KAHLEN DARR: Good evening. Welcome, everyone. Thanks for joining us today for the Ophthalmic Genetics: From Genetic Testing to Clinical Trials webinar. My name is Kahlen Darr. I'm a certified genetic counselor who works with patients at Mayo Clinic's inherited retinal disease here in Rochester, 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 webinar. We have Dr. Lisa Schimmenti, a board certified medical geneticist here at the Mayo Clinic in Rochester. Dr. Raymond Iezzi and Dr. Brittni Scruggs-- both are board certified ophthalmologists at Mayo Clinic here in Rochester.

And all three are physicians who treat patients with inherited retinal disease and are involved in the clinical research. And again, this is me, Kahlen Darr, and I'm a genetic counselor. I work hand in hand with Dr. Schimmenti, Dr. Iezzi, and Dr. Scruggs. [00:02:03.18] So the learning objectives 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 pearls for patients with presumed IRDs-- 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 in ophthalmology.

So as a beginning, Dr. Iezzi, could you just give us an overview of how the clinic works here and how things flow?

RAYMOND IEZZI: Absolutely. Thank you. So we have developed a multidisciplinary clinic where Dr. Scruggs, myself, Dr. Schimmenti our genetics counselors, and our low vision specialists all coexist within the same clinic. This gives us a coordinated response to our patients' needs.

And so what that allows is for a patient to come to Mayo and be seen by us, get a history, physical examination testing, see a genetics counselor or medical geneticist like Dr. Schimmenti, and then perhaps even get some low vision services, and even be seen by our state services for the blind.

And in this coordinated clinic, we can get things done.

BRITTNI SCRUGGS: Yeah, I can add a little bit. So I'm Brittni Scruggs-- going back a little bit. So in addition to seeing the patient and getting them involved with the low vision team, they can also work with occupational therapy, social work, a dietician, especially if diet is important to potentially decreasing the rate of their progression.

And so we have 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 refraction, and so a low vision specialist will see them.

And in this photo, there's a tinted contact lens. This is one of our patients with achromatopsia. So we have a wonderful contact lens service that can provide these services, provide tinted glasses, the patients can trial magnifiers, readers, CCTVs, telescopes-- different ways to improve and optimize their vision in the real world.

State services for the blind, as Dr. Iezzi mentioned, is actually on site partnering with our low vision services and allowing them to get resources in their homes and for long term care. They will essentially get the patient 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.

KAHLEN DARR: So what disease states are commonly diagnosed and managed by an inherited retinal disease specialist?

BRITTNI SCRUGGS: Dr. Iezzi, would you like to take that?

RAYMOND IEZZI: Absolutely. So the clinic was started as a specialty clinic about 15 years ago.

And over the course of those 15 years, we've developed a large cohort of several complex inherited retinal degeneration conditions, including retinitis pigmentosa of all forms, Stargardt, x-linked retinoschisis, stickler, cone rod dystrophies, choroideremia, achromatopsia, various pattern dystrophies and PRPH2-related diseases, occult dystrophies and gyrate atrophy, Leber's, albinism, congenital stationary, night blindness.

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 in understanding how they're functioning on a day to day basis.

Many times, a patient might come in with one diagnosis or a presumptive diagnosis, and ultimately, we inform them that, perhaps, we have to go down a different path, in terms of pursuing a more definitive diagnosis. And at Mayo, almost all paths lead to our genetics services in seeking a molecular diagnosis.

And Dr. Schimmenti was the first to be added to the team and has been a fantastic addition. Clearly, in 2023, it is very necessary to seek a molecular diagnosis. And the reason for that is that we're now starting to have treatments, and we'll get into that. Dr. Scruggs and I will discuss some of these treatments later.

But having an appropriate molecular diagnosis, meaning a genetic diagnosis, will allow us to more accurately pursue what the clinical situation is, where a patient is in their condition, how we can best enhance their function and perhaps rehabilitate them, and what interventions there may be for restoring sight.

I think it's very exciting that several of the newest therapies for many of these conditions overlap multiple conditions. So 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.

