that were in this space because of that
0:10:10 promise it was showing. And I think their reason at the time was a sound one. They wanted to use,
0:10:16 even if those companies were focused on rare disease, it was like this platform for them to
0:10:21 say, “Well, if I can get gene therapy to work in this small rare disease, that proves that as a
0:10:25 company, I’m capable of doing this and that eventually I can do it in a disease that affects
0:10:31 millions of people.” So, it was a really, really exciting time both scientifically and from kind
0:10:38 of a financial standpoint. And then at some point, right, there are these strong results
0:10:45 using gene therapy to treat a disease called LCA2, which is similar to LCA1, the disease you work on.
0:10:53 And that’s like a big moment in the field, right? Yeah, the RP65 LCA2 gene therapy trials were a
0:10:58 huge success. And then they went on to form the basis of Luxterna, which is the first approved
0:11:04 ocular gene therapy. And so everybody was super excited that, okay, they got this approved. We’re
0:11:10 going to see this flood of other gene therapies getting approved on the heels of Luxterna. And I
0:11:16 think that’s when it got hard. And there was a little bit of a reality check for the field.
0:11:22 What was that like for you? So, you’re working on LCA1, a very similar disease. Everybody is very
0:11:29 excited about LCA2. Are you like, “Yes, we got LCA2. I’m about to get LCA1.” Like, what was your,
0:11:34 where were you at that point? Oh, I was super excited. I was further behind,
0:11:40 obviously, in my pursuit of LCA1. But I had high hopes that it would go, that it would work.
0:11:48 Why didn’t it happen as fast as you thought? So, in 2014, I hit a stage where the technology
0:11:53 had been developed. I had done everything that I really could from the academic standpoint to get
0:11:59 this ready to move forward. But at that stage, you hit what the NIH calls the Valley of Death,
0:12:05 which is a period of time where you need a lot of capital and a lot of infrastructure to move
0:12:09 a gene therapy from bench to bedside. And you can’t do that in an academic lab.
0:12:15 To put it, to test it in people, basically. Testing it in people is obviously complicated
0:12:20 and expensive. And to at least some extent, rightly so, right? You’re injecting things into
0:12:28 people’s eyes. Yes. In 2014, my husband and I, who I work with, we were very much in a pattern of
0:12:35 developing technologies and then out licensing them to different companies. So, in around 2014,
0:12:40 we partnered with Genzyme, which was a company focused on developing gene therapies for rare
0:12:47 disease. And they took that technology. Shortly thereafter, they were acquired by Sanofi. And
0:12:53 together with Genzyme/Sanofi, we conducted all of the studies that were what we call
0:12:59 IND enabling studies, sort of like the really well-documented careful safety studies and efficacy
0:13:05 studies, dose-ranging studies that are required to show to the FDA before they let you go into people.
0:13:10 IND is an Investigational New Drug. That’s correct. So, you’re like doing all the work to say like,
0:13:14 look, this should be an Investigational New Drug that we can test in a very small number of people
0:13:20 just to see if it’s safe to start out with. Exactly. Yeah. So, and I’ll be honest, that moved
0:13:26 a little bit slower than I would have liked. But I mean, when you work with Big Pharma,
0:13:30 and I will say they were an amazing, amazing team, excellent group of people. But
0:13:35 Big Pharma is very siloed and it can take a long time for things to move. And then,
0:13:43 unfortunately, in around 2018, Sanofi decided to pivot away from ocular gene therapy altogether. So,
0:13:50 they wanted to give the program away. And I was heartbroken. I remember the night that someone
0:13:56 told me it was happening. I couldn’t believe it because we were just about to treat the first
0:14:01 patient and everything was ready to go and I just couldn’t believe it. But companies make
0:14:06 decisions like this all the time. So, when that happened, that was really what motivated my husband
0:14:12 and I to co-found our own company because we wanted, hopefully, to get that program back
0:14:18 so that we could make sure that it went forward. And that was just, that was one reason that we
0:14:23 founded Atcena Therapeutics. I would say that the broader reason we founded the company was
0:14:28 out of a sense of frustration because we had developed a lot of technologies and we had
0:14:34 out licensed them to a variety of companies. And there was a theme emerging that the technologies
0:14:39 weren’t getting to patients. And whether that was because of, you know, business decisions,
0:14:44 overriding science decisions, or just, you know, companies being too big and siloed,
0:14:49 there were a variety of reasons. But ultimately, we formed the company because we were frustrated.
