Inherited retinal diseases (IRDs) vary widely, but most of them lead to progressive and/or profound visual symptoms. Timely diagnosis, counseling, and resource discussions are imperative to improve quality of life. Depending on the condition, treatment may be available, often through clinical trials, with the goal to slow the disease for vision preservation. Watch to learn about Mayo Clinic’s comprehensive, multidisciplinary approach to diagnosing and treating IRDs.
Speakers:
Raymond Iezzi, Jr., M.D., Ophthalmologist, Mayo ClinicLisa A. Schimmenti, M.D., Medical Geneticist and Pediatrician, Mayo ClinicBrittni A. Scruggs, M.D., Ph.D., Ophthalmologist, Mayo Clinic
Good evening. Welcome. Uh Everyone. Thanks for joining us today uh for the ophthalmic Genetics from genetic testing to clinical trials webinar. My name is Colin Darr. I'm a certified genetic counselor who works with patients Mayo Clinic's inherited retinal disease here in Rochester. Um And I will be your moderator for today's discussion. So glad to have you with us today. I'm pleased to introduce our speakers for today's web webinar. We have Doctor Lisa Cement a board certified medical geneticist here at the Mayo Clinic in Rochester. Uh Doctor Raymond Ai and Doctor Britney Scruggs. Both are B board certified ophthalmologist at Mayo Clinic here in Rochester. And all three are physicians who treat patients with inherited retinal disease and are involved in the clinic, uh clinical research. And again, this is me Colin D and I'm a genetic counselor. I work hand in hand with Doctor Skii. Doctor is and Doctor Scruggs. So, the learning objective for this is to review the most important history, examination findings and testing for patients with suspected inherited retinal disease to highlight genetic testing options and counseling curls for patients with presumed Ir Ds inherited retinal diseases. Summarize the current clinical trials for inherited retinal diseases in the United States in 2023 and to discuss some barriers to clinical use for regenerative medicine and ophthalmology. So, as a beginning, Doctor Isaac, could you just give us an overview of how the clinic works here and how things flow? Absolutely. Thank you. Uh So we have developed a multidisciplinary clinic where Doctor Scruggs myself, doctor cement our genetics counselors and our low vision specialists all co uh exist within the same clinic. Uh This gives us a coordinate uh uh response to our patient's needs. Um And so what that allows is for a patient to come to NAO uh and be seen um by us, get a history, physical examination testing, uh see a genetics counselor or medical geneticist like doctor Sven. Uh and then perhaps even get some low vision services uh and even uh be seen by our state services for the blind. Um And in this coordinate clinic, um we uh we can get things done. Yeah, I can add a little bit. So I'm Brittany Scruggs. Um We in addition to seeing the patient and getting them involved with the low vision team, they can also work with occupational therapy, social work um a dietician, especially if diet is important to potentially decreasing the rate of their progression. And so we have um many teams that we try to coordinate in any one visit for the patient in terms of vision rehabilitation. We think this is extremely important for our patients who have inherited retinal disease and we make sure that they have the best for fraction. And so a low vision specialist will see them. And in this photo, there's a tinted contact lens. Um this is one of our patients with achromatopsia. So we have a wonderful contact lens service um that can provide these services um provide tinted glasses. Um They can, the patients can trial magnifiers readers, CCTV S telescopes um different ways to improve and optimize their vision in the real world. Um Services for the blind, as doctor A ASI mentioned, is actually on site partnering with our low vision services and allowing them to get resources um in their homes. And for long term care that they essentially get the patients set up with support groups, they do driving assessments if it's appropriate, make sure that they have mobility training, guide dogs, et cetera. So we really want to make sure we take care of the patient even when they're leaving our clinic. So what these states are commonly diagnosed and managed by an inherited rectal disease specialists. Doctor Aya Aya, would you like to take that? Absolutely. So um the clinic was started um as a as a a specialty clinic uh about 15 years ago. And over the course of those 15 years, we've developed a large cohort of uh several complex inherited retinal degeneration conditions, including uh retinitis, pigmentosa of all forms. Stargardt. Excellent predis stickler cone rod dystrophies, uh Correia, a chromatopsia, various pattern dystrophies and pr ph two related diseases. Um occult dystrophies and gyrate atrophy labors, albinism, congenital, stationary night blindness. Uh And what we found was in creating a specialized inherited retinal degeneration clinic. We were afforded the appropriate time that we need to properly take a history properly, do a physical and really engage with our patients um in understanding, you know, how they work, how they're functioning on a day to day basis. Um Many times a patient might come in with one diagnosis or presumptive diagnosis. And ultimately, we inform them that perhaps we have to go down a different path in, in terms of um pursuing uh a more definitive diagnosis. And and at mayo, almost all paths lead lead to our genetics um uh services um in, in seeking a molecular diagnosis. And doctor si was the first to be added to the, to the team. Um and, and has been a fantastic uh uh addition, clearly in 2023 um it is very necessary to seek a molecular diagnosis and for, and the reason for that is that we're now starting to um to have treatments and we'll get into that Doctor Scruggs and I will discuss some of these treatments later. But, but having an appropriate molecular diagnosis, meaning a genetic diagnosis will allow us to to more accurately pursue what the clinical situation is where a patient is in their, in their condition, how we can best enhance their function and perhaps rehabilitate them and what interventions there may be for restoring sight. Um I think it's very exciting that several of the newest therapies for many of these conditions overlap multiple conditions. So um in the most advanced forms of vision loss, regardless of the cause, assuming that it's not associated with an optic nerve disease, we can do things like optogenetics where we can restore light sensitivity to cells that would otherwise not perceive light. Um We could potentially place a device like a retinal prosthesis. Um And so, having an accurate understanding of what exactly this is um helps us in, in a multitude of ways. And I think doctors, Cini and doctor Scruggs can comment further on what implications this has for, you