WEBVTT - Using Gene Therapy to Help the Blind See 0:00:15.356 --> 0:00:24.276 Pushkin. Think about the basic idea of gene therapy. You 0:00:24.396 --> 0:00:27.276 string together a gene, put the gene inside a virus, 0:00:27.436 --> 0:00:30.276 put the virus inside a patient, and then the virus 0:00:30.276 --> 0:00:33.276 delivers the gene to the patient, sells, and then that 0:00:33.396 --> 0:00:37.076 new gene, if everything goes according to plan, makes the 0:00:37.156 --> 0:00:41.436 patient get better. It sounds hard, it is hard, but 0:00:41.596 --> 0:00:50.116 after decades of research, gene therapy is starting to work. 0:00:50.996 --> 0:00:53.196 I'm Jacob Goldstein and this is What's Your Problem, the 0:00:53.196 --> 0:00:55.196 show where I talk to people who are trying to 0:00:55.236 --> 0:00:59.756 make technological progress. My guest today is Shannon boy She's 0:00:59.796 --> 0:01:02.556 a professor of genetics at the University of Florida and 0:01:02.596 --> 0:01:06.996 the co founder and chief scientific officer of Atsina Therapeutics. 0:01:07.396 --> 0:01:11.036 Shannon's problem is this, how do you use gene therapy 0:01:11.316 --> 0:01:15.596 to cure blindness, or at least certain forms of blindness. 0:01:15.996 --> 0:01:19.636 Shannon has been working on gene therapy for twenty years, 0:01:19.716 --> 0:01:21.876 and I wanted to talk with her about the long 0:01:22.076 --> 0:01:24.636 arc of the field, from the wild optimism of the 0:01:24.676 --> 0:01:28.516 early two thousands to the realization that developing gene therapy 0:01:28.516 --> 0:01:32.036 would be a long, hard slog, to the recent promising 0:01:32.116 --> 0:01:35.636 results from an experimental drug that her company has developed 0:01:36.396 --> 0:01:39.796 that drug treats a rare disease that Sharon started studying 0:01:40.076 --> 0:01:42.436 as a grad student back in two thousand and four. 0:01:42.996 --> 0:01:45.236 The disease is called LCA one. 0:01:46.036 --> 0:01:49.276 So babies are born with the disease and usually within 0:01:49.316 --> 0:01:51.796 the first few months of life, their moms or dads 0:01:51.876 --> 0:01:54.956 notice that they're not looking at them directly, they're not 0:01:55.036 --> 0:01:59.156 fixating on objects. Oftentimes the babies will have a roving 0:01:59.236 --> 0:02:03.716 eye movement called nystagmus, and so they're diagnosed usually pretty 0:02:03.796 --> 0:02:09.036 quickly with this condition, and unfortunately, it's profound visual impairment, 0:02:09.196 --> 0:02:12.276 if not total blindness, and that remains with the patient 0:02:12.316 --> 0:02:15.236 throughout the course of their life. So that's really the 0:02:15.276 --> 0:02:18.596 reason that this lab was really interested in studying that 0:02:18.636 --> 0:02:20.036 gene AHU. 0:02:20.116 --> 0:02:23.996 So it's one of the somewhat rare instances where there 0:02:24.076 --> 0:02:27.956 is like a single gene that maps to a single 0:02:28.356 --> 0:02:33.836 in this case, profound problem basically blindness or severe problems 0:02:33.836 --> 0:02:37.076 with vision, which is kind of you would think would 0:02:37.116 --> 0:02:41.156 be the first wave of gene therapy, right exactly, This 0:02:41.276 --> 0:02:44.756 is what the early two thousands, when you're and so 0:02:45.436 --> 0:02:47.716 the human genome has just been mapped, there's like a 0:02:47.796 --> 0:02:50.836 sense of oh, now we know all the genes, right, 0:02:50.956 --> 0:02:53.516 let's figure out how to help people with this new knowledge. 0:02:53.596 --> 0:02:56.316 That's exactly right. This was sort of the step one 0:02:56.316 --> 0:02:58.756 in gene therapy was the simplest form, which is just 0:02:58.996 --> 0:03:02.156 gene replacement. Can we take a healthy copy of a 0:03:02.196 --> 0:03:04.796 gene and put it back into the patient's cells and 0:03:04.836 --> 0:03:06.836 then have that gene go on to make the protein 0:03:06.836 --> 0:03:09.356 it was supposed to make and then hopefully rett or 0:03:09.356 --> 0:03:10.596 the function to those cells. 