Chris Casey (00:00):
Hello and welcome to another episode of Health Science Radio. My name is Chris Casey and I'm the director of digital storytelling here on campus. It's a pleasure as always to be joined by my co-host, Dr. Thomas Flaig, vice chancellor for research at CU Anschutz. And I don't know about you, Dr. Flaig, but I'm very excited about digging into this topic we have today, retinal transplants.
Thomas Flaig (00:26):
It's a fascinating topic and I think the human impact of this disease, potential treatments are just huge. So I'm really looking forward to learning more about the great work that's being done.
Chris Casey (00:38):
Myself as well. And this is a disease that hits close to home for me. My 97-year-old father, who lives in Indianapolis, has had macular degeneration for five years, and so it's pretty advanced for him, and I know it's the situation for countless others. So it'll be very fascinating to learn more. And so today our guest is Dr. Val Canto-Soler, an associate professor of ophthalmology at the University of Colorado School of Medicine. She's the Doni Solich Family Chair in Ocular Stem Cell Research and director of CellSight at the School of Medicine. Val completed her PhD in Biomedical Sciences at Austral University in Buenos Aires, and a post-doctoral fellowship at the Wilmer Eye Institute at Johns Hopkins University.
Her research focuses on the mechanisms that control retinal progenitor cell differentiation and the use of human induced pluripotent stem cell technology to model normal and disease conditions of the retina. Her lab established a strategy to direct hiPSC to differentiate into three-dimensional light-sensitive retinal tissue in vitro. Dr. Canto-Soler's team is using retinal organoids to study the mechanisms of underlying retinal degenerative diseases such as age-related macular degeneration, and to develop therapeutic treatments for these conditions.
It's an honor to have you with us, Val, and welcome to our program.
Valeria Canto-Soler (02:24):
Thank you very much. It's an honor and a pleasure for me to be here. So thank you for the invitation.
Chris Casey (02:30):
Well, thank you for joining us. So can we just start off, Val, about just the magnitude of the problem of macular degeneration. Could you just talk about the scope of the problem, how many people suffer from it in the United States and maybe globally?
Valeria Canto-Soler (02:48):
Sure. I would start by saying that it's a really important problem, currently, an important problem that is going to be even bigger in the near future. So age-related macular degeneration is also referred as just AMD for short, and it is currently the leading cause of irreversible blindness in developed countries. So the estimates say that there are about 20 million people in the United States today that are affected by AMD and worldwide that number is close to 200 million people. What I think is even more concerning is the fact that the number of people affected by AMD is rapidly increasing and is actually expected to reach close to 300 million people worldwide within the next 10 to 15 years.
Thomas Flaig (03:48):
Maybe I could ask you a question, too. Our listeners are going to have a variety of different levels of medical knowledge and so forth, but maybe just start very basic. So, what is the retina and where is it in the body and what does it do?
Valeria Canto-Soler (04:02):
Wonderful, thank you for asking that. So the retina, it's a light-sensitive tissue and it covers the back of the eye and the main portion of the retina is what we call the neural retina, and it contains different type of neuronal cells, and they are just beautifully organized in specific layers within the retina. And so one of the layers in the retina is the photoreceptor layer that contains the photoreceptor cells – the rods and the cones. Humans have three type of cones – red, blue and green cones – and the photoreceptors are the light-sensitive cells within the retina, the cells that respond to light.
So basically when light enters the eye and hits the back of the eye where the retina is, photoreceptors capture that light and they transform light into an electrical signal. And then they transmit that electrical signal to the next layer in the retina, which is the inner nuclear layer where there are other neuronal cell types, including the bipolar cells, which capture the signal coming from photoreceptors and transmit it to the next layer where the ganglion cells are. And these ganglion cells project very long axons through the optic nerve towards the brain – transmit the signal to the brain – and there is where you have the formation of the visual image. And so open and close your eyes, light is getting in and you have a visual image, or you don't.