know, family planning and, and and examining Children and, and uh connecting with other relatives to understand inheritance. So this is a very diverse clinic. There's over 100 and 50 different forms of retinitis pigmentosa alone. Uh and as well as several forms of Stargard and um some of these conditions like stickler uh is, is something that may require surgery and regular monitoring to prevent vision loss from something that could be mechanically repaired uh via surgery. So, so it's very important I think to, to have an appropriate um clinic where we can devote our time, give a patient the time that they need. Um because these conversations go far beyond the testing results. They're more about how a patient is functioning and how they're doing and what can we do for them with this being such a complex area to be focusing on with uh inherit to retinal disease? And as you said, there's multiple different conditions. What does a retinal disease specialist look for in an exam? And what testing can this patient expect you to receive with this doctor? Do you have any insight on that? Yes. Um Thanks for the question. So we can start by just highlighting retinitis pigmentosa, which is the most common uh diagnosis that we make in this clinic. Um And it is actually the most common inherited form of blindness um anywhere between one and 3000, 1 4000 in the United States. And because this can be inherited in many different ways from autosomal dominant recessive, excellent et cetera, even mitochondrial, really important to partner with our genetic counselors and team to have a very accurate um pedigree. Um We also want to make sure that we're doing an amazing job of getting a good history and understanding. Is this a patient who potentially has a non syndromic form of RP or is there a syndromic form? And potentially we need to start um making referrals to other teams and making sure that they're being cared for on a systemic level. And so, um in order to kind of go through this, I thought we would start with the basics and versus history taking. Um And I can't say this enough of how important it is to, you know, sit down with these patients and have the protection, um the protected time to have a meaningful conversation about what they're dealing with. Um And first is, when did this start, what was your earliest symptom? Are you having central vision loss or peripheral vision loss? Really getting to the, you know, to the underlying pathophysiology? Is this potentially uh Cohn disease or rod disease? Um Is this progressive or is this a stationary disease? Um And then we wanna always check refractive error and been doing all of these things, asking good questions, getting a good history and a good exam. The goal is to increase your pre pre test probability of a diagnosis. You want to be pretty confident of what the diagnosis is before you even enter the world of genetic testing. Because if you're confident as a clinician, it makes it that much easier to interpret the genetic testing. And I know we'll be discussing that a little bit later. So a fract of error, if someone is a really high my myo so nearsighted and then also has a stationary disease, night blindness, likely that's going to be CS NB congenital night, you know, stationary night blindness. Um if they are potentially a hyper rope and they have the tele form lesions that increases your pret test probability for the form dystrophy like breast disease, color vision is also important. Um And that kind of helps determine how their cones are functioning. And over time sally testing to see how their optic nerves are doing because optic nerve disease can definitely occur. Um, over time with these patients, um, you wanna just determine their preference, bright or dark. Uh It's really telling if someone is wearing sunglasses inside of your dark clinic room when you walk in, likely they have some type of cone dystrophy and that helps just narrow down um the differential diagnosis for you. And with every question, you're getting closer and closer to the real answer. Um finally, you want to make sure that you are doing a good family history, birth history. Um You're thinking about other things in the eye, right? You're asking about hearing loss, I can't tell you how many patients they seem like they have perfect hearing and then you ask them like, yes, I've had hearing aids for the last 30 years. And if I had not asked that I would have never known same thing about seizures, extra digits when they were a child. Um These are things that are not evident unless you ask the question um whether or not they met milestones. So in this clinic, we see Children and adults. So you wanna make sure that um with infants and Children that they're getting um appropriate care and referrals. Um And then finally, there are many uh masqueraders. And so if a patient comes in, they don't necessarily have an inherited retinal disease. They potentially could have a cancer associated retinopathy or an autoimmune retinopathy. And so we have to do our due diligence and history taking um thinking about their medications, their other systemic um manifestations to make sure we're not missing something that potentially could be life threatening. And then with the systemic medications, things like PTO and other toxic medications could be the entire answer. Um And then genetic testing history and it's important to know what's been done, that kind of dictates what should be done next, whether or not you should go straight to genome sequencing or if you should get a targeted panel and we'll talk about these um nuanced things a little bit later exam. We don't have to belabor this too much, but I just wanna make sure that we high level view that with an inherited retinal disease consult, we wanna make sure we're doing a really good exam of the front of the eye, make sure we're not missing things like cataracts and inflammation. Um, something that could be uh treatable. Um and then in with Children, um things like fever and nori's disease, et cetera, sometimes the cataract is extremely significant. Um and we need to potentially address that. Um And in other diseases, the cataract may be limiting to the view to the back of the eye. We also want to make sure that we are doing a thorough exam um in order to again increase our diagnostic um probability that we have the right answer. And then finally, we want to do the testing and exams to try to figure out is there anything that's actionable? So, in many of these patients, they do have potentially like cystoid macular edema or inflammation, something that we could start drops, potentially injections, lasers, et cetera. So we wanna have a comprehensive eye exam for these patients And then testing um patients who come through our uh our clinics um often get testing the day before. Um and that's because there are lots of tests and it's kind of exhausting to do. And so then we'll see them on a