0:03:11.276 --> 0:03:15.156 And so what as a grad student are you trying 0:03:15.156 --> 0:03:15.836 to figure out? 0:03:16.916 --> 0:03:20.436 The lab was studying the biochemical underpinnings of this disease, 0:03:20.476 --> 0:03:23.076 and they were using a chicken model to do this. 0:03:23.676 --> 0:03:25.836 That's kind of a unique thing in a lab. Usually 0:03:25.916 --> 0:03:28.796 research labs are using mice or rats, but there was 0:03:28.836 --> 0:03:31.876 a naturally occurring chicken model of this disease that had 0:03:31.956 --> 0:03:33.796 profound visual impairment and blindness. 0:03:33.836 --> 0:03:37.716 So naturally occurring chicken model basically means this happens to 0:03:37.796 --> 0:03:40.836 chickens too, Yes, exactly, it is. That's right. 0:03:41.116 --> 0:03:44.876 Yeah. So, at the same time that the lab was studying, 0:03:45.076 --> 0:03:47.396 you know, what was going wrong in this chicken and 0:03:47.436 --> 0:03:50.116 why it was happening, they wanted to ask the question 0:03:50.796 --> 0:03:55.556 would gene therapy be a reasonable approach for treating these chickens. 0:03:55.556 --> 0:03:58.396 Can we restore visions to these chickens with gene therapy. 0:03:58.956 --> 0:04:02.836 So this was a collaborative effort with my other grad 0:04:02.876 --> 0:04:06.956 students and I where we took a vector called Lenti 0:04:07.076 --> 0:04:12.236 virus and we to the chicken embryos. I felt very 0:04:12.316 --> 0:04:14.396 much in grad school like I was a poultry farmer, 0:04:15.076 --> 0:04:18.596 because I would on my way into lab every day, 0:04:18.756 --> 0:04:22.036 stop at the farm, pick up the eggs, burning them 0:04:22.036 --> 0:04:25.196 into lab, and then my fellow grad students and I 0:04:25.276 --> 0:04:27.756 we would make these tiny little holes in the chicken 0:04:27.756 --> 0:04:30.996 egg and we would pull these glass micro needles and 0:04:31.196 --> 0:04:35.596 use them to inject into the chicken embryo. And remember 0:04:35.636 --> 0:04:37.756 this is a disease that you have from birth, so 0:04:37.796 --> 0:04:40.836 we needed to treat these chickens very early. But it 0:04:40.876 --> 0:04:44.236 was a difficult process to get that micro needle injection 0:04:44.316 --> 0:04:47.316 into the head of the chicken embryo and then for 0:04:47.396 --> 0:04:49.876 that chicken to make it all the way to hatch, right, 0:04:50.196 --> 0:04:52.556 And that was I think one of the hardest parts 0:04:52.556 --> 0:04:54.796 of that project. Actually, It's why I said I felt 0:04:54.796 --> 0:04:59.036 like a poultry farmer. Is all of the machinations you know, 0:04:59.116 --> 0:05:02.476 getting the humidity right, the temperature right, the position right, 0:05:02.596 --> 0:05:04.796 making sure you close that egg right, just getting that 0:05:05.236 --> 0:05:06.396 chicken to survive. 0:05:07.436 --> 0:05:13.596 And so you injecting the non mutated form of the gene, 0:05:13.596 --> 0:05:18.116 the good form of the gene, if you will, encased 0:05:18.156 --> 0:05:21.756 in this virus, into the head of the chicken embryo. Yes, 0:05:24.076 --> 0:05:24.716 did it work? 0:05:25.756 --> 0:05:28.116 For a while it did not, because again, it was 0:05:28.196 --> 0:05:32.156 difficult to manipulate a chicken embryo like that and actually 0:05:32.156 --> 0:05:34.756 have it to survive to hatch. But my fellow grad 0:05:34.796 --> 0:05:37.556 students and I did a lot of work to optimize 0:05:37.556 --> 0:05:41.076 that process, and eventually it actually did work. We had 0:05:41.396 --> 0:05:44.516 little chicks that were born, and I can distinctly remember 0:05:44.596 --> 0:05:47.756 them walking around on the lab bench and pecking at 0:05:48.116 --> 0:05:50.756 our jewelry or at Eminem's that we had laid out 0:05:50.796 --> 0:05:53.676 on the surface of the bench. Very different from the 0:05:54.076 --> 0:05:57.076 blind chickens. It was very clear. You know, chickens are 0:05:57.516 --> 0:06:02.076 very visually guided creatures. It's very obvious when a chicken 0:06:02.076 --> 0:06:03.396 can see versus Nazi. 0:06:03.836 --> 0:06:07.076 It was so fun. We were all so so happy. 