Imagine the eyes as cameras, where the cornea acts as the lens and the retina as the film. As with a camera, if something goes wrong in the eye, it needs to be fixed to address the specific problem and restore function. While some visual impairments can be corrected with glasses or surgery, some conditions require medicines – like those that slow or stop blood vessel growth in the eye. In this episode, co-host Danielle Mandikian joins guests Chris Brittain, Vice President and Global Head of Ophthalmology Product Development, and Dolly Chang, Group Medical Director, gRED Early Clinical Development, to explore the evolution of eye treatments, advancements in current solutions for vision loss, and their insights into the future of treating ocular diseases.
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Maria: I’m Maria Wilson.
Danielle: And I’m Danielle Mandikian.
Maria: And we are scientists. We. Love. Science.
Danielle: Yeah, we do. So, when we aren’t doing it, the next best thing is to talk about science! And what’s really awesome is that we’re surrounded by some of the most brilliant minds in research!
Maria: We are going to step away from the labs today to talk to other scientists about the cool stuff they are thinking about, working on and imagining…
Danielle: …as well as how some of these discoveries just might lead to new medicines. So, grab your favorite drink, get ready to unlock your science brain and join us for Two Scientists Walk into a Bar…
Maria: The show for scientists, science geeks and the people who love them!
Danielle: Ok. How many parts of the eye can you name?
Employee responses:
The cornea. The optical nerve.
Sclera. Let me think . . .
[Laughter] The cones.
Cornea, iris is all I know.
Anterior chamber.
There's one that starts with a V.
Conjunctival. Vitreous humor. Aqueous humor.
Retinal nerve fiber.
Puncta! Puncta!
You guys did all the ones I know!
Danielle: Those are great answers!
Danielle: Hi, everyone. Welcome to the show! I'm Danielle, and I'm super excited because today we're actually gonna talk about one of the coolest structures and hardest structures to treat – the eye. And I’m sitting here today with two awesome guests, Chris Brittain and Dolly Chang.
Chris: Great to be here, Danielle.
Dolly: Thank you for having me here.
Danielle: Thanks so much for joining us! So, before we dive into it, let me ask each of y'all what your research interests are. So Dolly, what do you study? What are you into?
Dolly: Yeah, sure. So my background is an ophthalmologist. And, I'm glaucoma trained. And before I decided on doing ophthalmology, I actually have my Ph.D. in epidemiology –
Danielle: Oh!
Dolly: – and clinical trial methodology. Right now, I'm currently in early clinical development. My research is mainly focusing on understanding unmet need and how to bring the molecule from the bench to Phase I and Phase II clinical trials.
Danielle: What about you, Chris?
Chris: I trained in the UK as an ophthalmologist for about four and a half years before I joined industry back in about 2010. So today, my research focus of the group which I work in, which is what we call late-stage clinical development, is around retinal vascular disorders – that means neovascular age-related macular degeneration, diabetic macular edema, retinal vein occlusion, really.
Danielle: Maybe we could take a step back and talk about the eye for a second, because sometimes we might not realize how difficult certain tissues or certain diseases actually are to treat. What are some kind of basics of the structure that can help us understand why we might dose somewhere versus another –
Dolly: Right.
Danielle: – and how we’d approach.
Dolly: Yeah, maybe we can start off with what are the most common types of vision loss and where is that coming from? So the eyeball overall you can think about as a camera, basically. It includes the front of the eye, which includes the cornea, the lens – you can think about it as the lens of the camera. So for example, refractive error, why patients need to wear glasses is correctable, but in some parts of the world, actually there's access problems. So that's actually the number one vision loss in the world. Then let's talk about cataract. That's where you can think about the lens of the camera getting cloudy over time. And so if you and me live long enough, everybody require a cataract surgery eventually. So, the treatment for that is a surgical approach that I would say pretty much fix all the problem right now. Chris, would you say that –
Chris: Definitely. Absolutely [Laughs].
