Exploring The Principles Of Genetic Research In Genetic Eye Disease - Part 2 | Episode 19
Episode 19
Exploring The Principles Of Genetic Research In Genetic Eye Disease - Part 2
Welcome to part 2 of the conversation with Dr. Kimberly Drenser! This episode navigates the landscape of research & development challenges and the amazing scientific breakthroughs that Dr. Drenser has been involved with. This episode starts with the story of how Dr. Drenser became interested in the field of ophthalmology and continues by highlighting the milestones in the industry and her career.
Your host, Dr. Patrick Droste dives into this captivating three-part series that covers innovative and promising research for the future. We invite you to share this episode with friends and family!
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0:00:10.5 Dr. Patrick Droste: Welcome to The Through Our Eyes podcast that takes you on a journey through the world of ground breaking research with our special guest, Dr. Kimberly Drenser. We are now going to go to part two, and we're going to talk particularly about Dr. Drenser's five skills in the relationship of research. And I'm going to ask her what was the first thing that got you interested in retinal research?
0:00:32.8 Dr. Kimberly Drenser: So, interestingly, it wasn't the typical pathway. I didn't have a family member who had a blinding disease or personal story. I actually became involved in ophthalmology and really retina due to my thesis as a graduate student. Because I was also in medical school, I wanted my research to have clinical implications. And my co-advisor was appointed in the department of ophthalmology, so he was familiar with certain eye diseases, and one of these was autosomal dominant retinitis pigmentosa. So I ended up my thesis and my project was creating a gene therapy to treat a very specific form of retinitis pigmentosa. During that time, I learned so much about retina in the eye and went to conferences and presented that. I knew that that was the area of clinical medicine that I wanted to be in. And importantly, I really wanted to continue to work on the translational research, the pilot studies that would allow us to identify the clinical problem and devise a way to approach answering the questions from a research standpoint.
0:01:50.1 DPD: One of the ways that you can collect DNA from patients with genetic diseases like Familial Exudative Vitreoretinopathy or other inherited retinal diseases that tend to bleed a lot like Coats disease or like Norrie's disease, is to take some of their tissue and store it in a bank, which you call a biobank. This was developed at the Eye Research Institute and PA Retinal Research Laboratory at Oakland University. Can you tell us a little bit about that?
0:02:23.5 DKD: So I started the biobank back in 2003 when I came to Michigan for my fellowship training. And I was really interested in being able to understand rare disease we had, and still have a really unique opportunity because I joined the practice of Tony Capone and Mike Tracy, which to this day still has the largest rare pediatric retinal disease practice in the world. And I realized that if we were able to get DNA samples from all of these patients, we could make meaningful progress in understanding FEVR. Essentially many of these diseases are very similar, so FEVR is kind of the retinal disease, but you can have FEVR plus other things making a syndrome. So, for instance, Norrie disease is a very, very severe form of FEVR and with the triad of deafness and cognitive delay, Osteoporosis-pseudoglioma is FEVR plus osteoporosis, and it's a syndrome. Or you can have some things where the only thing affected appears to be the eye, which then we just call it FEVR.
0:03:34.1 DKD: But we can't really understand that if we don't have enough patients, these are all rare diseases. So the first goal was to obtain DNA samples from every possible patient we could with these rare diseases and put them into a bank, put them into a biological warehouse where we could study them. And as you mentioned, we can do this. We basically just need to obtain enough cells that have chromosomes. So you can do this from sputum, you can do this by swabs, where you swab their cheeks and gums and enough cells come off, it's a little bit of abrasive, and you can do it the traditional way from a blood sample. And by doing that, the DNA is extracted from the cells and a DNA can live in extracted form like that for tens and tens of years. And that allowed us to be able to go back and then say, well, what do we want to analyze? Do we have specific genes? Do we have a gene panel? What are we trying to answer here? And from a very small amount of DNA you can query a number of different genetic changes by sequencing them, by basically reading out their alphabet and seeing comparing them, thanks to the Human Genome Project, comparing them to what we know is the "Normal Alphabet Reading" and what do we see in front of us. And so that's really how the biobank was started and has continued and is...