0:06:07.796 --> 0:06:12.236 Okay, so that's two thousand and four as twenty years ago. Yeah, yeah, 0:06:13.636 --> 0:06:16.116 at that time, is it like, well, we did it 0:06:16.156 --> 0:06:18.876 in chickens, let's do it in people or what. 0:06:19.556 --> 0:06:22.716 So that's actually where my thesis project comes in. So 0:06:22.796 --> 0:06:25.076 all of that chicken work was a really collaborative effort 0:06:25.116 --> 0:06:28.276 and it was exciting, but it had its drawbacks and 0:06:28.316 --> 0:06:31.996 it wasn't clinically translatable for a number of reasons. First 0:06:32.036 --> 0:06:34.476 and foremost, we were never going to do an embryonic 0:06:34.556 --> 0:06:38.316 injection and a patient. Maybe that'll happen one day, honestly, 0:06:38.436 --> 0:06:41.596 but it certainly wasn't close to happening in two thousand 0:06:41.636 --> 0:06:44.916 and four. So we needed a gene therapy that could 0:06:44.916 --> 0:06:50.076 be injected in a patient after birth, right, And unfortunately, 0:06:50.116 --> 0:06:52.596 the virus that we were using in the chicken experiments, 0:06:52.636 --> 0:06:57.276 the Lenti virus, is really poor at a gene delivery 0:06:57.316 --> 0:06:59.716 to a developed retina. So we needed to find a 0:06:59.716 --> 0:07:02.436 more clinically relevant vector to do the gene therapy. 0:07:02.956 --> 0:07:05.516 Let's just pause for a moment and talk about this 0:07:05.676 --> 0:07:11.236 idea of a vector in gene therapy. So the basic idea, right, 0:07:11.356 --> 0:07:13.636 is like, you know what the good gene is, you 0:07:13.676 --> 0:07:16.236 know the gene you want to get into, in this case, 0:07:16.356 --> 0:07:19.556 the person's eye. But there's this weird question of how 0:07:19.596 --> 0:07:21.716 do you get it there, right, Like, you can't just 0:07:21.836 --> 0:07:27.476 put a string of genetic material randomly in someone's body, right, 0:07:27.516 --> 0:07:30.796 It'll just get destroyed. And so there's this basic idea 0:07:30.916 --> 0:07:34.436 that you put it in a virus, right, because a 0:07:34.516 --> 0:07:38.836 virus is like, it's billions of years of evolution to 0:07:38.876 --> 0:07:41.116 be a genetic material delivery mechanism. 0:07:41.196 --> 0:07:42.196 That's exactly right. 0:07:42.276 --> 0:07:44.156 But that's hard for a number of reasons. So like, 0:07:44.236 --> 0:07:47.036 tell me sort of the state of vectors at this 0:07:47.196 --> 0:07:49.556 time twenty years ago when you're figuring this out. 0:07:49.996 --> 0:07:52.756 So there were a number of viral vectors that were 0:07:52.756 --> 0:07:55.476 being used to deliver genes, and each of them had 0:07:55.516 --> 0:08:00.316 their pros and their cons One was named adnovirus. This 0:08:00.476 --> 0:08:02.716 was a good virus because it's big, you can fit 0:08:02.796 --> 0:08:05.556 a lot of genetic material into it, and it was 0:08:06.076 --> 0:08:08.996 used in the early days of gene therapy and on. 0:08:09.236 --> 0:08:12.356 Fortunately it was discovered you know later on that it 0:08:12.396 --> 0:08:15.716 came with you know, some downsides. It's more immunogenic than 0:08:15.756 --> 0:08:17.556 the other viral vectors that are out there. 0:08:17.476 --> 0:08:20.316 Meaning it generates an immune response. So the body's like, oh, 0:08:20.396 --> 0:08:23.436 that's a virus. I'm going to destroy it, and you're like, no, no, no, 0:08:23.476 --> 0:08:25.756 this is a virus that's going to help you exactly. 