0:14:54 We wanted to have some more control over the direction that the science was taking.
0:14:58 It’s like you want it more than anybody else can want it.
0:15:03 Yes. It was, I mean, LCA1 is my baby, right? And so are some of the other indications that
0:15:09 I’m working on now. But yeah, I wanted to be the one to help usher them towards patients and
0:15:15 keep it moving in the right direction. And you mentioned your husband. So is he in the same
0:15:22 field as you? Like what is, what do you do? Yeah, he’s an AV Vectorologist. When I was a grad student
0:15:27 and I was tasked with my thesis project, which was, okay, come up with a clinically relevant
0:15:33 approach for treating this disease. So to do that, I needed to shift away from Lenti virus
0:15:38 and start using Adno Associated Virus, AAV. I needed to shift into a mouse model,
0:15:44 a mammalian model of the disease. And so to get help on the AAV aspect of the project,
0:15:48 I went to Bill Houseworth, who became my post-doc mentor. And he pointed me in the direction of
0:15:52 my now husband. He was a scientific research manager at the time. He said, you know, he can
0:15:57 field any questions you have about vector design. And so I went to him and then that, you know,
0:16:02 was an excellent collaboration, obviously, that blossomed into a nerd romance and then
0:16:09 eventually a marriage in two kids. Yes, it is a very nerdy meek cute. Yes. But yeah, we’re very
0:16:14 much in the same field, but we have very different skill sets, I would say. So we compliment each
0:16:21 other, which is nice. Obviously, to get from, you know, doing this in chickens 20 years ago
0:16:25 to doing it in people now, there were many, many, many things I’m sure that you had to figure out.
0:16:30 Is there, is there anything in particular that was a thing you figured out?
0:16:34 Maybe that was a thing that people doing gene therapy more broadly were trying to figure out,
0:16:39 just in the sense of, yeah, something, something you solved along the way.
0:16:44 In the early days, when I had first transitioned into testing the AAV vector in the mouse,
0:16:51 I did it over and over and over again, and it didn’t work. And I think one big mistake that I made
0:16:56 was that I was using the same gene, the same coding sequence that we had used in the chicken
0:17:03 experiment. And interestingly, that, that gene was a bovine gene. In the early 2000s, it was a
0:17:07 lot easier to generate bovine sequences for reasons I don’t even actually remember. But
0:17:12 what it took was figuring out that we needed to deliver the species specific gene. So
0:17:19 the mouse gene worked, the human gene worked, which was great, because that was very translatable.
0:17:24 So the, the, the species of the gene was important. Another really important thing
0:17:28 was the flame. So basically the versions of the gene exist in these different animals,
0:17:33 but they’re slightly different. Exactly. Yes. I have to say retrospectively,
0:17:40 out of my armchair ignorance, I feel like that one seems obvious in retrospect to me who doesn’t
0:17:45 know anything. But it was strange to me because this bovine sequence worked in a chicken. So I
0:17:50 figured. Yeah, and a mouse and a person is more like a cow, right? We’re all mammals. Yes, yeah.
0:17:54 Okay. What’s another one? What’s another one you had to figure out?
0:18:00 Another one was the flavor of AAV that we needed to use. So the particular nature of the vector?
0:18:05 Yes, exactly. So AAV comes in a variety of flavors and one flavor of AAV might be good at
0:18:10 infecting neurons and another flavor of AAV might be good at infecting skin cells, for instance.