Thomas Flaig (05:44):
I remember back in medical school we studied the eye and just being fascinated by the physiology. I mean the process you just described, it's a straightforward medical thing, but it just happens so seamlessly. We don't even think about it. It all works, until it doesn't work. So what happens when someone develops macular degeneration?
Valeria Canto-Soler (06:03):
Right. Okay. So there are actually two different kinds of macular degeneration, what we call types of macular degeneration. Wet and dry. And so in the case of wet AMD, what happens is that there is abnormal growth of blood vessels that affect the central part of the retina, the macula, and that causes loss of vision. In the case of dry AMD, the process is different. What happens in patients with dry AMD is, I forgot to mention, in addition to a neural retina with the different neurons, there is another layer of cells that is also part of the retina, which is the retinal-pigmented epithelium (RPE). It's a single cell layer of pigmented cells that covers the surface of the retina. And these cells are really critical for the health and the function of the neurons in the retina and specifically the health and the function of photoreceptors.
So in a patient with dry macular degeneration, what happens is that the RPE cells within the pigmented epithelium become dysfunctional and they begin to die. And as you lose RPE cells, the photoreceptors don't have what they need to be kept healthy and alive, and so they begin to degenerate as a consequence of the degeneration of the RPE cells. The disease progresses gradually until it reaches what we call the late stage of the disease that is generally known as geographic atrophy. And so when a patient reaches the late stage of dry AMD, RPE cells and photoreceptor cells within the retina have been lost, and that leads to blindness in the macula, the central area of the retina.
Thomas Flaig (08:04):
Just one point to that, thanks for the explanation of the anatomy, but because of the location of those first or the initial loss, it tends to be a blindness, it's right in the center of the vision. Is that right?
Valeria Canto-Soler (08:15):
Right, right. It starts very much in the center, in the area of the macula, and as it progresses, it extends towards the periphery, but it never really reaches the full extent of the retina. And so yeah, you get peripheral vision, but you lose central vision.
Chris Casey (08:34):
And in 2014, Val, you were part of a team at Johns Hopkins and were on a team that was among the first to produce mini retinas. Could you talk about what happened there and then how that helped drive some of your research to the direction it's gone today?
Valeria Canto-Soler (08:56):
Sure. It's one of my favorite stories to tell.
Chris Casey (08:59):
Great, great.
Valeria Canto-Soler (09:03):
So, actually the story I would say started back in 2007, 2008. 2007 was the time when Dr. (Shinya) Yamanaka developed this new technology of generating human-induced pluripotent stem cells, which are pluripotent cells – cells that are completely undifferentiated and have the capacity to become any cell type that is normally found in the body, which is really exciting about these cells. These pluripotent cells are actually reprogrammed from cells from a patient. Let's say we can get cells from your skin, we can get cells from your blood, take them to the lab. We can manipulate gene expression in those cells and reprogram them to become pluripotent, to become like the cells when you were an embryo, basically. From that point on, you can instruct those cells to go on differentiating, and in theory, they could generate any kind of cells that we find in an adult body, right?
So that happened. Back in 2008, I was just starting my lab and I basically started to dream. I started to dream about the possibility of inducing these human pluripotent stem cells into generating retinal tissue in a Petri dish. When I started to dream about that, I didn't think that it was going to be possible to recreate the organization and the cellular composition of the retina, but I was hoping to get to some level of mimicking the retina. And it was one of the most amazing times in my career when we realized that the cells were actually recreating the organization of the human retina very, very closely. They were generating all the different retinal cell types. The cells were spontaneously migrating and forming the retinal layers. And so the next thing was to dream about the possibility of photoreceptors being functional in those mini retinas growing in a Petri dish.