We could potentially place a device like a retinal prosthesis. And so having an accurate understanding of what exactly this is helps us in a multitude of ways, and I think Dr. Schimmenti and Dr. Scruggs can comment further on what implications this has for family planning and examining children and connecting with other relatives to understand inheritance.

So this is a very diverse clinic. There's over 150 different forms of retinitis pigmentosa alone, as well as several forms of Stargardt. And some of these conditions, like stickler, is something that may require surgery and regular monitoring to prevent vision loss from something that could be mechanically repaired via surgery.

So it's very important, I think, to have an appropriate clinic where we can devote our time, give a patient the time that they need 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?

KAHLEN DARR: With this being such a complex area to be focusing on with inherited retinal disease, and as you said, there's multiple different conditions-- what is a retinal disease specialist look for in an exam, and what testing can a patient expect to receive with this? Dr. Scruggs, do you have any insight on that?

BRITTNI SCRUGGS: Yes. Thanks for the question. So we can start by just highlighting retinitis pigmentosa, which is the most common diagnosis that we make in this clinic. And it is actually the most common inherited form of blindness-- anywhere between 1 in 3,000 and 1 in 4,000 in the United States.

And because this can be inherited in many different ways-- from autosomal dominant, recessive, x-linked, et cetera, even mitochondrial-- really important to partner with our genetic counselors and team to have a very accurate pedigree.

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 making referrals to other teams and making sure that they're being cared for on a systemic level.

And so in order to go through this, I thought we would start with the basics, and first is history taking. And I can't say this enough, of how important it is to sit down with these patients and have the protected time to have a meaningful conversation about what they're dealing with.

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 underlying pathophysiology-- is this potentially a cone disease or rod disease? Is this progressive, or is this a stationary disease?

And then we want to always check refractive error. And in doing all of these things-- asking good questions, getting a good history and a good exam, the goal is to increase your pretest 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 refractive error-- if someone is a really high myope, so nearsighted, and then also has a stationary disease-- night blindness-- likely, that's going to be CSNB-- Congenital Stationary Night Blindness.

If they are potentially a hyperope and they have vitelliform lesions, that increases your pretest probability for vitelliform dystrophy, like best disease. Color vision is also important, and that helps determine how their cones are functioning, and then over time, serially testing to see how their optic nerves are doing because optic nerve disease can definitely occur over time with these patients.

You want to just determine their preference-- bright or dark-- 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 the differential diagnosis for you. And with every question, you're getting closer and closer to the real answer.

Finally, you want to make sure that you are doing a good family history, birth history. 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. They're 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-- these are things that are not evident unless you ask the question. Whether or not they met milestones-- so in this clinic, we see children and adults. So you want to make sure that with infants and children, that they're getting appropriate care and referrals.

And then finally, there are many 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, thinking about their medications, their other systemic manifestations to make sure we're not missing something that potentially could be life threatening. And then with the systemic medications, things like pentosan and other toxic medications could be the entire answer.

And then genetic testing history-- And it's important to know what's been done. That 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 nuanced things a little bit later.

Exam, we don't have to belabor this too much. But I just want to make sure that we-- high level view-- that with an inherited retinal disease consult, we want to 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, something that could be treatable.

And then with children, things like fever, and Norrie's disease, et cetera, sometimes, the cataract is extremely significant, and we need to potentially address that. 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 in order to, again, increase our diagnostic 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, cystoid macular edema or inflammation, something that we could start drops, potentially, injections, lasers, et cetera. So we want to have a comprehensive eye exam for these patients.

And then testing-- patients who come through our clinics often get testing the day before. 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. 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 movement of the light, or automated visual fields can be helpful. Electroretinography, where we're looking at the electrical signal of the eye, can help differentiate and categorize these disease states.

And then finally, just a baseline photo or potentially autofluorescence to highlight some of the pathology that might be hard to see with your own eye. So just to highlight some of these tests-- so this is a patient who has an OCT here-- very classic for achromatopsia.