0:18:16 Yes. And interestingly, in this point, you want it to infect, right? Infecting is delivering the
0:18:23 gene. Exactly. So we tested for the first time in non-human primates, a certain flavor of AAV
0:18:30 called AAV5. And we really, for the first time, showed that that flavor of AAV was really useful
0:18:36 in the rod and the cone photoreceptors of a primate retina, rather. So that was the flavor
0:18:40 of AAV that we needed to figure out. And then I would say the third thing that we figured out was
0:18:47 a specific regulatory sequence that we used to drive expression of the gene. So it’s called a
0:18:53 promoter. And specifically, it’s the redox and kinase promoter, which drives expression exclusively
0:19:00 in photoreceptors. And so just to be clear, just to unpack that a little bit, so the idea is you
0:19:08 don’t just need to have the gene itself in this vector. You need to have the genetic information
0:19:13 that tells it in what kinds of cells should this gene be expressed. Exactly. And in what kinds of
0:19:18 cells should it not be expressed. Exactly. And that’s important from a safety standpoint, because
0:19:23 ideally, you don’t want this gene expressing a protein in cells where it’s not supposed to be
0:19:26 and potentially… In your arm, in your heart. Right, exactly.
0:19:33 In a minute, what happened when Shannon’s drug finally made its way out of the lab
0:19:36 and into the eyes of patients?
0:19:50 I asked Shannon how she got from figuring everything out in the lab and in animals
0:19:55 to actually doing a clinical trial, to actually testing her drug in patients.
0:20:02 So I will say that, fortunately, before Sanofi let the program go, they did dose a couple of
0:20:07 patients. So we did get them to start the trial, thankfully. And they were absolutely critical
0:20:13 in getting that off the ground. But when they handed it back to Atstina, obviously we had to
0:20:18 build a clinical team. And we worked closely with Sanofi during that transition period to
0:20:23 make sure there were no bumps in the road. And then we just continued with the trial.
0:20:28 We had some amazing clinical investigators at the University of Pennsylvania and OHSU,
0:20:34 which is Oregon Health Sciences University, at the KCI Institute. And so the surgeons there
0:20:40 did the injections. We also had a surgeon at Will’s Eye Institute. And just excellent teams of
0:20:45 physicians focused on inherited retinal disease that we worked closely with to monitor these
0:20:52 patients over time. So you have this virus that you have engineered to have this gene and this
0:21:03 promoter. You inject it into the back of somebody’s eye. Then what happens? So the virus infects the
0:21:11 photoreceptors. It unloads the DNA inside. And then that DNA remains inside that cell over the
0:21:18 lifetime of that living cell. So the gene will persistently remain inside that cell and express
0:21:24 that protein that it needs to express. It does not integrate into the genome. It remains outside
0:21:29 the genome. We call that epizomal. But it leads to persistent expression of that gene and continuous
0:21:36 production of that therapeutic protein. And when the cell dies? When the cell dies, the gene dies
0:21:41 with it. So in order for gene therapy to be successful, those cells need to be retained.
0:21:47 If the cells degenerate, then that therapeutic effect can be lost. And do cells, do those cells
0:21:53 last forever? It depends on the indication. So that’s why LCA1 was such an attractive target,
0:21:59 is because those patients retain their photoreceptor structure over their lifetime. So theoretically,
0:22:04 we could get persistent rescue over their lifetime. So photoreceptor cells just stay there. They
0:22:10 develop and then they just hang out receiving photons forever. Yes, in this indication. Yep.
0:22:17 So how many people are in this trial? So we had 15 people total enrolled in this trial.
0:22:26 And how long does it take to find out if it works? So with this condition, typically we saw responses
0:22:33 by about four weeks post-injection. And those responses get a little bit better up until about
0:22:38 two or three months post-injection at which time the response is plateau. So it’s a very quick,
0:22:44 very quick readout. And the patients, are they completely blind? Like what is there before,
0:22:48 before when they’re coming to you? What is the state of their vision? That’s a good question.