Dolly: Yeah, so it's something that is correctable surgically. And those are, you know, the common cause of blindness in the world. Most of them are reversible. Then we started to look at the back of the eye. So the back of the eye, including the film of the camera, which is the retina, that you know, we have been focusing on therapeutics for awhile – in between that there is a jelly part of the eye, which we call vitreous. You can think about, you know, a basketball that you want to keep inflated, then you have to have some substance, a jelly type of substance that keeps the shape. So that's the vitreous. And then the back would be the camera film, which is the retina. And one of the very important part of the eye for glaucoma specialists, the optic nerve – that is where the cable connecting between the eye to the brain where all the visual information collected from the film of the eye that connected to the brain. So that's kind of like the common structure of the eye. And the front of the eye is the cornea up until the lens. And then behind the lens we typically call it the back of the eye.
Danielle: What is the first treatment for ocular diseases that you know of?
Chris: Yeah. So not tens of years ago, not hundreds of years ago, but probably thousands of years ago, it was well established that the elderly, as you reach a certain age – and this is still the case today – your lens becomes naturally more cloudy. This is when, as Dolly described, you have a cataract. So probably one of the earliest procedures in ophthalmology was actually something called “couching.” Now this is where a patient or elderly person lies down, probably has a stick stuck into their mouth to bite down on, maybe there's some alcohol or other sort of anesthetic they will indulge, and then a needle is stuck into the front of the eye to poke the lens out away from the center of the camera. You can imagine how painful that is.
Danielle: Vividly.
Chris: But it does restore navigational vision.
Danielle: Just so people know, everyone that's sitting in the room right now is like gasping with their hands over their face and their eyes [Laughs].
Dolly: And I have to say, nowadays we don't do surgery that way.
Danielle: [Laughs]
Dolly: Just to be clear. Otherwise, I don't think anybody would want cataract surgery anymore. [Laughs]
Danielle: Now I know why the doctors don't want to move away from the lasers. They were like, "I'm cool with this." [Laughs]
Chris: In the last few hundred years, cataract techniques have certainly improved. So with the advent of anesthesia, that would become less painful –
Danielle: Or you don't remember that it's painful. [Laughs]
Chris: [Laughs] Or you don't remember it's painful, if you survived the anesthesia.
Danielle: Oh God.
Chris: And then in more recent times, with topical anesthesia, you could do the procedure much less painfully. And they started to scoop out the inside of the lens, the cataract. And around the time of basically the Second World War, when some of the Spitfire fighter pilots were being shot at, and they had some of the plastic from their windshields fly from their cockpits flying into their eyes, and it was discovered that the eye tolerates this material very nicely.
Danielle: [Laughs]
Chris: And actually, if you shape these bits of plastic, you can put – as a lens – you can actually replace the cataract once you've taken it out. And then the technique improved significantly over the subsequent kind of 20, 30, 40 years.
Danielle: That's a pretty solid –
Chris: Yeah.
Danielle: – silver lining.
Chris: Yeah.
Dolly: Yeah. I feel like I learn a lot from you, Chris. [Laughter]
Chris: I think it was Spitfires, not Hurricanes, but yeah. That's the birth of intraocular lenses, which would replace the natural lens within your eye.
Danielle: And I've been working on like, early research kind of development sciences stuff for eyes for awhile now, and still every time I hear a story about the eyes, I can't help but like cringe up a little bit. [Laughs] Just the thought of it. So that's for the treatments for the front of the eye, but let’s talk about the treatments for the back of the eye. The only ones I'm actually familiar with are the ones that center around targeting VEGF, which is the vascular endothelial growth factor. Were there other treatment options before that?
Chris: Yeah, that really kicked off with anti-VEGF. Just before that treatment, there was a laser treatment where you inject some dye into the arm of the elderly patients, and you'd use another different type of laser. And that laser activated the dye which accumulated in these new blood vessels in the back of the eye and helped to close those blood vessels down. The treatment, again, it slowed the deterioration of the vision down.
Danielle: Wait, wait, sorry. So you mean like there's a dye that is photoactivatable?
Chris: Yes.
Danielle: Very cool. You know, it's really funny how often that pops up in different technical stuff. [Laughter] Like photoactivation has been, like, just amazing for running Western Blots and things. It's totally changed a lot of things.
Wellington: Hey, Danielle!
Danielle: Hey, Wellington!
Karen: Hey, Danielle!
Danielle: Hey, Karen!
Wellington: I know this isn't quite your field, but what are the major eye diseases?