0:05:00.8 DPD: Well, how do genetic specimens get placed in this bank or DNA specimens better? And do you obtain them from blood? Do you obtain them from saliva? Do you obtain them from skin? And how long do they last in the biobank?
0:05:12.5 DKD: So we obtain them from all of those modes, and it really depends on really patient cooperation and age. If it's a baby, we can do a swab. The easiest thing to do is swab their gums in the office. They don't really love it, but you can do that. If it's an infant who's going to the operating room when they start the IV, we can get a sample of blood. If it's a child or a young adult who doesn't necessarily like blood draws, they can usually get enough spit and so they can spit in a cup. So those are all viable ways. And then what we do is we take that sample and we basically break the cells open. So you break the cells open and then you use different types of buffers to extract the DNA and it's in a stable solution, essentially. And then you just put it in the freezer until you're ready to do something with it. Now, we have some samples of rare diseases which we haven't studied yet because we're still working on those pilot projects. When it comes down to FEVR, Norrie disease, Osteoporosis-pseudoglioma, any of those types of vitreoretinopathies, we usually process those relatively quickly because we are actively working on those projects right now. And it's also of benefit to the families to be able to track if it's identifiable where that gene alteration is.
0:06:39.6 DPD: You mentioned that Norrie's disease was a severe form of familial exudative vitreoretinopathy. Can you tell us a little bit about the Pediatric Retina Research Foundation project in trying to obtain a medication that would combat or reverse this disease?
0:06:58.3 DKD: So the interesting thing about FEVR and Norrie disease is that it's called Norrie disease for the person who discovered it. And it's been identified that children with Norrie's disease have basically no function from one particular gene called the Norrin disease protein. And the NDP gene creates this very specific protein which turns on retinal development as a growing fetus. And without this protein, the eye is not able to develop normal retina. There is no... For lack of a better word. There's no backup protein. There's no backup quarterback that can come in and take over. So Norrie disease is the most severe of the spectrum of FEVR because it's always the Norrin protein that's affected, and it's affected so that it really is non functional. The spectrum of FEVR, it can be less severe mutations in the Norrin protein. So it works, it just doesn't work as well. Or it can be mutations in the receptor. So Norrin actually binds a receptor that sits on a cell and if that receptor can't bind it appropriately, you have the same problem of not being able to fully develop your retina.
0:08:18.2 DKD: So, that seemed to be a key in understanding that one protein in particular is responsible for the development of healthy, normal retina. And if we can identify that protein, which it happens to be Norrin, then we can probably overcome it by replacing it. And there's a potential for gene therapy there for families with known Norrie disease, it would have to be a very, very early intervention. For the less severe forms FEVR patients, we could potentially just reactivate that pathway and make meaningful improvements in the structure and function of their retina.
0:08:56.4 DPD: Now, my understanding is that many babies that are born with FEVR have normal looking and functioning retinas early in life, particularly neonatal. And it sometimes isn't too much later in life that they develop the proliferative disease that causes their blindness. Is that true?
0:09:16.5 DKD: So that is true that there's a very, very broad spectrum of how severe the eye disease is at the time of birth. I will say one of the problems we have is that we don't do retinal exams until we suspect a problem. So it's probably underdiagnosed in a lot of children. And it's not until the late stages that it presents itself because either the eye changes color or one of the most common ways it's picked up is because the eye has a lazy eye. One eye is drifting and not staying in alignment. But the same way that these different alterations in these genes, whether it's in the Norrin gene or whether it's in the receptor genes, can have a wide variety of defects. So, for instance, you could have a very severe mutation that essentially knocks out all of the function of Norrin and end up with Norrie disease. And that I would call a 100% loss of function. But you may have another child, not in the same family, but in a different family that also has a mutation in the Norrin gene, but it only knocks out 20% loss of function. So they will present very differently. The Norrie disease child will present very shortly after birth.
0:10:37.1 DPD: Very shortly. I mean, they have white reflexes, you can see they don't respond to light. And it's a very disappointing appearance when you look inside and see nothing but white areas where retina should be.
0:10:50.4 DKD: Exactly.