day when they're fresh. Um It's easy to talk to them. They've already had the testing that we've been able to review. And so in addition to the color testing that we've discussed optical coherence tomography, cross section, scans of the retina are really helpful visual field testing that can be either kinetic where there's kind of movement of the light or automated visual fields can be helpful. Electroretinograph where we're looking at the electrical signal of the eye can help differentiate and categorize these um disease states. And then finally, just a baseline photo or potentially auto fluorescence to highlight some of the pathology that might be hard to see with your own um eye. So just to highlight some of these tests. So this is a patient who has an oct here, very classic for a chromatopsia. Really no other testing, at least in our clinic is necessary because this patient is going to clearly have symptoms that are consistent with a cone dystrophy. Their color vision will be non-existent and their oct cross section scans will show the sub fal hyperreflective space that is classic for this disease state. And so genetic testing if it comes back positive um for an a chromatopsia gene, it was very clear that that's the answer because our pret test probability was high. This is visual field testing. This is a a Humphrey visual field and this is showing um a pretty dense ring scat toma in a patient who has retinitis, pigmentosa. I put this on here mostly to show that this patient has great vision. They're seeing 2020 2030 they're doing really well, but their peripheral peripheral vision is very limited. And so oftentimes we get visual field testing not to scare the patient or to sometimes we don't even show them the the visual fields, but more to guide us on whether or not there's progression. Um And now that we have clinical trials, this could be really helpful to determine when to intervene electroretinograph. Um This is a patient who came into clinic clinically looks normal. The retina looks normal oct scans were interpreted as normal. And then um the electroretinograph very clearly shows uh central loss and attenuation of the central rings indicating that there's some type of uh central loss of, of function. And so this is a patient who eventually went on to have genetic testing and had a code dystrophy. And then the last of the testing is auto fluorescence. And so I wanted to just stop here and have a very small uh mini case. Um as we transition to talking about genetic testing, this is a patient who was referred to our clinic um a few months ago and they were referred specifically for geographic atrophy. And the question that this patient has was, you know, what, you know, what is there to be done in regards to age related macular degeneration. And so getting auto fluorescence was extremely helpful in this case because this is not a classic appearance for age related macular degeneration. There's some interesting patterns and hyper auto fluorescence kind of around the area of geographic atrophy. And there are these kind of streaks um which look kind of like angio streaks that you would see in a different type of disease state. So getting a good history, um a few other systemic things were a little bit concerning. And so this patient really just wanted to know, are there options for geographic atrophy? Are there research opportunities for age related macular degeneration? But what we ended up talking about were alternate diagnoses and what we should do next. So we'll take a uh kind of a pause in the case as I transition to my colleagues and we'll come back to the answer here. So I think that's a great time to just kind of pivot and just doctor Si. Could you tell us a little bit about the process of genetic testing and our philosophy of the care clinic here at Mayo? Yeah. So I, you know, I wanna what uh both Scruggs and a have just said I as a geneticist, I rely very heavily on their phenotyping And even though I do get a good visual history, um after I do that, I go back and look at their notes and see what they said. Um If there's visual imaging, you know, if there's retinal imaging, I'll go back and look at that. I do look at the er G report and the OCT. So it, it all feeds in uh because genetic testing is not magical, it's not like we order the test and it, and it gives you the answer right away. We really do need the phenotype to interpret the testing. And so we do work as a team. Um Colin and I uh work as a team and uh we've decided to divide our labor a little bit in sort of a um a fast and slow, so fast, meaning uh Colin is embedded in the inherited retinal disease clinic in ophthalmology. And his partner Madeleine Lepore is also in, in the clinic and together they're seeing the patients right away uh with my ophthalmology teammates and they're ordering targeted testing, which are panels of genes that are known to cause retinopathy. And they are also genes that are uh basically the regions of the genes that are being um interrogated for abnormalities are, are just the coding regions of the gene. Um And so even though I'm not seeing those patients at first, um Colin is seeing them with the ophthalmologist. Do you want to talk more about that? Colin? Because it, it, it's been really efficient. Yeah. So we um Doctor Scruggs and I are uh clinical partners and uh Madeleine poor and Doctor Ay are clinical partners and so on her inherited retinal disease day. Doctor Scruggs and I will see parent patients together. Doctor Scruggs will go on and do their retinal evaluation. Um And basically we go through their, their eligibility criteria. One of the main things that we, we look for is which test is gonna be the most appropriate. Um We do have a couple of sponsored panels that we like to use. Um And then we think about what are the goals? Are you looking for a diagnosis? Um Many people are thinking about things along the lines of, can I preserve my vision? Can you give me a prognosis of how my vision might end up? And sometimes we, we can do that and sometimes we can help with that and it's really powerful, it's a really great space to be in. Um But sometimes we definitely have to set some expectations and let them know that testing isn't a magic like a magic bullet. As Doctor Sini said, um we have to basically understand what it can do and what it can do. A big question that a lot of people have is what does this mean for my kids? You know, this is why I think genetics is very important to have these conversations when we think about these testings because it's not just about the patient in front of you. It's not just about what's going on with them. It can affect long term down the road, things, Children, whether they're gonna have Children, whether they're, if they already have Children, if the Children are gonna be affected, um siblings, parents, there can be very complex family dynamics that we have to wade through to make sure that