Danielle: Well, you know, when I think about diseases of the eye, I think about all of the structures that are necessary for vision. So if that part of the eye is necessary for vision, there can be a disease associated with it. So in the front of the eye, you have the lens – and we talked a little bit about cataracts. And then the back of the eye, which receives information and transmits it to the brain, that can get all disheveled from problems with blood vessel formation. And that's where you have stuff like age related macular degeneration, where you have wet or dry AMD, but that's also the site where you get damage from glaucoma retinopathy.
Karen: Danielle, I was curious. Are there any risk factors associated with these eye diseases?
Danielle: I think the usual culprits – age, genetics, and any kind of comorbidities. But, you know, thinking about genetics, interestingly enough – like I'm Armenian, and Armenians are disproportionately affected by macular degeneration. So every time I go home, because this also runs in my family, we'll have like my kind of half-blind grandma, and then my aunt will be sitting there and it's always, I have to report out. Did we make any progress? Like, how long am I going to see this? [Laughter] It's the truth!
Danielle: What kind of treatment options are available?
Chris: Maybe I can go back into the history. So, when I first started practicing, which was in the early 2000s, or the noughties if you like, they’d just launched a product which was what we call an anti-VEGF therapy. It wasn't available in the UK, but before that product launched, this form of macular degeneration, or neovascular MD, where the blood vessels at the back of the eye leak and bleed and cause vision loss, the prognosis, the outcomes of that disease were that everybody was gonna go blind. Suddenly, when much more effective anti-VEGF therapies came along, the prognosis actually became much, much better, and actually half the people, with a correct treatment, could still retain their ability to drive. That obviously leaves another 50 percent who are unable to drive, so an enormous amount of unmet need kind of remains. But the background is that, at the time, this wet form or neovascular age-related macular degeneration was the worst disease to have. Because there was another form called the dry form or geographic atrophy, and that was the form which you wanted to have. Now suddenly, this is completely reversed whereby the wet form is the form you want to have because we can treat it and maintain your vision. And this dry form, this atrophic form, is the form which you don't want to have because, up until very recently, there’s no effective treatment.
Dolly: Yeah. I think in addition to what Chris mentioned, that in the past we don't really have effective treatment for neovascular MD, so it was amazing that now we can cut the blindness into half. I think the other patient population that can be treated with anti-VEGF is diabetic macular edema, or retinal vein occlusion. So historically, those were treated by laser. Basically, you see which blood vessels are leaky and you use laser in the clinic to kind of scar it down. So you can imagine that you may stop the problem from leaking, but you also create scar in the retinal tissues that's really bad. So I would say that it's really incredible that now we have treatment that you do injection directly in the eye –
Danielle: Mm-hmm.
Dolly: – and can really help patients' vision. But still, there's still quite a lot of unmet need, especially for diabetic macular edema patients. They are working-age patients. They still have to work, and they still have a lot of doctors appointments that, without good vision, this has been very challenging for them. So I think that there is still a lot of work from our side trying to improve, if we can improve further upon, even though we have a very good treatment on that.
Danielle: I think on one hand, you can think about getting like a laser into the eye to scar things up kind of terrifying. But I'd still have to say that the shots in the eye make me a little queasy to think about. So is that like the only way to administer that treatment, or are there other like, new devices or other strategies to administer those types of therapies?
Chris: Yeah. Well, maybe a quick comment on the laser first.
Danielle: [Laughs]
Chris: So lasers have been around for, you know, several decades. And people really enjoy – as unpleasant as it sounds – people really enjoy treating patients with lasers because it's very easy. You sit them on the chair, and you target these lesions. And it was very hard to get physicians to move over to treat with these intravitreal injections in the early days but they knew the outcomes with this laser didn't improve vision – it simply stopped it getting worse. But as we saw the data coming in from these new anti-VEGF therapies, the outcomes actually, patients improved vision. So that really helped and inspired patients to kind of ask for these new treatments and physicians to want them. But then to your question about are there better ways of doing this –
Danielle: [Laughs]
Chris: – absolutely. I mean, in the early days, the clinical trials said you need these injections every month to get the best possible outcomes. Since those early trials, we've not actually had efficacy, as in treatment outcomes, which are better. So we've not improved efficacy or effectiveness in the real world. But what we have done is we've developed treatments which you can have less frequently. So better molecules which have different mechanisms of action target different molecules in addition to anti-VEGF. And therefore, you can go longer between injections, maybe three or four months. So that's one route. And then there's some device, drug-device combination approaches, which can potentially, you know, even prolong the treatment intervals up to six months. And then there's further down the line potentially gene therapy and cell therapies, which are even more exciting.