Really, no other testing, at least in our clinic, is necessary because this patient is going to clearly have symptoms that are consistent with the cone dystrophy. Their color vision will be nonexistent, and their OCT cross section scans will show the subfoveal hyper reflective space that is classic for this disease state.

And so genetic testing, if it comes back positive for an achromatopsia gene, it was very clear that that's the answer because our pretest probability was high. This is visual field testing. This is a Humphrey visual field, and this is showing a pretty dense ring scotoma and a patient who has retinitis pigmentosa.

I put this on here mostly to show that this patient has great vision. They're seeing 20/20 and 20/30. They're doing really well, but their peripheral vision is very limited. And so oftentimes, we get visual field testing not to scare the patient, or sometimes, we don't even show them the visual fields, but more to guide us on whether or not there's progression.

And now that we have clinical trials, this could be really helpful to determine when to intervene. Electroretinography-- this is a patient who came into clinic, clinically, looks normal-- the retina looks normal. OCT scans were interpreted as normal, and then the electroretinography very clearly shows central loss and attenuation of the central rings, indicating that there's some type of central loss of function.

And so this is a patient who eventually went on to have genetic testing and had a cone dystrophy. And then the last of the testing is autofluorescence. And so I wanted to just stop here and have a very small, mini case as we transition to talking about genetic testing.

[00:18:53.04] This is a patient who was referred to our clinic a few months ago. And they were referred specifically for geographic atrophy. And the question that this patient had was, what is there to be done, in regards to age related macular degeneration?

And so getting autofluorescence was extremely helpful in this case because this is not a classic appearance for age related macular degeneration. There's some interesting patterns and hyperautofluorescence around the area of geographic atrophy. And there are these streaks, which look like angioid streaks that you would see in a different type of disease state.

So getting a good history, 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 pause in the case as I transition to my colleagues, and we'll come back to the answer here.

KAHLEN DARR: So I think that's a great time to just pivot. Dr. Schimmenti, could you tell us a little bit about the process of genetic testing and our philosophy of the care clinic here at Mayo?

LISA SCHIMMENTI: Yeah, so I want to stress what both Dr. Scruggs and Dr. Iezzi have just said. As a geneticist, I rely very heavily on their phenotyping. And even though I do get a good visual history, after I do that, I go back and look at their notes and see what they said. If there's visual imaging, if there's retinal imaging, I'll go back and look at that.

I do look at the ERG report and the OCT so it all feeds in because genetic testing is not magical. It's not like we order the test, 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.

Kahlen and I work as a team, and we've decided to divide our labor a little bit in a fast and slow. So fast, meaning, Kahlen is embedded in the inherited retinal disease clinic in ophthalmology, and his partner, Madeline Lepore, is also embedded in the clinic.

And together, they're seeing the patients right away with my ophthalmology teammates. And they're ordering targeted testing, which are panels of genes that are known to cause retinopathy, and they're also genes that are-- basically, the regions of the genes that are being interrogated for abnormalities are just the coding regions of the gene.

And so even though I'm not seeing those patients at first, Kahlen is seeing them with the ophthalmologists. Do you want to talk more about that, Kahlen? Because it's been really efficient.

KAHLEN DARR: Yeah so Dr. Scruggs and I are clinical partners, and Madeline Lepore and Dr. Iezzi are clinical partners. And so on her inherited retinal disease day, Dr. Scruggs and I will see patients together. Dr. Scruggs will go in and do the retinal evaluation.

And basically, we go through their eligibility criteria. One of the main things that we look for is which test is going to be the most appropriate. We do have a couple of sponsored panels that we like to use,

And then we think about, what are the goals? Are you looking for a diagnosis? 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 can do that. Sometimes, we can help with that, and it's really powerful. It's a really great space to be in.

But sometimes, we definitely have to set some expectations and let them know that testing isn't like a magic bullet, as Dr. Schimmenti said. We have to basically understand what it can do and what it can't do. A big question that a lot of people have is, what does this mean for my kids?

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 going to have children, if they already have children, if the children are going to be affected, 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 role is very powerful in helping them understand what those downstream effects can be.