And, of course, I thought, again, that's probably not possible. And that was another amazing moment when we realized that the photoreceptors growing in these mini retinas in the lab were actually functional and if you give them light, they can respond to light just the way our photoreceptors are responding to light right now. And that was actually a decisive moment in my career. That was the moment when I decided that I wanted to devote the rest of my professional career to find ways of translating that technology, that mini retina that we could grow in the lab, into potential treatments to restore vision in patients that are going blind because they are losing their photoreceptors.
Thomas Flaig (12:03):
So these pluripotent cells have the potential to do some regenerative work within the retina to regenerate some of those photosensitive cells that are lost, right? That's the approach.
Valeria Canto-Soler (12:13):
Exactly. So the approach that, the next dream that we have is to use these mini retinas that have functional photoreceptors. We can also generate the retinal pigmented epithelial cells. And so we grow them in parallel and then we bring them together and we build a transplant that has the RPE cells and the functional photoreceptors already organized as they are normally organized in the retina. And so our hope and our dream is to be able to transplant those implants into patients that have macular degeneration, regenerate the cells that they have lost because of the disease, and hopefully restore vision in these patients.
Thomas Flaig (12:58):
And without getting into any of the current treatments, just suffice to say that none of the current treatments are regenerative. They're not therapies that can regenerate the cells that have been lost. I think just the very appealing part of this is the idea that you'd be potentially regenerating cells, restoring vision for patients.
Valeria Canto-Soler (13:14):
So you are actually touching on a very important point because of what is really, really concerning. I mentioned how the number of people, the people affected by AMD, is increasing very rapidly, and we do not have any treatment to help these patients. There is no treatment available to either prevent or to cure macular degeneration. So there is no, I mean, these patients are irreversibly going blind and we can do nothing to help them. And the only way that we may be able, if things work the way we hope, we may be able to restore vision in these patients by regenerating those cells, putting new healthy cells that can function normally and restore visual perception in these patients.
Chris Casey (14:27):
And could you talk a little bit about what advantages being situated on the CU Anschutz campus poses for your research then, Val? The Gates Institute is here and that is what they do, regenerative medicine and treatment. So could you talk a bit about how you're collaborating with other scientists and entities on campus?
Valeria Canto-Soler (14:55):
Sure. I would go a little back in time and I would say that when I started dreaming about building a program like CellSight to develop stem cell-based treatments to cure blindness was several years before I came to CU. But I was getting convinced that my dream was too big of a dream and it was not feasible until I came here to visit CU and interview for a position in the Department of Ophthalmology. And I can tell you that those two days that I spent on campus really convinced me that this was the right place with the right people, with the right infrastructure to make my dream come true. And I think that a lot of that has to do with the commitment of the leadership in the Department of Ophthalmology for sure, but the commitment of the leadership on campus, the vision. I just found people here that share my vision and that were committed as I was to try to make it happen.
You don't find that everywhere. And so I want to just mention that because it was decisive for me to come here. And then, of course, the creation of the Gates Institute – it's for me, it's one of those moments where all the stars align because we were ready to transition from proof-of-concept studies to preclinical studies, which are the requirement for you to be able to reach clinical trial and test treatments in patients. And it would have been really, really hard for us to transition that path towards clinical trial without the infrastructure and the expertise that the Gates Institute brings to campus. So they are providing the infrastructure and the expertise that we need to succeed hopefully in that path to bring a treatment to clinical trials. Perhaps we can do it alone, but it would take another three to five years to get there.
Thomas Flaig (17:14):
This work you're doing, research and regenerative work around macular degeneration. Is that being done in many places? Is this approach being looked at many ways or is this pretty unique what you're doing here?