Wellington: Danielle, vascular endothelial growth factor.
Danielle: Whoo! That was so perfectly said.
Wellington: What's a growth factor?
Danielle: Scientists are really bad at naming things. They're as obvious as you could ever imagine. So a growth factor is a protein that signals the growth of something. So for vascular endothelial growth, when that pathway is activated, that protein sets off that internal signaling cascade, it causes blood vessels to grow.
Karen: So why is VEGF so important in the eye?
Danielle: Well, you need VEGF everywhere, right? Because if you don't have blood vessels formed, you don't feed that tissue and the tissue dies. The problem isn't that there's VEGF, the problem is that there's too much of it where there's not supposed to be any, and then you get these new blood vessels that form and they either like – you know, it's kind of like having roots grow too much under the foundation of a house, and it starts to jack up plumbing and stuff like that. It’s the same kind of thing. You start to develop all these bits and pieces that aren't supposed to be there, and instead of being helpful, it becomes destructive.
Danielle: So for the VEGF treatments, which came first? Was it VEGF treatment in retina, or in tumor?
Dolly: Actually, almost approved at very similar times –
Danielle: No way!
Dolly: – if I remember correctly, about 20 years ago?
Danielle: And so as those VEGF treatments were coming out, you know I guess, I don't want to say classes of them, but there was an evolution, right? So what were those incremental changes that really, you think, drove the improvement of those therapies for VEGF treatment in the back of the eye?
Dolly:Yeah, I think that that's a very interesting question because there are some unique features of the eye and for ophthalmology treatment. So, because this is a confined space, so what we are trying to achieve is different from oncology. So for example, we really want to make sure the drug stays in the eye, but when it leaves the eye, it's being metabolized really quickly or cleared very quickly. So I would say that for the anti-VEGF in the eye, this is number one. We are trying to make sure that it reduces systemic toxicity. But number two is we also think that tissue penetration is important because some of the blood vessels are relatively deeper. So that's how you can see that the evolution of anti-VEGF for the eye, they're trying to be smaller. They're trying to be clear – better clearance, and that's how it differentiates from some of the engineering – antibody engineering for systemic.
Danielle: Can I be momentarily obnoxious? So you'd mentioned that the tissue penetration is really important. I'm really curious like when people are thinking about these therapeutics [laughs], like is it known that the penetration of the therapies into, like, the retina is what's really critical. Because this is a hot debate actually behind a lot of closed doors is whether or not it matters. So what's your take on that?
Dolly: You know, that's a really interesting question. I think that for me, I think it still matters. But there's probably a threshold that it doesn't matter anymore. So we know if it's super big, that doesn't penetrate. That's not great. But to some extent, if you can penetrate the retina – I'm not quite sure if there's a huge difference between small versus smaller versus tiny.
Danielle: I think there is.
Dolly: [Laughs]
Danielle: You know why? You know why? Because like – okay, well, so first of all, just to be clear, like we gotta sop up that VEGF. And I think it's almost like the Goldilocks situation. Like you don't wanna have something so big that it can't get in. But if it's too small, then you're gonna be exiting the eye through additional path, like more than one pathway. It's not just gonna go from, you know, if you introduce something really small into the vitreous, it's not just gonna go from vitreous, retina, and then across the RPE barrier. It's also gonna go out through, like the ciliary bodies and these other structures that are there to like help clear things out. So it's almost like I think you gotta hit that right spot.
Dolly: That's absolutely true. So how we calculate the molecule inside the eye – one of the way is calculate based on size space.
Danielle: Mm-hmm.
Dolly: So there's always a balance. When you make the molecule too small and penetrate a tissue, it clears from the eye too quickly as well. So there's definitely a sweet spot that if you're much smaller than a certain size, then it clears too quickly. You probably have to inject the drug very frequently, and patient cannot take that. But meanwhile, there are also other ways to make the molecule bigger and stay in the eye. So you may want to conjugate with other polymers and such to make it stay in the eye for longer. So definitely, there's a tradeoff between the two in terms of size, in terms of staying in the eye.
Chris: We've got a great scientist, Bob Kelley. He's got a great curve which –
Danielle: Bob Plot? I know all about that Bob Plot.