0:22:55 So there’s a range, but we would consider all LCA1 patients to be profoundly visually impaired. So
0:23:04 ranging from 20 to 100 all the way to light perception only. So legally blind to folks
0:23:12 that can only see light. And so when do you first hear about the results? Like how do the results
0:23:21 come into you? Well, you have to be very careful as a co-founder and CSO of a company. I don’t
0:23:26 have any direct interaction with the patients. It’s kind of a conflict of interest, right? But
0:23:34 we do, the data starts pouring in into the software that we use to collect that data as a company.
0:23:42 And you start to see the numbers. And on occasion, a patient will anecdotally tell the physician
0:23:47 something. And that physician will report it back to the company like, wow, this person was able to
0:23:54 see the lines in the crosswalk for the first time outside last night. Or this woman was really
0:23:59 excited because this Halloween was the first time that she could read the labels on her kids’
0:24:06 Halloween candy. So you hear little stories like that. And it’s like, they make you cry, right?
0:24:11 Like you just can’t believe that it’s happening. It’s one thing to see a mouse regain vision and
0:24:17 be able to, you know, swim through a maze, but to hear that a patient can read something for
0:24:20 the first time or navigate outside their home for the first time, that’s something else.
0:24:25 Yes, you’re not spending your career trying to cure blindness in mice.
0:24:25 No, no.
0:24:30 So what was the outcome of that trial?
0:24:37 Sure. So it was a very positive outcome. We just published the results in the Lancet a few weeks
0:24:43 ago looking at all 15 of the Phase 1-2 patients out to one-year post-treatment. And we showed that
0:24:49 the gene therapy had a very, very good safety profile. There were no, you know, serious adverse
0:24:57 events related to the medicine itself. And we showed very profound efficacy. So we used a test
0:25:02 called FST, which is just a measure of retinal sensitivity. And we saw, for instance, in one
0:25:08 patient, there was a 10,000-fold improvement in retinal sensitivity. And what that means is
0:25:15 it’s akin to someone being able to navigate under bright sunlight versus someone being
0:25:21 able to navigate in the light of the full moon. So a huge improvement in retinal sensitivity.
0:25:24 And what is there like a median improvement?
0:25:28 Yeah, so the median improvement was about 100-fold improvement.
0:25:34 So really exciting and significant. And then, of course, the anecdotes come in. We have one video
0:25:40 of a little girl who saw snowflakes for the first time. So it’s more than the cold hard numbers,
0:25:46 like 100-fold improvement in retinal sensitivity. You’re seeing a genuine improvement in the patient’s
0:25:55 quality of life, which is amazing. So what’s next? So next will be Phase 3. Before you can get
0:26:00 anything commercialized for broader use, you have to do a Phase 3 trial. So we’re fortunate
0:26:04 because our LCA1 program has received what’s called an RMAT designation and put simply that
0:26:12 is a designation given to programs that cause a profound illness at birth and for which you have
0:26:17 promising proof of concept data showing that you might have a cure. So we receive that designation
0:26:22 and we need to align on a path forward with the FDA. So in other words, what is our Phase 3 trial
0:26:28 design need to be? And once we decide on that, then we will execute that Phase 3 trial and then
0:26:34 hopefully after that we’ll seek approval from the FDA to commercialize it for broader patient access.
0:26:43 How many people, more or less, have LCA1? So there’s about 3,000 patients, I would say,
0:26:50 in the US and the EU that have this indication? So, I mean, a lot on a human level, but on a
0:26:56 kind of population level, not a lot. It’s very rare. That’s correct. And so what does that mean?
0:27:01 Well, what does that mean? I guess on the business side, right? On the science side,
0:27:05 it sort of doesn’t matter. It’s the same science whether a million people have it or
0:27:09 10 people have it. But what does it mean on the business side? It’s, you know,
0:27:15 the pendulum has swung back since the early 2000s where investors and Big Pharma were all
0:27:22 very eager to throw money into the space. And they’re less excited about rare disease, obviously.