0:08:25.796 --> 0:08:27.356 It's like, I don't care. I've gotten rid of it. 0:08:27.596 --> 0:08:28.836 Yes, yeah. 0:08:28.876 --> 0:08:30.916 And then of course there was lenty virus, which is 0:08:30.916 --> 0:08:33.476 what we were using in the chickens. It is not 0:08:33.636 --> 0:08:36.356 the vector of choice, for instance, in the eye where 0:08:36.396 --> 0:08:39.316 I work, because it's not very good at delivering genes 0:08:39.356 --> 0:08:43.756 to developed cells in the retina. And then in the 0:08:43.876 --> 0:08:48.196 nineties some exciting work was going on evaluating a newer 0:08:48.316 --> 0:08:53.956 vector called Adno associated virus or AAV. Since the nineties 0:08:54.116 --> 0:08:57.996 early two thousands, AAV has become the gold standard gene 0:08:57.996 --> 0:09:01.236 delivery vector for essentially all of gene therapy. 0:09:01.836 --> 0:09:04.996 And so at this time in two thousand and four, like, 0:09:05.076 --> 0:09:07.156 what was the state of gene therapy? 0:09:08.116 --> 0:09:10.516 Oh, my gosh, it was the heyday. It was such 0:09:10.516 --> 0:09:13.716 a fun time and it was so it was so exciting. 0:09:13.916 --> 0:09:17.716 The my grad school days, my postdoc days, it was 0:09:17.796 --> 0:09:20.596 an extremely exciting time in the field that I would 0:09:20.636 --> 0:09:23.396 say it was filled with hope because there was so 0:09:23.636 --> 0:09:26.916 much proof of concept work going on in animal models 0:09:26.916 --> 0:09:31.196 of disease showing that gene therapy could restore vision, could 0:09:31.236 --> 0:09:34.316 restore muscular function, could restore clotting. 0:09:34.756 --> 0:09:35.516 You know, you name it. 0:09:35.516 --> 0:09:39.116 It was these successes were being seen across neuromuscular disease, 0:09:39.236 --> 0:09:44.836 CNS disease, ocular disease, but everybody was just really excited 0:09:44.876 --> 0:09:48.156 about it, and that extended beyond the scientists in the lab. 0:09:48.996 --> 0:09:51.956 That was true of the macro environment too, So you know, 0:09:51.996 --> 0:09:52.356 I mean. 0:09:52.316 --> 0:09:55.756 Like in the media or like the industry, like the 0:09:55.756 --> 0:09:56.916 pharmaceutical industry. 0:09:57.156 --> 0:10:00.116 Yeah, I'm talking more about like investors and big pharma. 0:10:00.236 --> 0:10:03.116 So I mean investors were keen to throw their money 0:10:03.476 --> 0:10:05.636 at gene therapy at the time because of how much 0:10:05.676 --> 0:10:08.676 promise it was showing in these pre clinical studies, and 0:10:08.756 --> 0:10:12.356 big Arma was keen to acquire, you know, startup companies 0:10:12.356 --> 0:10:14.436 that were in this space because of that promise it 0:10:14.516 --> 0:10:17.836 was showing. And I think their their reason at the 0:10:17.876 --> 0:10:20.196 time was a sound one. They wanted to use. Even 0:10:20.236 --> 0:10:23.436 if those companies were focused on rare disease, it was 0:10:23.516 --> 0:10:25.996 like this platform for them to say, well, if I 0:10:26.036 --> 0:10:28.876 can get gene therapy to work in this small, rare disease, 0:10:29.356 --> 0:10:31.996 that proves that as a company, I'm capable of doing 0:10:31.996 --> 0:10:33.636 this and that eventually I can do it in a 0:10:33.676 --> 0:10:36.796 disease that affects millions of people. So it was a 0:10:37.196 --> 0:10:41.236 really really exciting time, both scientifically and from kind of 0:10:41.276 --> 0:10:43.036 a financial standpoint. 0:10:43.636 --> 0:10:46.596 And then at some point, right there are these these 0:10:46.636 --> 0:10:50.396 strong results using gene therapy to treat a disease called 0:10:50.596 --> 0:10:54.036 LCA two, which is similar to LCA one, the disease 0:10:54.076 --> 0:10:56.916 you work on, and that's like a big moment in 0:10:56.956 --> 0:10:57.636 the field, right. 