Chris: The Bob Plot, we call it
Danielle: [Laughs]
Chris: And it describes very clearly, the smaller the molecule, the faster it disappears from the eye, and the larger the molecule, the slower.
Danielle: Yeah. Yeah, yeah, yeah, because it could act – because that's a really hot – okay, from a treatment thing, that's a really interesting philosophical question, because people don't know like that VEGF that everyone's trying to sop up and like stop from forming new blood vessels, it can start off being like generated in like the retinal layers, in those cell layers. But it doesn't mean that it necessarily stays there because it's a free protein, right? So –
Dolly: Right.
Danielle: – it could go into the vitreous, and you could have like a sink there to try to also function.
Chris: And I think that's also relevant for the different retinal diseases. So –
Danielle: Ah!
Chris: – wet AMD, for example, the whole retina is really disrupted. So it could be that these larger proteins can go in much more easily, whereas diabetic macular edema is more kind of higher up in the retina. So you may get less disruption. And then obviously, you know, geographic atrophy, it's really – which is an atrophic condition of the retina – killing the photoreceptors and the retinal pigment at the base of the retina, there's not any disruption of the inner layers. So you probably need molecules which find it easier to penetrate. So I agree.
Dolly: There's another point I want to make to Chris's point that, for example, diabetic macular edema. We know that there is a lot of VEGF actually in the jelly portion of the eye –
Danielle: Mm-hmm.
Dolly: – the vitreous. So one of the treatments that some places are still doing it, is removing the jelly. So you –
Danielle: No!
Dolly: – drastically reduce the burden of the VEGF. And actually, there are some treatment benefits as well. However, do you want to have surgery versus having injection? So that may be the tradeoff that you want to make.
Danielle: What about for other types of diseases? Like what is it about them that makes it so hard to treat? You mentioned a little bit about like, what part of the eye gets messed up and what might get there. But how do y'all think about this as like a broad perspective on where you'd like to see the field go to help those types of diseases?
Dolly: I think that the harder to treat diseases are the ones that are very similar to neurodegenerative disease, like Alzheimer's. So slowly progressive, getting more atrophic, but the patient doesn't really notice the vision loss until very later on. And when you notice that, it's already too late. So how do you alter a very chronic course? That's very challenging. So there are not that many examples, I think, that we are really fortunate that we have really good treatment for cataract. You remove it, and patient can see. You have the retina swollen up, you get some injections, patients gain a lot of vision. But some of the hardest to treat diseases are those kind of degenerative ones. That's where I think it's very difficult to develop a drug, and it's also very difficult to develop a clinical trial. It has to be very long and involving a lot of patients. And the detection of the devices has to be very sensitive to measure these slow changes.
Danielle: So what's the new stuff that's coming out?
Chris: Yeah. So there's an enormous amount of unmet need. So since the 2000s, we've been looking at different mechanisms of action really to address the other areas of retinal diseases that we think could get the patient and those inflicted with these diseases back up to good reading vision and to really again to have that step change in terms of their quality of life. And we've got exciting opportunities and programs out there looking at different mechanisms such as ischemia, reversing fibrosis, looking at vascular stability, looking at reducing vascular permeability.
Danielle: Oh, wow.
Chris: So, lots of different opportunities. And those are for these vascular disorders. And then outside of that, some of the exciting things the next five to ten years, around cell therapies and really starting to replace the cells, because antibodies can't replace dead cells. Only cells can replace dead cells. So there are exciting opportunities in terms of cell replacement.
Dolly: Yeah, so I think why I am so excited, obviously I'm an ophthalmologist, but I think two things. One thing is the eyeball is immunoprivileged. So some of the therapy then may not be able to treat systemically. You can treat it in the eye, so for example, the gene therapy that we talked about. The other very unique one is cell therapy, that you can imagine if you have an organ transplant, you need to be on immunosuppression lifetime. Otherwise, you get organ rejections. But if you put cells in the subretinal space, you only need a short course of systemic immunosuppression. And the immune cells doesn't attack those transplant cells anymore. So that makes the eye a very unique place to test different new platforms like gene therapy, cell therapy. And you can imagine that for, you know, atrophic or neurodegenerative disease, if we can replace those cells, that doesn't exist anymore as one of the ways of therapy.
Danielle: So it's kind of like, you know, everything about the eye that makes it at first glance really hard to treat also makes it really awesome because you can –
Dolly: Yes.