0:27:28 But, you know, as a scientist who sees the obvious impact it’s having on these patients,
0:27:34 I’m going to push it forward with full force. We’ve successfully raised money at Outsina to
0:27:40 keep this program going. We have plans for it moving forward. And I think our ability to continue
0:27:46 to raise money is increased or strengthened by the fact that we have other ongoing clinical
0:27:50 programs that are also showing success. So, you know, if you have one rare disease that you have
0:27:55 in clinic, you might be only quasi-interesting to investors or Big Pharma, but we have a bunch
0:27:59 of things going on at Outsina that I think will improve the chances that this program moves forward.
0:28:05 What else are you working on? So, we are working actively on another inherited retinal disease
0:28:11 called X-linked retinoskesis or XLRS. We’re also in a phase one-two clinical trial and already
0:28:18 showing structural and functional improvements in those patients using a novel flavor of AAV,
0:28:24 which has been interesting. So, really excited. So, you have a separate indication where you’re
0:28:32 in clinical trials. Yeah. And anything else? I feel like remember seeing a couple more on
0:28:37 the website now. Yes. Anything else? Yeah. So, we’re also working on a dual vector technology. So,
0:28:43 there are some indications caused by mutations in large genes that don’t fit inside a standard AAV
0:28:49 vector. So, we’ve developed a technology wherein we split that large gene in half. We deliver the
0:28:55 front half via one AAV and the back half via a second AAV. Those two. Whoa. Yeah. That’s really
0:29:01 cool. It’s one gene. It’s one gene and you’re putting it into two different suitcases. That’s
0:29:07 right. Basically. Yeah. And then, dumb question, how does it get put back together? So, there’s a
0:29:13 complementary sequence shared between the front and the back half. So, when the two suitcases unpack
0:29:19 their respective front and back half genes, they find each other via that complementary
0:29:24 sequence and then they recombine to form a full-length gene. That is wild. Have people
0:29:32 done that technique in other indications of gene therapy in other domains? They have. Yes.
0:29:38 There’s a company recently that is in the hearing space, actually, but they use dual vectors to
0:29:44 deliver a certain gene to patients that had hearing loss and restored hearing to these children.
0:29:50 So. And is the issue the gene is just too long? Like it physically just doesn’t fit inside the
0:29:56 virus? That’s correct. Yeah. So, standard AAV can only fit about 5,000 base pairs of DNA. And some
0:30:03 of these genes are just too big to fit. That is so clever. I love it when people are so clever.
0:30:15 So, let’s zoom out. And you’ve been working on gene therapy for 20 years-ish, which is close
0:30:20 to the life of gene therapy, right, of the field. You got in early. You’ve been there a long time.
0:30:26 A lot has happened. Like when you zoom out, what do you see? Like where is the field now?
0:30:31 Where is it now? What’s the big picture for gene therapy right now?
0:30:36 I think the big picture for gene therapy right now is we’re a little bit bruised, right?
0:30:42 We had the success of Luxterna getting approved. Then you’ve got Zolgensimo,
0:30:48 which is a huge success story. And those were the successes, but we entered a period
0:30:54 around that same time where I think, unfortunately, folks were taking a one-size-fits-all approach to
0:30:58 gene therapy. In other words, like, okay, if this flavor of AAV or this regulatory region
0:31:03 or this dose worked for Luxterna, then it’s going to work for this other indication, right?
0:31:10 And I think that hasn’t played out, right? It’s not a one-size-fits-all approach. Every indication
0:31:17 needs a treatment tailored to that indication. What cell type is impacted? Does the gene expression
0:31:22 need to be restricted? What dose needs to be used? What’s the underlying immune status of
0:31:27 that patient’s retina, for instance? So it’s not a one-size-fits-all approach, and I think people
0:31:34 have realized that. So does that mean it’s going to be hard every time? I mean, it’s going to be
0:31:39 hard forever, and it’s not like, great, we figured it out, and we can just put any gene into this
0:31:45 vector and we’ll cure everything. Yeah, I mean, I think it’s somewhere in the middle, right? It’s
0:31:50 never going to be just plug-and-play, right? But there are certainly tools that are being developed
0:31:57 along the way that can be used in one trial and used in another trial. But I think you always have
0:32:02 to put a lot of thought into it. It can’t just simply be, okay, if this worked for LCA2, then
0:32:07 it’s going to work for disease X, right? There always has to be a thoughtful process.