we're understanding things, things that patients just don't understand. They're just like it's a test, we're just doing a test like anything else. And I think my my role is very powerful in helping them understand what those downstream effects can be. Um We can also help identify like if there's gonna be other associations. So um generally what we like to do is if it's more syndromic case, that's when we will definitely send it to doctor Sini for consideration of more broad-based testing, sometimes we will still do the panel testing first cause that might find us an answer. And if, if it's more complex and there's more medical management that is, of course, where Doctor Si's expertise comes in. Um And then we also kind of think about what are the clinical trial possibilities? Like, is there things that might be effective because there is a lot of things that are coming down the pipeline that are very, very um exciting and, and great to see coming up, um and kind of getting into what we were talking about. That's the pre and the post test counseling. That's what I basically do. That's very much genetic counselor led, but focusing on with the uh providers as well. Um And we kind of do this shared decision making model. Um Sometimes we in the pre-test counseling, what we'd like to do is help them understand that there's basically three types of results. We can have a positive result, which means we found a clear answer, we call that pathogenic. And that's when we can make kind of trouble decisions, we can have a negative result. And as we discussed before, that's sometimes when we might refer off to doctor sc for broad-based testing such as whole genome exome. But sometimes we get something called an uncertain result, which can be very hard for patients to understand. Basically, that just means that there's a genetic change found, but the lab doesn't have enough evidence to say yes, this is a harmful change or no, this is just normal human variation. And so helping them understand that on the front end can be very, very powerful on the back end to help them really work through things. And so bringing this back to uh the little mini cases that doctor uh Scruggs was talking about. Do you wanna jump in there? Doctor Scruggs? Yeah. So this is a patient who is in our clinic and we paused, right? And we said, well, we're thinking that this could be something else. It could be something other than age related macular degeneration. I think that's important for all of us and everyone on the call to remember is that it could be something else than the diagnosis that was placed on that patient um before they got to you. And so we did everything that Colin just mentioned in terms of counseling and then eventually genetic testing and making sure that they were set up for success to receive this information. Um Interestingly, this patient had shared with us in clinic at the first initial visit that um he had extremely severe leg cramps to the point where it was debilitating and decreasing quality of life. Um And so with the auto fluorescence being a little bit concerning for pseudo xanthoma elastic and these leg cramps, the genetic testing did come back with ABC C 62 variants, one that was pathogenic and one that was a variant of unknown significance. And so um this is just a very interesting case because pseudo Xanthoma elastic affects a lot of um organs, including the eye. Um that's one of the most common affected organs, but it also can affect the G I tract, the heart, the skin. Um And so, and it also can cause limb claudication, which is what the underlying problem was for this patient. And thankfully, he's gotten in the correct clinics. But at this point, getting the testing back, we have to figure out who should this patient see what work up should be done is this V US relevant? And so that's when I'm just so thankful to have the team of uh Doctor Sinti and Colin to really help make these um informed decisions with the patient. And with me, doctors come to your colon, do either of you wanna address uh this pathogenic variant or V or how we initiated the work up or I, I'll talk a little bit about that. So this is a recessive condition. So that means that you need variants in both copies of the gene, one from your mom and one from your dad. And so this is a patient whose parents are no longer with us. So we couldn't set phase is the the term. And on top of that, one variant was a known pathogenic variant. Uh you know, also known as a mutation in the gene ABC C six. The other variant um did not meet the American College of Medical Genetics and genomics criteria for being a mutation. And so when uh a genetic variant is not benign, but it's not a pathogenic variant. It gets sorted into this third bucket. So the, the things that we know about the patient is the careful phenotyping. Uh And so this is such uh a characteristic retinal phenotype and the other clinical findings were characteristic uh that we really felt that this was most likely um PXE uh just for full disclosure, this patient does not have skin uh xanthomas And uh one of the variants is a very mild uh is already associated with a mild phenotype. And so um from a management standpoint, uh we're managing him uh like ESPXE but keeping in mind that um it, it would be nice to get uh the second variant upgraded. And so, one of the things we do is we do follow these patients longitudinally. Uh We use resources through the Center for individualized medicine at mayo uh to do uh a reanalysis as databases improve. And um and the hope is at some point, we might be able to do some functional testing of the ABC C six gene uh to uh really understand the full significance of the second variant, but at least clinically right now, um this is our, our working, our working diagnosis. Um Furthermore, uh just to make sure we weren't missing anything. Um We also did um a, a larger test, we did either whole exome or whole genome sequencing on this patient and didn't find a second a second condition that could potentially explain the phenotype. And so this is our our working diagnosis right now. And I think an important, I was gonna say real quick, I think an important thing to, to know with the multidisciplinary clinic and understanding is sometimes those broader testing, you have to understand the technical aspects of them and what they can do and what they can't do. So we have to make sure that, that we're utilizing our different subspecialties correctly to understand that when a genome would show the second hits or when the exome could possibly show an answer as well? Could you comment on the Genomic Odyssey Board's role in, in, in that kind of a of an analysis? Yeah. So one of the things we have here at the Center for Individualized Medicine is a group called the Genomic Odyssey Board. And the role of the General M Odyssey Board is to do a deep dive into uh variants of uncertain significance that have been identified