Danielle: – you can't get in, that's true, but maybe you can keep some stuff in that you actually need.
Karen: Hey, Danielle.
Danielle: Yes?
Karen: So Dolly was talking about the eye being immunoprivileged. That's – you know, I was doing more like neuroscience, stem cell research – I'm not super familiar with what that means and why that's important in the eye.
Danielle: So I actually haven't heard that phrase used in that way for this, but it's actually the perfect phrase, because what she's really kind of talking about is the fact that the eye is segregated from everything else. And so that means that because of the barriers that are in place in terms of like different cellular layers and structures, it actually prevents things from getting in and things from coming out. And so that can be for like proteins passing, but it can also be, you know, encompassing molecules that are used for signaling in inflammation response or certain types of cells that are involved for inflammation response.
Danielle: So what are some of the key takeaways from everything that we've been learning about the fundamental biology of the eye that's kind of driving these innovations?
Dolly: So for example, injection in the eye, anti-VEGF, we talk about gene therapy, we talk about cell therapy. I think that's number one. I think the other thing that, at least my learning, is the eye is still part of the body. So a lot of the biology is overlapped, right? Anti-VEGF was an oncology drug. So we're really trying to leverage the known biology and trying to leverage the unique property of the eye and combine that to become a therapy that is unique for the eye. So I think that's part of the learning that I had over the past couple of years.
Chris: I agree. So I often joke with some of my colleagues that, you know, the eye is the most important organ. That's not a joke – it is the most important organ.
Danielle: [Laughs]
Chris: But my colleagues really contribute to it because we have colleagues doing studies in respiratory. The eye needs a lot of oxygen – it's like the most metabolically active organ in the body. We need our GI colleagues to take away the waste. You know, we need our rheumatology colleagues to make our body move around so we can see where we're going. And the brain needs the eye, obviously, to make sure it doesn't bump into things.
Danielle: [Laughs]
Chris: I think the other thing that we've learned about the eye over the, you know, last couple of decades is the imaging and our ability to explore some of the fluids in the eye and understand the proteins which were in the eye and correlate those with diseases. There's a great paper, which I think it was Stanford, which looked at several thousand proteins in the eye and correlated those with different cell types. And then if you take that and correlate them with the body's general genetics, and then on top of that look at the images of the eye, then you can really start to deduce some very interesting opportunities in terms of identifying new targets for some of these diseases. So we're at that stage where it's kind of a real tipping point, I'll describe it.
Danielle: So like I think everyone and their mom is now talking about AI and ML to some extent. So, we're trying to get a feel from folks as they come in on the podcast, what's up with that in your area? How does AI and ML impact maybe either new treatment strategies or targets? Or even like mega correlations? [Laughs]
Dolly: Yeah, I think while ophthalmology has a lot to talk about for machine learning or AI, I think everybody probably remembered that there were a lot of press and papers talking about, just by analyzing the images of the retina, they can predict if you are male or female, or your cardiovascular risk, for example. So there are a lot of information that you can directly look at a retina, looking at a vasculature, and the machine potentially, the algorithm, can pick up the features that we as an ophthalmologist doesn't even pick up. I don't know what is so different between men’s eyes versus women's eyes, but clearly, the algorithm can differentiate them.
Danielle: That's so wild.
Chris: Yeah. It's amazing. In the last few years, there have been some machine learning algorithms which have enabled automatic diagnosis of images. So this is important for large-scale screening. So different countries around the world have some great screening, so particularly diabetic retinopathy screening. Some countries are not so good at it. So some of these AI algorithms have enabled us to allow patients or people with diabetes just to go into a clinic, have a quick photo, and then they're told, do you have diabetic retinopathy? Do you need to see a doctor, or do you not? And that's the really impressive potential to kind of streamline medical services for ophthalmology and get treatment faster for those patients.
Danielle: Before I let you go, I just wanted to dig a little bit deeper into these diseases for the back of the eye. So some of the listeners might not be aware of this, but when you really think about it, if you have cell death in the retina, these are cells that are connecting into the brain. And so these diseases are often classified as neurodegenerative disorders. So here's where I want to talk about neuroprotection. Can you speak a little bit to how the ophthalmology field is considering this neuroprotection or ways to prevent cell death in terms of treatment strategies in the clinic?