0:10:58.196 --> 0:11:02.276 Yeah, the RP sixty five LCA two gene therapy trials 0:11:02.356 --> 0:11:04.876 were a huge success, and then they went on to 0:11:05.476 --> 0:11:08.196 form the basis of Luxterno, which is the first approved 0:11:08.236 --> 0:11:12.156 ocular gene therapy, and so everybody was super excited that, Okay, 0:11:12.196 --> 0:11:15.436 they got this approved. We're going to see this, you know, 0:11:15.636 --> 0:11:18.436 flood of other gene therapies getting approved on the heels 0:11:18.436 --> 0:11:20.996 of luxtern And I think that's I think that's when 0:11:21.036 --> 0:11:23.396 it got hard, and you know, there was a little 0:11:23.396 --> 0:11:25.196 bit of a reality check for the field. 0:11:25.596 --> 0:11:27.636 What was that like for you? So you're working on 0:11:28.276 --> 0:11:32.436 LCA one, a very similar disease. Everybody is very excited 0:11:32.436 --> 0:11:34.916 about l c A two, are you like, yes, we 0:11:34.996 --> 0:11:37.236 got l c A two, I'm about to get LCA one. 0:11:37.436 --> 0:11:40.076 Like what what was your where were you at that? Oh? 0:11:40.196 --> 0:11:41.756 I was I was super excited. 0:11:41.796 --> 0:11:42.076 I was. 0:11:42.156 --> 0:11:45.076 I was further behind obviously in my pursuit of l 0:11:45.156 --> 0:11:47.276 c A one, but I had, you know, high hopes 0:11:47.316 --> 0:11:49.156 that it would it would go, that it would work. 0:11:49.596 --> 0:11:52.076 Why didn't it happen as fast as you thought? 0:11:52.236 --> 0:11:56.676 So in twenty fourteen, I hit a stage where you know, 0:11:56.716 --> 0:11:59.436 the technology had been developed, I had done everything that 0:11:59.476 --> 0:12:02.036 I really could, you know, from the academic standpoint, to 0:12:02.116 --> 0:12:06.076 get this ready to move forward. But at that stage 0:12:06.116 --> 0:12:08.636 you hit what the NIH calls the valley of death, 0:12:08.676 --> 0:12:11.716 which is, you know, a period of time where you 0:12:11.756 --> 0:12:13.956 need a lot of capital and a lot of infrastructure 0:12:13.996 --> 0:12:16.436 to move a gene therapy from bench to bedside, and 0:12:16.556 --> 0:12:18.596 you can't do that in an academic lab. 0:12:18.676 --> 0:12:21.356 So to put it to test it in people, basically 0:12:21.476 --> 0:12:25.356 testing it in people is obviously complicated and expensive and 0:12:25.596 --> 0:12:28.476 very at least some extent rightly so, right you're ingesting 0:12:28.956 --> 0:12:30.196 things into people's eyes. 0:12:30.716 --> 0:12:31.076 Yes. 0:12:31.316 --> 0:12:34.716 In twenty fourteen, my husband and I who I work with, 0:12:35.116 --> 0:12:39.036 we were very much in a pattern of developing technologies 0:12:39.156 --> 0:12:43.516 and then out licensing them to different companies. So in 0:12:43.596 --> 0:12:47.036 around twenty fourteen, we partnered with Genzyme, which was a 0:12:47.036 --> 0:12:51.076 company focused on developing gene therapies for rare disease, and 0:12:51.116 --> 0:12:54.716 they took that technology. Shortly thereafter they were acquired by 0:12:54.796 --> 0:12:59.596 Santafie and together with Genzyme Slash Santafee, we conducted all 0:12:59.636 --> 0:13:02.556 of the studies that were what we call I and 0:13:02.636 --> 0:13:06.276 D enabling studies, sort of like the really well documented 0:13:06.356 --> 0:13:10.676 careful safety studies and efficacy studies, dose ranging studies that 0:13:10.716 --> 0:13:13.476 are required to show to the FDA before. 0:13:13.276 --> 0:13:14.476 They let you go into people. 0:13:14.716 --> 0:13:18.036 I INDA is an investigational new drug's exactly. So you're 0:13:18.116 --> 0:13:20.076 like doing all the work to say, like, look, this 0:13:20.116 --> 0:13:22.556 should be an investigational new drug that we can test 0:13:22.596 --> 0:13:24.676 in a very small number of people just to see 0:13:24.716 --> 0:13:26.676 if it's safe to start out with exactly. 