Lecture: The Past, Present, and Future of Retinitis Pigmentosa (RP)

The clinical diagnosis of typical RP has been recognized for decades. With the exciting advances in the dynamic field of ocular genetics and new therapies emerging to now treat this disease it is now imperative that ophthalmologists turn the well-recognized phenotype into a genotype by carefully considering the whole patient, their family and the details of their presentation to make a diagnosis of a specific type of RP. In the talk, the speaker will go over the clinical and genetic work-up of these patients as well as the other ocular and systemic findings that such patients may have and how to best lead these patients towards clinical trials and possible treatment. We will discuss the current and emerging therapies to maximize patient outcomes. There is an exciting revolution occurring in inherited retinal diseases. All eye health professionals should be aware of what we currently (and soon will) have available to help these patients.

Lecturer: Dr. Alex Levin, Chief, Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute, Rochester, NY, USA


Dr. Levin: OK, well, welcome to today’s session, and thank you to Orbis for making this webinar possible. This is an opportunity for us to share thoughts on the topic of retinitis pigmentosa. And I know that many of you are sitting there thinking, well, get to the gene therapy, get to the cool stuff, and we will get there, I promise, but there is a path to get there, and there’s a path both figuratively and literally, and that’s a path that is involved in taking care of patients so that we can get to the point where we can make life-altering changes in their vision and in their condition. And in their daily lives, and that’s with where we’re going to go. If we go back in time, we could take ourselves back to the 1800s, the time of Fransiscus Cornelius Donders, who’s credited with the name of retinitis pigmentosa, and actually there were reports as early as 1744 of individuals who described this general condition, but the name was applied, as you can see, retinitis pigmentosa, thinking that it was a pigmentary reaction to inflammation. That’s where the itis of retinitis comes from. In 1858, in 1888. 976 families were described, in 1914 Usher. How many things as Leber named after him. He changed the name to tapeto-retinal degeneration. It wasn’t until 1945 that Karpe showed the retinogram. In 1964, Gours, Carr showed that rods were greater than cones. And in 1981, autosomal dominant and X-linked patterns of dominance could be seen in this condition. In 1988, I was past medical school then, we have Retinitis Pigmentosa, the textbook by John Rheckenlively. As you’re going to see from 1988 to now, there’s been rapid advances and rapid changes. What is RP? Well, if we take the whole sphere of retinal dystrophies, that is, genetically based degenerative disorders of the retina and if we were to include the nongenetically based, a significant percentage of those are RP, and the incidence is about 1 in 4,000. Another percentage of those, and I’m sorry that the circles are not proportionate, are macular dystrophies, about 30 percent of cases. I would include with RP, the photoreceptor dystrophies, we’ll talk about that later, and then there’s about 10% of other things, like the vitreal retinopathy and fever and so on. So here’s question No. 1. You can respond to this according to the instructions. Retinitis pigmentosa is a rod-cone dystrophy, a cone-rod dystrophy, a rod dystrophy, or a cone dystrophy, we’ll give you about 30 seconds and see what you guys are thinking out there. Is retinitis pigmentosa a rod-cone dystrophy, a cone-rod dystrophy, a rod or cone dystrophy, what do you think Well, about 66 percent of you said it was a rod-cone dystrophy. And we’re going to talk about this as we go forward. So rod-cone dystrophy is really the way to characterize retinitis pigmentosa. The rods are affected more than the cones and before the cones, but the cones are eventually affected. It’s a disorder that’s characterized by the first symptom of a loss of night vision. Then comes a loss of peripheral vision, and that’s followed lastly by central visual loss. It’s a slowly progressive disease. I tell my patients it stays, it goes down a level for a while, goes down a little level for a while and actually very rarely takes vision away, as we’ll see. It is also the most commonly misdiagnosed retinal disorder I see. It’s as if, when the people who are general ophthalmologists and not as familiar, they see anything with pigment in the retina, they say it’s retinitis pigmentosa. But of the 30% of patients that I see that come with a misdiagnosis, most have RP. It’s the most commonly misdiagnosed. So