Valeria Canto-Soler (17:26):
So there are many groups around the world that are focused on finding treatments and cures for AMD. People have been trying to do this for many years, and that's what is really perplexing, the fact that even through years and lots of effort, we still don't have a treatment. So yes, there are many groups. I would say, in terms of developing stem cell-based therapies for this disease, there may be somewhere between five to 10 groups in the world. There are two main approaches that are being pursued. One approach is already in clinical trials. There are two trials in the US, one in London, one in Israel, and a few more in Japan and other places. That is a simple approach that is basically based on, remember I mentioned how patients lose the retinal pigment epithelial cells first before losing the photoreceptors? So that simple strategy aims at replacing only the pigmented cells before the photoreceptor cells have been lost. So it's not regenerating cells and restoring the vision that has been lost. It is rescuing those photoreceptors and maintaining vision.
The approach that we are pursuing, we are pursuing that approach, but our ultimate goal is to develop a more complex transplant that, as I mentioned before, that has the pigmented cells and the photoreceptor cells so that we can restore vision in people that are already blind. That approach is fairly unique. I'm not going to say we are the only ones, but I would say that in a way we have been the pioneers and that, in a way, we are pioneering that field, which makes it more challenging, too, because we are breaking ground in everything we do. We are doing everything for the first time.
Thomas Flaig (19:36):
It's important to acknowledge that, I think. That's great work you're doing.
Chris Casey (19:40):
I was just about to ask you, what are the biggest challenges that you are still facing in terms of making a retinal transplant a reality?
Valeria Canto-Soler (19:52):
We have already faced a lot of challenges. So far, we have been able to overcome most of them. It is really exciting that we are getting into preclinical studies, but this is the time when we are going to evaluate the safety of the transplant. Of course, we do that in animal models, but that will be an important challenge to really demonstrate that it's safe to go into patients. And then I would say that the biggest challenge we will probably face is for the cells that we are transplanting to connect to the other neurons that are in the retina of the patient. I told you how photoreceptors transform light into electrical signal and they have to transmit it to bipolar cells and ganglion cells. So the cells that we are transplanting need to establish those communications with the cells in the retina of the patient. And well, we are just hoping and praying that they will know how to do it.
Of course, we are evaluating possibilities on how to help those cells to integrate into the retina and to reestablish those connections. But that's, I think, the biggest barrier that we have. But I have to tell you, I have become a believer, having experienced the challenges of, or having seen how cells in a Petri dish can build a retina and they can be functional and respond to light, things that I didn't think were possible. I have become a believer. So I think that cells have the capacity to do a lot more than what we think is possible.
Thomas Flaig (21:35):
So you're able to make these cells that are responsive. The question is once they're treating patients at that level, can they integrate with the existing neurologic infrastructure in a way that they can send the signal to the brain?
Valeria Canto-Soler (21:48):
Exactly. That's the most challenging barrier, I think. But I do hope that they will know how to do it because so far they seem to know what they need to do.
Chris Casey (21:58):
You talk about the photoreceptor cells, the RPE cells. Are either of those cells more challenging to try to get to integrate into the neurological network?
Valeria Canto-Soler (22:07):
The most challenging cells are the photoreceptors. The RPE cells are just very simple epithelial cells that don't have to, this is going to sound technical, but it's the only way to explain it. They don't need to form synaptic ...
Chris Casey (22:29):
Connections.
Valeria Canto-Soler (22:29):
... connections, thank you so much. Synaptic connections with other cells, but photoreceptors do and they need to find the right bipolar cells to connect with. And that's a lot more complicated. But, I think that, I mean, during development, those cells establish those connections. So there are signals in the microenvironment of the retina that help photoreceptors find the right cells to connect and establish those connections and be able to communicate with each other. I think that when we put these photoreceptors in the retina, some of those signals will be there, that bipolar cells will be looking for the photoreceptors that they have lost, and photoreceptors will be looking for the bipolar cells that they are friends with. And so I think that the biological mechanisms will be recapitulated at the time. But again, we really have to see, and the only way to know if that is going to happen is by doing the preclinical studies and eventually the clinical trial in patients.
Chris Casey (23:40):
Was there a particular reason you decided to go down the road of studying the retina and retinal transplants? Because you put so much of your focus in your career on that structure. I'm just curious what drew you to that?