0:13:27.156 --> 0:13:27.476 Yeah. 0:13:27.516 --> 0:13:30.556 So, and I'll be honest, that moved a little bit 0:13:30.796 --> 0:13:33.596 slower than I would have liked. But I mean, when 0:13:33.596 --> 0:13:36.156 you work with Big Pharma, and I will say they 0:13:36.196 --> 0:13:39.236 were an amazing, amazing team, excellent group of people, but 0:13:39.636 --> 0:13:42.156 Big Pharma is very siloed, and you know, it can 0:13:42.196 --> 0:13:45.636 take a long time for things to move. And then unfortunately, 0:13:46.276 --> 0:13:50.756 in around twenty eighteen, Cianna FI decided to pivot away 0:13:50.756 --> 0:13:55.476 from ocular gene therapy altogether, so they wanted to give 0:13:55.476 --> 0:13:59.116 the program away, and I was heartbroken. I remember the 0:13:59.196 --> 0:14:01.796 night that someone told me it was happening. I couldn't 0:14:01.836 --> 0:14:04.476 believe it because you know, we were just about to 0:14:04.516 --> 0:14:07.396 treat the first patient and everything was ready to go, 0:14:07.476 --> 0:14:10.636 and I just couldn't believe it. But you know, companies 0:14:10.676 --> 0:14:13.916 make decisions like this all the time. So when that happened, 0:14:13.996 --> 0:14:16.516 that was really what motivated my husband and I to 0:14:17.276 --> 0:14:20.396 co found our own company because we wanted hopefully to 0:14:20.436 --> 0:14:23.796 get that program back so that we could make sure 0:14:23.796 --> 0:14:26.796 that it went forward. And that was just that was 0:14:26.876 --> 0:14:30.076 one reason that we founded at Seena Therapeutics. I would 0:14:30.076 --> 0:14:32.596 say that the broader reason we founded the company was 0:14:33.076 --> 0:14:35.876 out of a sense of frustration because we had developed 0:14:35.916 --> 0:14:38.716 a lot of technologies and we had outlcensed them to 0:14:38.796 --> 0:14:42.836 a variety of companies, and there was a theme emerging 0:14:42.956 --> 0:14:46.436 that the technologies weren't getting to patients. And whether that 0:14:46.556 --> 0:14:50.756 was because of you know, business decisions overriding science decisions, 0:14:50.876 --> 0:14:53.836 or just you know, companies being too big and siloed, 0:14:54.516 --> 0:14:57.356 there were a variety of reasons, but it ultimately we 0:14:57.436 --> 0:14:59.716 formed the company because we were frustrated. We wanted to 0:14:59.756 --> 0:15:02.916 have some more control over the direction that the science 0:15:03.036 --> 0:15:03.516 was taking. 0:15:03.836 --> 0:15:06.636 It's like you want it more than anybody else can 0:15:06.716 --> 0:15:07.236 want it. 0:15:07.356 --> 0:15:08.636 Yes, it was. 0:15:08.676 --> 0:15:11.596 I mean one is my baby, right, and so are 0:15:11.636 --> 0:15:13.876 some of the other indications that I'm working on now. 0:15:13.876 --> 0:15:16.356 But yeah, I wanted to be the one to help 0:15:16.436 --> 0:15:19.396 usher them towards patients and keep it moving in the 0:15:19.436 --> 0:15:19.956 right direction. 0:15:21.076 --> 0:15:24.196 And you mentioned your husband, So is he in the 0:15:24.196 --> 0:15:25.796 same field as you, like, is. 0:15:25.916 --> 0:15:26.556 What's he doing? 0:15:26.676 --> 0:15:30.916 Yeah, he's an AV vectorologist. When I was a grad 0:15:30.956 --> 0:15:34.396 student and I was tasked with my thesis project, which 0:15:34.516 --> 0:15:37.636 was okay, come up with a clinically relevant approach for 0:15:37.716 --> 0:15:40.636 treating this disease. So to do that, I needed to 0:15:40.716 --> 0:15:43.756 shift away from Lenti virus and start using ad no 0:15:43.876 --> 0:15:47.756 associated virus AAV. I needed to shift into a mouse model, 0:15:47.796 --> 0:15:50.876 a mammalian model of the disease, and so to get 0:15:50.916 --> 0:15:53.516 help on the AAV aspect of the project, I went 0:15:53.596 --> 0:15:56.516 to Bill Houseworth, who became my post docmentor, and he 0:15:56.596 --> 0:15:59.396 pointed me in the direction of my now husband. He 0:15:59.436 --> 0:16:01.716 was a scientific