0:10:50.9 DPD: So that's probably one of the reasons why we as a professional or PDA Retinal Research Foundation, are interested in finding a cure for this disease. Can you tell us name of the medication that's being developed and how will it be administered, and what's the name of the company performing this research?
0:11:11.8 DKD: Once the data from the biobank and the sequencing showed that Norrin was such an important player in being able to modulate this pathway and development, we started working in the lab with being able to make essentially a synthetic Norrin-like growth factor. So we call this Noregen or CTR 107. And the company that we started for this is called Caeregen Therapeutics. And that's what the CTR stands for. And essentially, like I said, this is a synthetic Norrin-like growth factor that's been slightly modulated from the endogenous Norrin to be able to turn this pathway back on. So it's going to be initially administered as an injection, which sounds terrible, but we actually, every retina therapy has really emerged as a intravitreal injection since 2005. And it has the benefit of you can give a very small dose and it goes right where you need it in the eye and it's bizarrely tolerated. And we even use these injections in very small children and infants for some very severe diseases that we use other medication. Ultimately, there's a lot of interest in being able to also do this as a gene therapy so that in the most severe cases you would be able to potentially intervene even while the baby is still a fetus and developing and introduce that normal gene so that they could actually grow their normal retina.
0:12:51.0 DPD: Does the genetic research that we're talking about, you said by direct injection, I mean, is this direct injection of the gene per se, or is the gene carried by a vector? Or we call it carrier pigeon, like a virus, to the certain area and then released.
0:13:11.2 DKD: So two different ways of delivery. So for the gene therapy, it's in a viral backbone, so it's still injected with viral vectors. You oftentimes, though, need to do a more invasive surgery because you generally will have to put that vector right up against the retina and sometimes right under the retina. And then that virus is really a shell that's carrying the gene of interest. So in this case, it would be the Noregen product and that virus does what viruses do. It infects the host cell, in this case being the patient's retina. And once it gets inside the cell, then it turns on the viral replication system. But instead of making virus, it's actually making the gene that you've implanted into the backbone of the virus. So it would be creating its own Noregen supply and expressing that in the cells. When it's given as an intravitreal injection it's already a formed protein. So you would be injecting a direct therapy that this protein would be dispersed throughout the vitreous and find the receptors on the surface of the retinal cells and turn on that dormant pathway.
0:14:37.1 DPD: Now, how do you determine as a clinician which method you're going to use for a certain patient?
0:14:44.1 DKD: So, for gene therapy, it's going to be a very, very small section of patients. It obviously will need to have be proven that it's a patient that has a mutation in the Norrin gene, because you're only going to be replacing that gene. So that would be the one that you would use gene therapy for. You would use the intravitreal injection of protein. You could use it... You'd have your choice, really, for what's called X linked FEVR. So the less severe cases that don't meet Norrie criteria, you could really use either. And then for the receptor mutations, you would use the injectable protein. And the reason is because these receptors, again, they're not 100% dysfunctional, those are very, very, very rare mutations. They're usually somewhere between 20% to 60% dysfunctional. And what we found is that if you overload it with enough of the therapeutic medicine Noregen, you actually activate it. You kind of force it to function at 100% or close to 100% because you're just kind of bombarding it with so much signal. And so that's how that determination would be made as to what the appropriate therapy is. And it may be that in some instances, both are appropriate.
0:16:07.4 DPD: Well, thank you very much. We've covered a lot in the last 40 minutes and I think now would be a good time to see if we have any questions from our panel.
0:16:17.8 Nicole Guidici: I have a couple for you.
0:16:18.8 DKD: Okay.
0:16:19.4 NG: Dr. Drenser, it's Nicole. I have a question from Shelby and then I have a couple questions I came up with listening to your presentation. So, Shelby wants to know, there's obviously alot of different research areas that are proving to be very promising for scientists. What sort of area of research is proving to be the most exciting and the most beneficial as far as breakthroughs in how to combat FEVR and Norrie disease?