We can also help identify if there's going to be other associations. So generally, what we like to do if it's a more syndromic case, that's when we will definitely send it to Dr. Schimmenti for consideration of more broad based testing. Sometimes, we will still do the panel testing first because that might find us an answer

But if it's more complex and there's more medical management, that is, of course, where Dr. Schimmenti's expertise comes in. And then we also 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 exciting and great to see coming up.

And getting into what we were talking about, that's the pre and the post-test counseling. That's what I basically do, and that's very much genetic counselor led, but focusing with the providers, as well. And we do this shared decision making model.

Sometimes, in the pre-test counseling, what we 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 where we can make actionable decisions.

We can have a negative result. And as we discussed before that's sometimes when we might refer out to Dr. Schimmenti for a broad based testing, such as whole genome or whole 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 the little, mini case that Dr. Scruggs was talking about-- do you want to jump in there, Dr. Scruggs?

BRITTNI SCRUGGS: Yeah. So this is a patient who was in our clinic, and we paused. 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 that it could be something else than the diagnosis that was placed on that patient before they got to you.

So we did everything that Kahlen 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. Interestingly, this patient had shared with us in clinic at the first initial visit that he had extremely severe leg cramps, to the point where it was debilitating and decreasing quality of life.

And so with the autofluorescence being a little bit concerning for pseudoxanthoma elasticum and these leg cramps, the genetic testing did come back with ABCC6-- two variants-- one that was pathogenic, and one that was a variant of unknown significance.

And so this is just a very interesting case because pseudoxanthoma elasticum affects a lot of organs, including the eye. That's one of the most common affected organs, but it also can affect the GI tract, the heart, the skin, 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 workup should be done? Is this VUS relevant? And so that's when I'm just so thankful to have the team of Dr. Schimmenti and Kahlen to really help make these informed decisions with the patient and with me.

Dr. Schimmenti or Kahlen, do either of you want to address this pathogenic variant or VUS or how we initiated the workup or anything?

LISA SCHIMMENTI: 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 term.

And on top of that, one variant was a known pathogenic variant, also known as a mutation in the gene, ABCC6. The other variant did not meet the American College of Medical Genetics and Genomics criteria for being a mutation. And so when a genetic variant is not benign, but it's not a pathogenic variant, it gets sorted into this third bucket.

So the things that we know about the patient is the careful phenotyping. And so this is such a characteristic retinal phenotype, and the other clinical findings were characteristic that we really felt that this was most likely PXE. Just for full disclosure, this patient does not have skin xanthomas and one of the variants is a very mild-- is already associated with a mild phenotype.

And so from a management standpoint, we're managing him like he has PXE, but keeping in mind that it would be nice to get the second variant upgraded. And so one of the things we do is we do follow these patients longitudinally. We use resources through the Center for Individualized Medicine at Mayo to do a reanalysis as databases improve.

And the hope is, at some point, we might be able to do some functional testing of the ABCC6 gene to really understand the full significance of the second variant. But at least clinically, right now, this is our working diagnosis. Furthermore, just to make sure we weren't missing anything, we also did a larger test.

We did either a whole exome or whole genome sequencing on this patient and didn't find a second condition that could potentially explain the phenotype. And so this is our working diagnosis right now.

KAHLEN DARR: I think an important thing 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 we're utilizing our different subspecialties correctly to understand when a genome would show the second hits or when an exome could possibly show an answer as well.

BRITTNI SCRUGGS: That's a great point, Kahlen.

RAYMOND IEZZI: Could you comment on the Genomic Odyssey Board's role in that kind of an analysis?

LISA SCHIMMENTI: Yeah, so one of the things we have here at Mayo through the Center for Individualized Medicine is a group called the Genomic Odyssey Board. And the role of the Genomic Odyssey Board is to do a deep dive into variants of uncertain significance that have been identified in patients with phenotypes that we suspect that variant may have a causative role.

And so the Genomic Odyssey Board meets almost every Wednesday. We were just at Genomic Odyssey Board before we got here. And they then take the results from our patients, review, do a very deep dive in the literature, reach out to labs that are doing research on certain genes, and try to come up with a conclusion.