research manager at the time. He said, 0:16:01.756 --> 0:16:03.556 you know, he can field any questions you have about 0:16:03.636 --> 0:16:05.956 vector design, and so I went to him and then 0:16:05.996 --> 0:16:09.556 that you know was an excellent collaboration obviously that lossoened 0:16:09.556 --> 0:16:12.316 into a nerd romance and then eventually a marriage in 0:16:12.316 --> 0:16:12.676 two k. 0:16:12.876 --> 0:16:16.276 Yes, it is a very nerdy meet cute, yes. 0:16:17.396 --> 0:16:19.956 But yeah, we're very much in the same field. But 0:16:20.476 --> 0:16:22.676 we have very different skill sets, I would say, so 0:16:23.076 --> 0:16:24.196 we compliment each other. 0:16:24.116 --> 0:16:24.996 Which is nice. 0:16:26.396 --> 0:16:30.276 Obviously to get from, you know, doing this in chickens 0:16:30.316 --> 0:16:32.476 twenty years ago to doing it in people now. There 0:16:32.476 --> 0:16:34.476 were many, many, many things I'm sure that you had 0:16:34.516 --> 0:16:38.316 to figure out. There is there anything in particular that 0:16:38.436 --> 0:16:41.076 was a thing you figured out? Maybe that was a 0:16:41.076 --> 0:16:43.636 thing that people doing gene therapy more broadly were trying 0:16:43.636 --> 0:16:47.356 to figure out, just in the sense of, yeah, something 0:16:47.436 --> 0:16:48.596 you solved along the way. 0:16:49.196 --> 0:16:51.636 In the early days, when I had first transitioned into 0:16:51.676 --> 0:16:55.676 testing the AV vector in the mouse, I did it 0:16:55.716 --> 0:16:57.516 over and over and over again, and it didn't work. 0:16:57.796 --> 0:17:00.956 And I think one big mistake that I made was 0:17:00.996 --> 0:17:03.916 that I was using the same gene, the same coding 0:17:03.996 --> 0:17:07.836 sequence that we had used in the chicken experiments, and interestingly, 0:17:07.956 --> 0:17:12.156 that gene was a bovine gene. In the early two thousands, 0:17:12.436 --> 0:17:15.196 it was a lot easier to generate bovine sequences for 0:17:15.236 --> 0:17:18.556 reasons I don't even actually remember. But what it took 0:17:18.756 --> 0:17:21.076 was figuring out that we needed to deliver the species 0:17:21.116 --> 0:17:25.916 specific gene. So the mouse gene worked, the human gene worked, 0:17:25.916 --> 0:17:29.116 which was great because that was very translatable, So the 0:17:29.956 --> 0:17:33.836 species of the gene was important. Another really important thing 0:17:33.956 --> 0:17:34.356 was the foot. 0:17:34.556 --> 0:17:37.436 So basically the versions of the gene exist in these 0:17:37.476 --> 0:17:39.316 different animals, but they're slightly different. 0:17:39.516 --> 0:17:40.036 Exactly. 0:17:40.316 --> 0:17:44.116 Yes, I have to say retrospectively out of my armchair ignorance. 0:17:45.156 --> 0:17:49.236 I feel like that one seems obvious in retrospect to me. 0:17:50.476 --> 0:17:53.596 But it was strange to me because this bovine sequence 0:17:53.636 --> 0:17:54.796 worked in a chicken, so. 0:17:54.956 --> 0:17:56.916 I think, and a mouse and a person who's more 0:17:56.996 --> 0:18:02.436 like a cow. Yes, okay, what's another one? What's another one? 0:18:02.476 --> 0:18:03.156 You had to figure out? 0:18:03.316 --> 0:18:06.036 Another one was the flavor of AAV that we needed 0:18:06.076 --> 0:18:06.396 to use. 0:18:06.476 --> 0:18:09.316 So the particular nature of the vector. 0:18:09.276 --> 0:18:10.076 Yes, exactly. 0:18:10.156 --> 0:18:12.876 So AV comes in a variety of flavors, and one 0:18:12.916 --> 0:18:15.716 flavor of AV might be good at infecting neurons, and 0:18:15.756 --> 0:18:18.916 another flavor of AV might be good at infecting skin cells, 0:18:18.956 --> 0:18:19.436 for instance. 