in patients uh with phenotypes that we suspect uh that variant may have a positive role. And so, uh the, the genomic Odyssey Board meets almost every Wednesday. We're just at General Odyssey Board before we got here and um they then take the results from our patients uh review, do a very deep dive in literature, reach out to labs that are doing research on certain genes and, and try to come up with a conclusion whether uh a gene is positive or conversely will say, you know, this isn't it? Um So we're, we're wasting our time with the variants that we found. And, and so that's really helpful. Um The other thing are genomic auto board um has, is a process called renew. And so these are for patients that uh we really didn't make a diagnosis and we with patient consent because this is done on a research basis, we actually reanalyze uh their genome um multiple times a year. And, and it's been really um wonderful because I've had patients who have had um genome or exome sequencing, no diagnosis was achieved. And then through the renew process, we've, we've gotten a diagnosis. Um I've had two families with optic atrophy where we've been able to get an answer uh using that process. So it's um it's been really nice. And then the other nice thing is we never say we're done uh to patients. So for those patients where we don't make a diagnosis, uh they can be uh reassured that we're gonna continue to look and we do see patients back and we follow them up as inform, you know, as this information uh becomes available. And then also watch to see how their, their phenotype, their condition evolves over time because sometimes the evolution of a phenotype can help us with making a diagnosis. That's a great, that's a great uh point. Doctor Si um and I, I think we put this in here to kind of just show how complex these results really can be. So I think a vast majority of the participants that are watching, this are medical professionals. And even from us, this can be very confusing information, imagine what this looks like to a patient when it comes back. So you see all these different things. And one of my uh one of my long standing things that I tell my patients on the post test counseling is doctor Google will tell them the scariest things first. So it is very important for them to have us to be able to suss through these things and also for other providers as well. You know, if you don't have a specialty or you don't have a background in genetics, there's a lot of moving parts. This is a fairly complex result here. So I thought I could walk, walk you guys through this and what we're looking at here. So this is a result that comes from one of our more common panels that we order. Um This one does the nuclear DNA that's related to inherited retinal disease. It's a very comprehensive panel, but it also includes the mitochondrial DNA. And as many of you probably know the nuclear DNA and the mitochondrial DNA are separate. So this kind of goes back to my point about knowing the technology and knowing which test is doing what. And so for this patient, they were found to have a change, at least one change in a mitochondrial gene. And so to make this a little more complicated, when we think about mitochondrial genes, we have to think about something called heteroplasty. And basically what ends up happening with the mitochondrial genes is some of the mitochondria can have this one genetic change and some can have just the normal wild type or just have the typical compliment that we would expect. And that can really change even depending on the tissue that we're testing or where it's at. So it could be a higher percentage of the retina, a higher percentage in the muscle or in the blood. And sometimes we have to be careful about where we're getting this from and thinking about those things from there. And I think right now we're in this really great area. Uh And ophthalmology is a great space for all these clinical trials that are starting to happen. And doctor Ay and doctors uh Scruggs, I kind of thought this is a great time for you guys to go through like what is available for these practical side of things for what can patients actually do. So this is uh as you said, it's a very exciting time. We're, we're actually uh able to intervene in, in several uh of these conditions. And one of the most exciting studies uh that I'd like to briefly review now is the um is the nak attack trial? Why is it so exciting? Well, it's a an oral medication and acetylcysteine that could potentially have a role for all patients with retinitis pigmentosa. Um regardless of their genetic subtype. Why is that critical? Well, we know that retinitis pigmentosa happens one in 4000 patients. But for an individual that has a specific genetic type, they may be only one in 100,000. So perhaps the chances that a gene therapy are going to be developed may be lower because companies that develop these therapies typically like to try to find groups of patients that are greater in number. Uh And so, so for those more rare forms of RP or for all of those forms of RP, that just simply don't have a treatment yet, which is most uh we're very excited about the, the nac attack trial. An acetylcysteine is an oral antioxidant. It's uh uh on a medication that's used to break up mucus. But it's found that patients with retinitis, pigmentosa likely have a significant burden in their retinas of oxidative stress. And there's several theories as to why some believe that because rods die first leaving cones behind that there's extra oxygen in the outer retina that can in then injure cones. And so this extra oxygen if you will causes free radicals that then damage cones. There are several more reasons why cones die after rods are already gone because there's, there's a an entity called rod derived cone viability factor. So when the rods are gone this rod derived cone viability factor, uh hormone goes away and the cones can subsequently die. Um But the goal here is to, is to try to use this antioxidant to slow down the progression of RP. And it turns out that inflammation is driven by oxidative stress. And we know from studies that I've done in rats that neuro inflammation which is a very specific form of inflammation, uh is driven by free radicals. Hydrogen peroxide is a secondary messenger within the photoreceptors and within the microglia and muer glia cells that can become fag acidic like little pacman heating up the outer retina. We can shut down that type of inflammation by using antioxidants. So we're very excited that an acetylcysteine and other antioxidants may have a multidimensional role in slowing down the progression of RP in all comers. So the N attack trial is set up to actually deter determine if all of this theory actually has value in practice. Peter Campano Johns Hopkins did a did a fight RP study a phase one clinical trial where he looked at um a few groups of patients that were on different