Chris: So, last couple of decades, neuroprotection is a very, very hot topic in ophthalmology because, specifically for a disease called glaucoma, which is classically only treated by lowering intraocular pressure, since we only have IOP lowering therapeutics, there still remains an enormous unmet need. Some patients still continue to have their glaucoma worsening. So we've been looking for neuroprotective agents to really offer a different treatment regimen and a different approach to protect patients from vision loss.
Dolly: In the clinic, we gave patients a lot of eye drops, and we still see patients losing vision over time, in some of the patients. We take them to do surgeries and such, and it's just really hard to see them still losing vision despite all the things that you do. So to Chris's point, that I think it's very important that if we have a neuroprotective agent, that to make the retinal ganglion cells, which is the nerve cells in the eye, a lot more resilient to those eye pressure, that would be potentially very transformative for the way we treat.
Danielle: Do you think we're actually gonna be able to overcome those hurdles for all of the diseases?
Dolly: I think we may not be. But one of the very important thing is going earlier on. So, we're really trying to identify patients who need treatment before vision loss and hopefully get those critical windows and develop the therapy that can help them preserve vision before they even develop vision loss. I think that's very important.
Chris: Fully agree. And I'd also add there are patients who have genetic diseases, and we only identify them late on in their disease, so when they've already lost vision. So one of the exciting programs which we're also working on, and as are many other groups around the world, is something called optogenetics, when we convert – in patients who've lost their photoreceptors, which are the seeing cells in the back of the eye, we use an optogenetics approach to convert some of the more superficial cells in the retina into light sensitive cells. And that has the potential to restore vision in those kind of much more severely disabled patients. So, returning them from not being able to perceive light at all to maybe being able to, in the first stages, navigate around their house and even be able to leave their house and go for a walk safely.
Danielle: That's amazing! Are you hinting at the “c” word?
Chris: That would be potentially curing blindness, that approach.
Danielle: You guys are so like conservative.
Chris: I'm excited about it. [Laughs]
Danielle: You're like potentially, maybe. [Laughs] I like it. You know, I mean, with all of the things that you're mentioning with like, you know, different strategies for early detection and treatment, where do you think we'll be in 25 years?
Dolly: I think that – I'm hoping we are reaching the stage that we can customize, personalize treatment, based on the information from the eye genetics or some of the biomarkers in the eye. Then everybody get different treatment, depending on why they lost vision and their phenotype.
Chris: Yeah. Fully agree. The ability to have a patient walk into a clinic, have a couple of tests, maybe a blood test, maybe take some fluid out of the eye, have an image of the back of the eye, and be told there and then that you have to have this injection and take this tablet, and very, very personalized care. Yeah. Fully agree.
Danielle: I really hate for this to end. I would keep y'all here longer if I could. But thank you so much for joining us today. I mean, this was a lot of fun.
Dolly: Thank you so much. This is fun!
Chris: Thanks, Danielle. Really good to meet properly!
Wellington: That was an awesome episode. I learned so much. How do you know so much about ophthalmology? And does this relate to some of the work you're doing?
Danielle: Actually, yes. You know, sometimes I only ever mention that I'm stalking cancer cells, but really my whole shtick is trying to figure out how to develop therapeutics to get them into the nooks and crannies that are very hard to get access to. So for me, that means solid tumors, which sometimes I mention, but I also specialize in drug delivery to the back of the eye and into the brain. And so anytime we talk about like these hard to cross barriers, that's where you get this really kind of interesting cross-functional learnings about how do you get stuff across places that there's not any access.
Karen: And what are some of these strategies to get across these barriers? Cause I've heard like the blood brain barrier, for instance, is like formidable.
Danielle: That's like a wild one. And I have kind of a weird view on that. But really, the thing is, like, you know, you can think about it from like, imagine there's a gate there. What are ways I can trick that gate into opening to let something through? Or how do I use the fact that the gate's there and like physically bypass the gate and use it as a retention strategy. So I guess it goes without saying. I'm super excited about where all this is heading.
Danielle: And that's our show. Thanks so much for listening. If you haven't already, rate our podcast, wherever you listen – it will help new people find us. And make sure to subscribe. If you have any questions about the show, you can contact us at [email protected]. And now for me, it's back to stalking cells!
The name Two Scientists Walk Into A Bar is under license and used with permission from the Fleet Science Center.