0:18:19.556 --> 0:18:23.396 Yes, and interestingly, in this point, you want it to infect, right, 0:18:23.556 --> 0:18:26.996 Infecting is delivering the gene exactly. Huh. 0:18:27.476 --> 0:18:30.636 So we tested for the first time in non human 0:18:30.676 --> 0:18:34.956 primates a certain flavor of AV called AAV five, and 0:18:35.236 --> 0:18:38.236 we really for the first time showed that that flavor 0:18:38.236 --> 0:18:40.796 of AV was really useful in the rod and the 0:18:40.836 --> 0:18:44.196 cone foto receptors of the human of a primate retina rather, 0:18:44.676 --> 0:18:46.676 so that was the flavor of AV that we needed 0:18:46.676 --> 0:18:48.276 to figure out. And then I would say the third 0:18:48.316 --> 0:18:52.076 thing that we figured out was a specific regulatory sequence 0:18:52.116 --> 0:18:55.716 that we used to drive expression of the gene. So 0:18:55.916 --> 0:19:00.356 it's called a promoter, and specifically it's the adoptin kinase promoter, 0:19:00.436 --> 0:19:03.276 which drives expression exclusively in photo receptors. 0:19:03.476 --> 0:19:06.396 And so just to be clear, just to unpack that 0:19:06.596 --> 0:19:10.036 a little bit, so the idea is, you don't just 0:19:10.116 --> 0:19:15.356 need to have the gene itself in this vector. You 0:19:15.436 --> 0:19:18.556 need to have the genetic information that tells it in 0:19:18.636 --> 0:19:22.196 what kinds of cells should this gene be expressed exactly, 0:19:22.236 --> 0:19:23.916 and in what kinds of cells should it not be 0:19:23.956 --> 0:19:24.956 expressed exactly. 0:19:24.996 --> 0:19:27.836 And that's important from a safety standpoint, because ideally you 0:19:27.876 --> 0:19:31.196 don't want this gene expressing a protein in cells where 0:19:31.196 --> 0:19:32.196 it's not supposed to be. 0:19:32.276 --> 0:19:38.916 In potent harm in your heart right exactly in a minute. 0:19:38.996 --> 0:19:41.996 What happened when Shannon's drug finally made its way out 0:19:41.996 --> 0:19:54.796 of the lab and into the eyes of patience. I 0:19:54.836 --> 0:19:57.676 asked Shannon how she got from figuring everything out in 0:19:57.716 --> 0:20:01.516 the lab and in animals to actually doing a clinical 0:20:01.556 --> 0:20:04.716 trial to actually testing her drug in patience. 0:20:05.396 --> 0:20:09.156 So I will say that, fortunately, before Santafie let the 0:20:09.196 --> 0:20:11.836 program go, they did dose a couple of patients, so 0:20:11.876 --> 0:20:14.836 we did get them to start the trial thankfully, and 0:20:14.916 --> 0:20:17.796 they were absolutely critical and getting that off the ground. 0:20:18.436 --> 0:20:21.516 But when they handed it back to at Sina, obviously 0:20:21.556 --> 0:20:24.876 we had to build a clinical team and we worked 0:20:24.876 --> 0:20:27.476 closely with Santa fe during that transition period to make 0:20:27.516 --> 0:20:30.276 sure there were no bumps in the road, and then 0:20:30.796 --> 0:20:33.676 we just continued with the trial. We had some amazing 0:20:33.676 --> 0:20:38.316 clinical investigators at the University of Pennsylvania and OHSU, which 0:20:38.356 --> 0:20:42.116 is Oregon Health Sciences University at the CACI Institute, and 0:20:42.156 --> 0:20:45.556 so the surgeons there did the injections. We also had 0:20:45.596 --> 0:20:49.356 a surgeon at Will's I Institute, and just excellent teams 0:20:49.396 --> 0:20:53.036 of physicians focused on inherited retinal disease that we worked 0:20:53.036 --> 0:20:55.156 closely with to monitor these patients over time. 0:20:55.956 --> 0:21:00.476 So you have this virus that you have engineered to 0:21:00.596 --> 0:21:05.196 have this gene and this promoter, you inject it into 0:21:05.716 --> 0:21:08.116 the back of somebody's eye. 0:21:08.756 --> 0:21:13.876 Then what happens, So the virus infects the photo receptors, 0:21:14.596 --> 0:21:18.716 it unloads the DNA inside, and then that DNA remains 0:21:18.996 --> 0:21:22.636 inside that cell over the lifetime of that living cell. 0:21:23.036 --> 0:21:26.876 So the gene will persistently remain inside that cell and 0:21:26.956 --> 0:21:30.356