0:32:18 I mean, is it harder than you thought it was going to be? Yes. In my grad school days, it was hope,
0:32:24 hope, hope, excitement, excitement, excitement, and then forming my own company and being in charge
0:32:32 of the fundraising behind keeping these programs going. It’s been a lot of work, but I believe
0:32:36 strongly in what I do and that it’s having a positive impact on patient lives, and so it’s
0:32:43 worth that effort. We’ll be back in a minute with the lightning round.
0:33:01 Let’s finish with the lightning round. Okay. What’s the best thing about working with your husband?
0:33:11 Oh, let’s see. I think that at the end of the day, we can understand each other’s stresses. It’s
0:33:17 not like coming home and he has no idea what I’m talking about. It’s like, if I have a problem,
0:33:23 he can think through it very clearly because he understands it at its core and give me advice
0:33:28 on how to navigate the situation and vice versa. What’s the worst thing about working with your
0:33:38 husband? Sometimes there’s evenings where I’m done talking about AAV. I’ve done it all day long,
0:33:42 and we’re sitting over the dinner table with our kids, and he’s still talking about designing a
0:33:47 vector to do whatever, and I’m like, okay, we’re done here. We’re done for the night, but I mean,
0:33:51 it’s with us all the time, and I think that’s what makes us better scientists for it.
0:33:57 What’s one interesting or surprising thing you’ve learned about the human eye?
0:34:09 The human eye. I would say most of all that you can be 70 years old and have had a congenital
0:34:13 form of blindness since you were a baby and still benefit from gene therapy,
0:34:18 and that’s wild to me. I got my PhD in neuroscience, so I’m always thinking about,
0:34:23 so what if we restore function to the retina? What’s that going to mean in the brain? Is the
0:34:28 brain going to be able to be receptive to that message if it’s been turned off from that message
0:34:35 input its entire life, right? But we had a 70-year-old patient in our LCA1 clinical trial that
0:34:41 showed some benefit following gene therapy, and that tells me that the brain is extremely plastic,
0:34:48 more plastic than I gave it credit for before. It’s not the eye but the brain. We’re not really
0:34:52 seeing with our eye. The eye is just like the window, and the brain is really where the seeing
0:35:01 is happening. That’s right. I read that you have a boat called Wet Lab. We do. What was the runner-up
0:35:07 name? Oh, I don’t think we had a runner-up. We planned that one for years.
0:35:17 What’s the biggest fish you ever caught? Oh, my goodness. We go all the time, and we catch
0:35:22 big fish so often. I don’t remember the biggest one. Look at that. You catch so many big fish.
0:35:29 You don’t even need to tell a fish story. Thank you so much for your time. It was
0:35:32 very interesting to talk to you. I learned a lot. Thank you. Thank you. You’re a great
0:35:33 interviewer. This was a pleasure.
0:35:42 Shannon Boy is a professor of genetics at the University of Florida and the co-founder and
0:35:47 chief scientific officer of Acena Therapeutics. Just a quick note, the show is going to take
0:35:53 a break. We’ll be back with new episodes in a couple weeks. In the meantime, please let us know
0:35:58 who you’d like to hear on the show, who I should interview, or just how we can make the show better.
0:36:05 You can email us at problem@pushkin.fm. Today’s show was produced by Gabriel Hunter Chang.
0:36:10 It was edited by Lydia Jean Cotte and engineered by Sarah Bouguere.
0:36:16 You can email us at problem@pushkin.fm. I’m Jacob Goldstein, and we’ll be back next week
0:36:24 with another episode of What’s Your Problem?
0:36:34 [BLANK_AUDIO]
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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