Valeria Canto-Soler (23:56):
I would say that when I was a teenager, I had a very close friend who was blind, and I always thought about how wonderful it would be if we could help people recover vision. And I had an opportunity to do my PhD studies in diseases related to the retina. And I think at that point is when I became more aware about the burden of blindness in the world and how little we can do for those patients. And it was at that time when I was doing my PhD that I thought I really would like to devote my career to things that can be translated to clinic, that can eventually reach the patients and improve their quality of life and eventually, hopefully, restore vision.
But I wasn't thinking about working with stem cells or really developing a transplant. Life is fantastic. I mean, it takes you on paths that you don't envision. But, I don't know. It has been an amazing journey. So I think that there have been times when I have made decisions and then it has been life, providence, that leads you through that path. I'm not sure I am answering your question properly.
Chris Casey (25:27):
You answered it great. That was a great story. Thank you.
Thomas Flaig (25:31):
I mean, the impact that such a therapy could have just on human existence. The loss of vision is such a dramatic event for people. Again, I've seen it in my own life as well, and people that are close to me. To be able to impact that, as you point out when we started by talking about numbers, is a very noble endeavor indeed.
Valeria Canto-Soler (25:51):
I would say that at this point, I see this as my calling and my mission.
Thomas Flaig (26:02):
It's a worthy mission, to be sure.
Chris Casey (26:06):
Absolutely. And so, I'm just curious, Val, say the research advances, the transplant is possible. Do you have any idea on, say, what it ends up looking like for, say, a transplanted, somebody who gets the retinal transplant. How does their world change? What kind of vision are they going to have, perhaps?
Valeria Canto-Soler (26:33):
So, the straight answer is that we don't know exactly what the endpoint will be. The ideal will be that we are able to regenerate all the cells that were lost, that they establish all those connections and they restore vision to almost hundred percent normal vision. I don't think that we will get there on our first trial. I think it may take some iterative work and improving the transplants and understanding how things work in the patient. My hope is that even if we cannot restore vision to normal conditions, that we may be able to restore some meaningful level of vision to help patients at least navigate and recover some visual capacity that they have lost. But I'm hoping that it won't just be lights and shadows, that they will be able to see more. But again, we will not really know until the transplants are in the patients and we see how they respond.
Chris Casey (27:50):
Well, I think it's terrific. As he said, Dr. Flaig, very noble work and kudos to you for continuing to dream big. That seems to be a running theme here with the tale of your research and every progression you've reached, it's like you just continued to dream about it and then keep pushing forward.
Thomas Flaig (28:14):
That's true, Mr. Casey, and I would say that you've used the word journey several times. You've been in this journey for a long time, years and years and years. We're still joining and discussing things today as you're getting ready for pre-clinical studies, the next step. So, we talked about what's your scientific obstacle now. I bet you the last years, decade or whatever, you've had multiple scientific obstacles, which you've had to go through, and I think I will certainly watch with great interest as you address these next couple and when you're at this point in the development and the translation of this dream.
Chris Casey (28:48):
I would love to be able to follow up with you to see how it progresses, say in the next three years or so, or perhaps sooner.
Thomas Flaig (28:55):
Perhaps sooner.
Chris Casey (28:58):
I mean, if my dad makes it to 100, he would love to have a treatment available, and I know that's a goal of his at this point, just to make it to a hundred. But other people with this horrible illness, disease, are I'm sure welcoming a bit of hope on the horizon, which is what you're providing. So thank you for that.
Valeria Canto-Soler (29:22):
Well, thank you so much for your enthusiasm, and I will be happy to come back in the next three years or so if we are making important progress.
Thomas Flaig (29:33):
Look forward to it.
Chris Casey (29:33):
Terrific. We look forward to that. And thank you again, Val, for joining us today.
Valeria Canto-Soler (29:35):
Thank you so much for inviting me.