0:16:47.1 DKD: That's a great question. So, technology has come such a long way in such a short period of time. And I think that the Human Genome Project and how that really changed our understanding of genetics and how it plays into disease is a great example. And what we've really seen is that you're getting more and more kind of individualized therapies that are becoming real and they're becoming options. So something that's tailored to the patient specifically. We see this a lot with cancer treatments now where they'll look at genes and common genes that are found to have alterations in that particular cancer and they'll make what they call an immune modulated targeted cancer therapy that's very specific for the individual. So we're starting to go into that field in the eye where as technology increases and our technical capabilities increase, the cost goes down to being able to make these kind of uniquely individually tailored therapies. I think that's going to be the biggest change we see moving forward is that it's not going to be a one size fits all. We're going to see a lot more where each patient has a genetic snapshot and based on what that shows, there's a more tailored approach to the therapies that they're offered or that are being developed.
0:18:21.2 NG: It was fascinating to hear you talk about the gene therapy versus the direct injection into eye. Given that, and that FEVR and Norrie disease are already rare diseases, how hard is it for you to recruit patients for trials, given that there's probably a very specific patient profile for each one of those?
0:18:42.5 DKD: So it's very, very difficult to recruit effectively for rare diseases because they're rare. So generally what will happen is that, one, there will be a kind of involvement of multi centers. For instance, centers that have a pediatric retinal doctor. So, to make them aware, bring them into the program, be actively looking for these patients so that you can kind of streamline them towards recruitment. The other thing that helps is that by nature of being rare, the FDA actually really recognizes that. So the burden is much lower on a recruitment level than it is for, say, diabetic retinopathy. So whereas for a diabetic retinopathy study, the FDA may say you need to recruit 1200 patients before you can submit for commercialization. For a rare disease, the FDA may only require 50 patients. And what they require is not necessarily that you can show, "Yes, look, I completely rescued this patient's retina." They want to see that it's safe. Because they recognize that it's, in a rare disease with an unmet need, there's no current therapy that's really effective, that the best way to get this into the hand to the people who need it is to just make sure it's safe.
0:20:14.7 DKD: And if it shows efficacy, any efficacy at all, that's a huge bonus in the FDA's mind. They want people with rare diseases to have access to potential therapies. So they really do work very hard with the investigators and the companies and the researchers to try to make sure that that gets moved along as quickly as possible.
0:20:38.7 NG: When is it too late in the disease process for eligibility for either one of these therapies? I know you talked about fetal identification, but how long or how old in life is it okay to try these?
0:20:55.0 DKD: So, it's going to be an evolution because in the way... It has to do with the way that clinical trials are designed. So you want to take the patient that you think has the best chance early in clinical trials. So it'll be probably a very narrow specification in the early stages of clinical trials, and then it tends to get opened up once safety has been shown. So, there's no absolute cut off or cut in as to who would be eligible or not eligible. It's kind of an evolving gradation, because you're going to work to try to save as many eyes as you possibly can, and you might not know in the early trials whose eyes those are. So it will start as a fairly narrow window, which will broaden as you go further down the pathway. There will always be some eyes that are just too injured and damaged to be able to reverse, but what we don't know is will you be able to use it as an adjunctive therapy, meaning maybe this eye is so detached you need to do a surgery, but maybe the Noregen medication will actually help the surgery heal better because you're helping to regrow vascular networks and rebuild the retina. And that's going to be a much further downstream. You usually don't start your trials with kind of a very complicated surgical adjunct and then trying to see how the eye is behaving.
0:22:38.4 NG: I may have missed this, but did you mention how close to prime time you think this is?
0:22:45.3 DKD: So we are looking at a timeline, our goal is to be starting clinical trials by mid 2024.
0:22:52.3 NG: That's awesome. Do you think further down the road the research that you're doing now in a rare disease will translate into a more common retinal disease, for instance diabetic retinopathy?
0:23:04.9 DKD: So there's very good evidence to suggest that it could be a very effective therapy for, unlike inherited diseases, we call these the acquired ischemic retinopathies. And there's a very, very, very good evidence that we could actually use this to treat those eyes as well.
0:23:22.2 NG: This has been fascinating. Thank you so much.
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Show Notes
Dr. Drenser and her partners started Caeregen Therapeutics to make a synthetic Norrin-like growth factor called this Noregen or CTR 107. Find out more about Caeregen here.