Whether a gene is causative, or conversely, we'll say, this isn't it. So we're wasting our time with the variants that we found, and so that's really helpful. The other thing our Genomic Odyssey Board has is a process called Renew, and so these are for patients that we really didn't make a diagnosis.

And with patient consent-- because this is done on a research basis-- we actually reanalyze their genome multiple times a year. And it's been really wonderful because I've had patients who have had genome or exome sequencing, no diagnosis was achieved, and then through the Renew process, we've gotten a diagnosis.

I've had two families with optic atrophy where we've been able to get an answer using that process. So it's been really nice. And then the other nice thing is we never say we're done to patients. So for those patients where we don't make a diagnosis, they can be reassured that we're going to continue to look.

And we do see patients back and we follow them up as this information becomes available, and then also watch to see how their phenotype, their condition evolves over time because sometimes, the evolution of a phenotype can help us with making a diagnosis.

KAHLEN DARR: That's a great point, Dr. Schimmenti. And I think we put this in here to 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 long standing things that I tell my patients on the post-test counseling is Dr. 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.

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 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.

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 mitochondrial DNA are separate. So this 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 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 heteroplasmy.

And basically, what ends up happening with the mitochondrial genes, is some of the mitochondria can have one genetic change, and some can have just the normal wild type, or just have the typical complement 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, and ophthalmology is a great space for all these clinical trials that are starting to happen. And Dr. Iezzi and Dr. Scruggs, I thought this was a great time for you guys to go through, what is available for these practical sides of things, or what can patients actually do?

RAYMOND IEZZI: So this is-- as you said, it's a very exciting time. We're actually able to intervene in several of these conditions. And one of the most exciting studies that I'd like to briefly review now is the NAC Attack trial. Why is it so exciting?

Well, it's an oral medication, N-acetylcysteine, that could potentially have a role for all patients with retinitis pigmentosa, regardless of their genetic subtype. Why is that critical? Well, we know that retinitis pigmentosa happens in 1 in 4,000 patients.

But for an individual that has a specific genetic type, they may be only 1 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.

And 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, we're very excited about the NAC Attack trial. N-acetylcysteine is an oral antioxidant.

It's a medication that's used to break up mucous, 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 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 an entity called rod derived cone viability factor. So when the rods are gone, this rod derived cone viability factor hormone goes away, and the cones can subsequently die.

But the goal here 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 neuroinflammation, which is a very specific form of inflammation, is driven by free radicals.

Hydrogen peroxide is a secondary messenger within the photoreceptors and within the microglia and Mueller glia cells that can become phagocytic, like little Pac-Men eating up the outer retina. We can shut down that type of inflammation by using antioxidants.

So we're very excited that N-acetylcysteine and other antioxidants may have a multidimensional role in slowing down the progression of RP in all comers. So the NAC Attack trial is set up to actually determine if all of this theory actually has value in practice.

Peter Campochiaro at Johns Hopkins did a FIGHT RP study, a phase 1 clinical trial, where he looked at a few groups of patients that were on different doses of N-acetylcysteine, and he found some very interesting things.

He found that with oral dosing of this medication, he could get good levels of the drug in the eye, and he could find good levels of N-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 microperimetry, which is a sensitive form of visual field testing, which we have not seen these kinds of effects before. And so what Dr. Campociaro's group did was then appeal to the National Institute of Health.

And over the course of the last 4 and 1/2 years or so, we've all been working to getting this trial moving and Mayo Clinic, as a site, now currently enrolling in the NAC Attack trial. And I think 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. There are some barriers to entry. It turns out that you have to have a measurement on the OCT of a certain number of photoreceptors before you can enter. 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 save or rescue, then there's nothing that can be measured. And this study happens to be using the OCT test, as opposed to visual acuity and microperimetry as the primary outcome measure. So the OCT has to be within a certain range.

And so for those interested, we're more than happy to do screening on patients that might be interested in NAC Attack trial, but we're all very excited that the retina community has been hopeful for this for many years.