doses of an acetylcysteine. And he found some very interesting things. He found that with oral dosing of this medication, he could get good in good levels of the drug in the eye. Uh and he could find good levels of, of, of an acetylcysteine in the blood. And he found that there was a gradual and steady improvement in vision in these patients. Not only that he found a gradual and steady improvement of micro perimetry, which is a, a sensitive form of visual field testing, which we have not seen these kinds of effects before. And, and so what, what that group did, what Doctor Ciccio's group did was then appeal to the National Institute of Health. And over the course of the, the last 4.5 years or so, we've all been working to getting this trial moving. And Mayo Clinic is a site now currently enrolling in the N A attack trial. And um I think the the biggest excitement is that it may have a role. And of course, this is a science project, this is a study and we need to scientifically prove if this actually, in fact, does have a role. Um There are some barriers to entry. It turns out that you have to have a measurement on the oct uh O of of a certain number of photoreceptors before you can enter. Uh And that's because patients who are pretty advanced in RP, have fewer photoreceptors. And there's something called a floor effect where if you don't have something to, to save or rescue, then there's nothing that can be measured. And there ha and this study happens to be using the OCT test as opposed to visual acuity and micro perimetry as the primary outcome measure. So the OCT has to be within a certain range. And so uh for those interested, you know, we're more than happy to, to do screening on patients that might be interested in that attack trial. But we're all very excited that the RTA community has been hopeful for this for, for many years. All right. Um I can transition to talking about uni rare. Um This is a the largest natural history study for inherited retinal diseases. That is um one, it's one of many studies under the consortium for the FFB, the Foundation for Finding blindness. And this is an IRD specific consortium made up of 40 sites across the United States, all clinical research centers. And the goal of this study, which we are a site for is to recruit at least 1500 people who have diagnosed inherited retinal disease um with a rare gene variant. And the reason this is so powerful is because many of the clinical trials are to study diseases that are more common. Um you know, think of like ST Stargardt disease and um other clinical trials like Correia and retinitis pigmentosa. Um But the, the diag maybe if you know, maybe diagnosis of one in 100,000, maybe those di you know, disease states are not being studied as frequently. And so this is a way to incorporate all patients, all comers who have rare gene variants across all of these sites. And the goal here is to really understand the natural history of these diseases and with all of these sites coming together, we have really powerful data about the disease state progression, the characterization of the disease and be able to identify more people for clinical trials, for therapies. Be able to inform our design of clinical trials and really be able to identify therapeutic targets for more people. And so we are excited to be able to recruit patients um in the upcoming few months and, and I think we are just a few minutes away from needing to do questions and answers. So we'll just wrap up a little bit with the active gene therapy trials and the and research in the United States. Um There are several trials and the excellent retinitis pigmentosa trial is the one that I think we should highlight here um because we're running out of time and that trial has not yet started. So I don't know if Doctor Ayoze, if you wanna mention that um briefly. Certainly. So X linked retinitis pigmentosa represents only about 8% of RP patients. But unfortunately, these are patients that are among the most severely affected. So the idea of having a treatment for X linked retinitis pigmentosa is critical to us in that we really want to get to these patients early while we can still save vision. Because all of these gene therapy studies really are designed to preserve vision if vision has already been lost. We're not in a position to restore vision in these trials. So the um the vista trial uh is, is designed to treat RPGR patients. These are patients with um with this excellent form of retinitis pigmentosa. And it involves a uh a subretinal injection of an adenovirus which can insert the appropriate gene uh and, and, and potentially uh reverse some of the effects of the RP. Um This trial has not yet started. Um and um is currently uh in the uh the late phase planning. We've been working with the inventors of this and the companies that have been involved initially was a company called A GTC. And now it's Beacon Therapeutics. We've been working with them for several years uh as they have refined their clinical trial protocol and we await a final notification as to when that's all gonna start. But it's an important uh treatment because this is a very um a serious form of retinitis pigmentosa. And so overall, I think the importance of this is timely and accurate diagnosis can be essential for these patients with presumed inherited retinal disease. As doctor I just mentioned a lot of this is about preserving vision. So the sooner that we can get the clear diagnosis, the sooner we can start preserving and the more vision that we can help um history, examination and testing for diagnosis of inherited retinal disease um should be a sys systematic and complete looking at all the pieces and all the, all everything put it put together as a holistic. Um the management of these conditions requires a team approach. So as we kind of discussed a little bit, some of these can be syndromic, we can see multiple different health systems involved. So it's important to have people with specialties and um focus on different areas to be able to, to, to help these patients in the best way possible. Uh And then the genetic testing should be performed by physicians who are able to perform and arrange pre and post test counseling. I will give a big shout out to this cause I can tell you it is very helpful to the patients. It is very helpful uh um all across the board to have that, that expectation settings and the understanding on the back end as well. And uh finally, there's several clinical trials are underway for many inherited retinal diseases, including the phase three neck attack for RP. Um We just mentioned a few today, but there are many, many that are going on right now and it is an area of extreme research that's being done and there's a lot of focus that's happening right now. So with all that being said, thank you all for being here with us. I appreciate your time. Um And being interested in this as, as we are, I mean, we wanna open this up to any questions. If anybody would like to put any questions in the Q and A, we'd be happy to queue those up. Um I do have one already here from AOA. She, they excuse me, are asking, would you consider starting treatment on patients less than 18 with retinitis pigmentosa? I responded to that question, the chat. Um and I would point out that many gene therapy trials are eager to uh seek uh younger patients even in the pediatric age category. Uh Luxturna, which is a product that um we will likely be offering at some point. Um Thanks to Doctor Scruggs efforts in working with the company. Um uh Luxturna tends to work better in younger patients. And so it's not uncommon to see pediatric patients enrolled in gene therapy trials. Um Some of the other trials have um age limits. Um And so we just go go with those protocols and I think the point of not recommending treatment outside of a clinical trial is really important. And so even with an acetylcysteine, um that is a supplement that you can get off of the counter at a drugstore. Um However, the, the N A, the anac cysteine that is being provided in a clinical trial is pure and it is quantified. And so the amount the milligrams per dose is regimented. And so um it's really important to make sure that you're discussing everything that you start with your physician and making sure that it's safe. Um and clinical trial enrollment and these studies are done in a controlled environment for a reason. Doctor Scruggs, that's a fantastic point, you know, nutraceuticals, uh sold, um online are not subject to the kinds of pharmaceutical controls that um, the NA Attack trial is, is adhering to. So NC Attack is providing a pharmaceutical grade product which is a drug. Um, whereas as you point out if you were to buy an N acetylcysteine on the internet, um you really wouldn't know exactly what it is. There would be no validation, there could be contaminants in it. It may be something other than an acetylcysteine. Um And so you don't wanna potentially put yourself in, in harm's way by using something that you really don't know what it is. There's another great question in the chat um asking is there any resources or studies that you would point providers to, to help them understand what the current gene therapy trials are or even the clinical trials or uh gene therapies that are available? Doctor Sar, did you want to comment on that? Yeah, I would love to. So I think this is a common question for our own patients and something that we are working on as a team. Um This takes a lot of effort and we are um de designing essentially handouts that have the up to date um clinical trials per disease state. So that when a patient comes in, say there's a new diagnosis or a new clinical trial for this patient, we can offer them the information, the contact information, the eligibility criteria for that trial. Um Unfortunately, these trials are um always changing. Um The recruitment and enrollment is always um something that is, you know, you have to look up. And so clinical trials.gov, although not completely perfect um is the, the number one source for determining what trials are out there for any specific disease state or gene and whether or not there is enrollment going on, if it's active, it points you to the papers and the publications um to so you can, you know, do your own research on it. And it usually gives the contact information for the um the primary site. So you can contact the coordinator. And I do this commonly, I will go to clinical trials.gov knowing that this is a trial that potentially my patient would be eligible for. And I will personally contact the coordinator and many of my patients have gotten into clinical trials um because of that and it's very easy. Um I just send the records to that clinical site, they review them and then my patient potentially can be um screened. So, um I wish I had a better answer, but I, I think that's definitely the best way is to have individual individualized like institutional based handouts and then to make sure that you're giving, you know, accurate information to your patients by having up to date information. I totally agree. Ok. No, go ahead. Some resources from foundation fighting blindness and research to prevent blindness can also be helpful. And um individuals with inherited rental conditions or, or individuals with family members, with those conditions can connect with each other. And I found that um many times this is a very reasonable uh uh form of education where um people talk and, and get to be in the know. So one question, um there are many people who are starting to do targeted gene panels and this is a question maybe for Colin and for doctors Clementi um but say a comprehensive ophthalmologist doesn't have a um a partner who does inherited retinal disease. Um And so they get a, a targeted panel and it comes back with, you know, a V US. Um I, I I'm curious, do you see in your practice um that you're, you see patients who maybe have A V US and they were told that they have a disease. Um and it's not actually accurate or potentially, they were told that they don't have a disease um because of the V US. And it actually is the answer. So can you kind of speak to um how often do patients get misinformed before seeing you? Um It's not an unusual occurrence um that somebody will get a panel. Um And yes, there will be variants of uncertain significance and um patients are sent to me to interpret that panel and, and that's sometimes helpful. I think sometimes too, we end up with a panel. Um You know, I had a situation recently with a patient with optic atrophy and uh a retinal panel was sent, well, the differential diagnosis for optic atrophy is really different uh than inherited retinal disease. So they need, needed different genetic testing. And so I think the issue is um you know, yes, some of these panels are, are no charge. Uh but for patients, uh the time spent waiting for those results is really stressful. And so, uh I guess, I think the, the one message is uh use if you know, have a panel that's appropriate for the diagnosis. And, and I do think it's really important to have pret test and pote post test counseling. Um they, for patients because they get these results and they don't know what to expect or, or they didn't know what a variant of uncertain significance was. And because the lab called it out, it must be important, I'll let you, I'll let you speak Colin because this is, it's definitely um it's definitely not out of left field for it to happen for us to have a patient come in with a uh misunderstanding of a report. Um Sometimes through no fault of the referring provider's own, sometimes patients just get confused and it's, it's hard to understand as you saw those reports are very complex. Um So i it's another big plug for having that pre and post test counseling and we understand there's not enough geneticists, there's not enough