BRITTNI SCRUGGS: All right. I can transition to talking about Uni-Rare. This is the largest natural history study for inherited retinal diseases. It's one of many studies under the consortium for the FFB, the Foundation for Fighting 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 1,500 people who have diagnosed inherited retinal disease 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.

Think of like, Stargardt disease and other clinical trials, like choroideremia and retinitis pigmentosa. But maybe if diagnosis of 1 in 100,000-- maybe those 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'll have really powerful data about the disease state progression, the characterization of the

Disease. And being 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 in the upcoming few months.

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 research. In the United States, there are several trials.

And the x-linked retinitis pigmentosa trial is the one that I think we should highlight here because we're running out of time. And that trial has not yet started so I don't know if-- Dr. Iezzi-- if you want to mention that briefly.

RAYMOND IEZZI: 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 Vista trial is designed to treat RPGR patients. These are patients with this x-linked form of retinitis pigmentosa.

And it involves a subretinal injection of an adenovirus, which can insert the appropriate gene and potentially reverse some of the effects of the RP. This trial has not yet started and is currently in the late phased planning. We've been working with the inventors of this and the companies that have been involved.

Initially, it was a company called AGTC, and now it's Beacon Therapeutics. We've been working with them for several years as they have refined their clinical trial protocol, and we await final notification as to when that's all going to start. But it's an important treatment because this is a very serious form of retinitis pigmentosa.

KAHLEN DARR: 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 Dr. Iezzi 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.

History examination and testing for diagnosis of inherited retinal disease should be systematic and complete, looking at all the pieces and everything put together as a holistic. The management of these conditions requires a team approach.

So as we 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 focus on different areas to be able to help these patients in the best way possible.

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 because I can tell you it is very helpful to the patients. It is very helpful all across the board to have that expectation settings and the understanding on the back end, as well.

And finally, several clinical trials are underway for many inherited retinal diseases, including the phase III NAC Attack for RP. 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 is happening right now.

So with all that being said, thank you all for being here with us. I appreciate your time and being interested in this as we are, and we want to open this up to any questions. If anybody would like to put any questions in the Q&A, we'd be happy to queue those up.

I do have one already here from a Noah. They are asking, would you consider starting treatment on patients less than 18 with retinitis pigmentosa?

RAYMOND IEZZI: I responded to that question in the chat, and I will point out that many gene therapy trials are eager to seek younger patients, even in the pediatric age category. Luxturna, which is a product that we will likely be offering at some point, thanks to Dr. Scruggs' efforts in working with the company.

Luxturna tends to work better in younger patients. And so it's not uncommon to see pediatric patients enrolled in gene therapy trials. Some of the other trials have age limits, and so we just go with those protocols.

BRITTNI SCRUGGS: And I think the point of not recommending treatment outside of a clinical trial is really important. And so even with N-acetylcysteine, that is a supplement that you can get off of the counter at a drugstore. However, the NAC-- the N-acetylcysteine 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 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. And clinical trial enrollment and these studies are done in a controlled environment for a reason.

RAYMOND IEZZI: Dr. Scruggs, that's a fantastic point. Nutraceuticals sold online are not subject to the kinds of pharmaceutical controls that the NAC Attack trial is adhering to. So NAC Attack is providing a pharmaceutical grade product, which is a drug.

Whereas, as you point out, if you were buying N-acetylcysteine on the internet, 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 N-acetylcysteine. And so you don't want to potentially put yourself in harm's way by using something that you really don't know what it is.

KAHLEN DARR: There's another great question in the chat 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 gene therapies that are available?

RAYMOND IEZZI: Dr. Scruggs, do you want to comment on that?

BRITTNI SCRUGGS: 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. This takes a lot of effort.

And we are designing, essentially, handouts that have the up to date 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.

Unfortunately, these trials are always changing. The recruitment and the enrollment is always something that you have to look up. And so clinicaltrials.gov, although not completely perfect, is 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 so you can do your own research on it, and it usually gives the contact information for the primary site so you can contact the coordinator. And I do this commonly. I will go to clinicaltrials.gov, knowing that this is a trial that potentially, my patient would be eligible for, and I will personally contact the coordinator.