genetic counselors, you know, um we're happy to be resources for whoever needs it. Um and um be here whenever we can. But again, it's just the plug that um it can be very useful to, to reach out when there's those concerns. So there's a couple of questions. Um I'm not sure what this is, but maybe uh doctor A and Doctor Scruggs will know perspective on proms and favorite mobility mazes. I'm not familiar with what that is. Yeah. So patient reported outcomes. Mhm Yeah. So for, for the mobility maze, we do have a mobility maze uh at Mayo that will be used for the clinical trial again, not currently enrolling but will be hopefully in 2024. Um So that is that is an important way of how Luxturna eventually got approved. Um that was really powerful data and I think it it still serves a role in clinical trials. Um pa patient reported outcomes wonderful in clinical trials, I think from a day to day standpoint, a clinic um very hard to implement in a busy clinic. Doctor Aya, what do you think? No, I agree. I think that that that's primarily a research based tool. It it takes a long time to administer it. They're done under controlled lighting conditions. You need more than one staff member to oversee the um recording of it. It's a videotape thing and it requires computer based um analysis. So those are very useful for um measuring in my view. Um ultra low vision where you know, the outcome isn't really realizable on an eye chart but rather on a mobility testing uh paradigm. And it looks like we have one more question um asking if you can discuss the status and promise of cell based therapies for her for inherited retinal diseases. Doctor Scruggs and I are working um diligently in this area. This is a, a very active area at Mayo. We have a uh stem cell program um that's primarily geared toward um regenerating the retina pigment epithelium underneath the retina. Um I've also done some preliminary work in the area of photoreceptor sheet transplantation. Uh uh So I I'd say that there's a lot of excitement in the area of cell based therapy. Um I think that we have to be very objective in assessing the role of these therapies. Um And at the moment, we um it's simply not ready. We just don't have good data. Um I would be very cautious and I would, I would strongly recommend that individuals stay away from uh clinics that offer quote unquote stem cell based therapies. These are often these in chally derived cells from bone marrow and um they offer a lot of risk. There have been several patients who have gone blind as a result of their um enrollment in not even clinical studies. These are patients that went for treatment and had stem cells, quote unquote stem cells injected into their eye and have suffered very severe inflammation and retinal detachments and blindness. So, so I think that the only role for investigating and applying stem cell in these conditions is under the auspices of a clinical trial where there's a data Safety monitoring Committee where there's a whole bunch of oversight and there's standardization. I think there's a lot of clinics that offer bone marrow um based or blood based um stem cell injections and those are uh have been shown to be unsafe in the eye. Is there anything that you wanted to add to that? Doctor Scruggs? So there are, there are several trials um more so in in Europe, um because the the hurdle of doing trials is a is a little bit less and a little bit lower for them. But there is a trial currently in the NAT at the National Eye Institute in Bethesda. Um the first patient um for age related macular degeneration that was treated with stem cells um using uh you know, a new biodegradable scaffold. And there you know, cells grown on top of the scaffold, that patient was treated earlier this calendar year. However, no published data currently exist to review. There are no long term data. And so this is experimental, right? We're try, we're still trying to figure out what cells are appropriate. What scaffold is the best the actual surgical approach. Do these cells even integrate into the retina? How do we decrease the inflammation? Um the blood supply under the retina? Is it enough to like feed this new implant. Um There are, there's so many unanswered questions and the only way to do this is with large animal models and then eventually phase one trials. So there are a lot of people, a lot of smart people thinking about this and working on this. But, um, I think that we would be doing a disservice to the, you know, to the group listening if we said that we are any closer than, you know, than we were and we are still in the infancy of figuring this out. So, uh we have one last question if you all are OK with the time. And I think it's, it's good cause it's a practical question. Um There's a question about what do we counsel for our Stargard phenotype patients with the two pathogenic ABC A four variants regarding vitamin A. And I know Doctor Scruggs and I have been diligently working on this in our clinic. Yeah, we have um we have a dietician group, the dietetics group at mayo, who we partner with. And this is a work in progress because this is something that we, we adamantly want for our patients, for them to be informed on how do you have a good healthy diet? Um but not overdue vitamin A. And so I think that the takeaway since we're running out of time is that you want to be on the low end of normal for the vitamin A level if your vitamin A level is really high, super normal, then potentially that could be um causing a higher rate of progression for patients with ABC A four retinopathy. So getting a vitamin A level is important, getting a vitamin A level over time is important. And I've been incorporating that into my practice and then the dietician will sit down and help curate a diet um that's meaningful. And I I also want to make, make a point that you should not have them take away healthy foods. It's not nothing that is, is stopped. It's everything in moderation. So you don't want a lot of vitamin A rich foods all at the same time as you know, three different side dishes. So it's all about being mindful and understanding what foods have the highest levels of vitamin A and then um you know, curating your diet accordingly. So, great questions everybody. Uh Thanks again, Doctor Hay Ciment Scruggs. Uh Thank you to everyone for participating today. There were 250,000 outpatient visits for eye care each year across all of our sites in Minnesota, Arizona and Florida Mayo Clinic. Welcomes referrals for rare and serious complex eye conditions. We are here to help um to discuss your patient or learn more about referring a patient to the Mayo Clinic, contact or referring physician services at 1 805 331564 or book by visiting Mayo clinic.org/medical Dash professionals. Uh Thank you again for joining us today and we hope to see you again on our next webinar on November 30th at noon, central time for an update on glaucoma therapies.