we’re going to try and get specific here and answer what is this darn disease? We can look at many pictures. They share in common what they call bone spiculated pigment in the mid periphery of the retina, sometimes extending out a little bit further, sometimes coming out back a little further. In the bottom left we see a more advanced stage of the disease with macular involvement but in other pictures we see the macula is generally spared. The retinal veins are attenuated, and that’s because as the photoreceptors die, the tension in the outer retina increases and there’s a reflex, diminishment of the retinal vascular size. You know, RP is really a thousand different disorders. It’s incredible. If we consider every mutation and every known gene, it really is a thousand different disorders. And put on top of that, every individual with a given mutation is going to respond differently, because we’re not all twins and the genetic background is going to be different. It can be inherited as autosomal dominant, autosomal recessive, X-linked recessive. There’s mitochondrial influence that can characterize, there’s digenic forms where you need two different disease, one mutation in each gene to combine to give you different disease. There’s many different inheritance patterns. Likewise, the age of onset is different, now, the LCA patients of which there’s at least three different genes, they can have a variety of phenotypes. Ranging from those that look like actual retinitis pigmentosa, a picture of which I just showed you, to those that look really different and really aren’t RP but are sometimes lumped in. We have SECORD and ECORD. SECORD being legal blindness before the age of 10, ECORD being functional blindness after the age of 10. Some people talk of juvenile RP but of course it’s the adult one that’s more common, the 1 in 4,000, the typical RP that we’re more familiar with. And RP can be isolated, that is nonsyndromic, no other medical manifestations that are related, and syndromic, the most common being Usher Syndrome where you have hearing loss and vision loss and that is the most common cause of deafblindness in the developed world. And Bardet-Biedl and there are many other syndromic features that can be talked about that can be associated with RP. Now, what RP is not, is the pseudoRPs. That’s when we get pigmentary changes in the retina that can be in the periphery, due to drugs, trauma can cause it, following a retinal detachment, infection, and many others. But these are nonprogressive. They have a different course. They don’t start out with night blindness, go to peripheral vision. These are kind of acute onset or reactive onset, often asymmetric, as well and these are not retinitis pigmentosa. RP has many faces. In general. RP, like most retinal dystrophies is symmetric between the two eyes, however, there are asymmetric and sectoral forms. Some genes have a nasal involvement, monotreme practical. I’ve listed them theory, and as you begin to see, there’s a reason I’m doing it this way. I’m trying to show you that phenotyping is more than for genotyping. We can look more carefully and not lump everything as oh, it’s just RP and begin to dissect out different features, whether it be inheritance pattern, geography, age. These are all things that help us understand what we mean by RP. There’s perivascular sparing forms where the paraarterioles are spared. The macula is generally spared as I showed you in RP, but there are some particular times when the macula is involved. Any form of AB CA4, which is typically associated with Starr-Bard disease. Are associated with the macula. And of course I didn’t list those with the chorioretinal defect in the macula And any disease state can eventually affect the macula. Others are intraretinal space genes. There are some genes where it’s more common than others. So question No. 2, after discussing all of these things, which of the following are important in evaluating a patient with RP? Pedigree? Family history? 2, systemic medical history? 3, refraction? Or 4, all of the above? So when you’re evaluating a person with retinitis pigmentosa, which of these three do you think are necessary to type your RP? To help you help the patient? Let’s let it play out, and the answers are: Well, good. 75% said all of the above, and that’s the correct answer. But we’re going to see why so few of you put refraction, when refraction is really a critical player. OK. So as I said, phenotype, phenotype, phenotype. Then genotype. We have this reflex where we see RP, boom, order a big panel. That’s not the way to do it. You want to consider what’s the age of first symptom. Now, remember that’s not the age of diagnosis, some people go undiagnosed for decades. But if a person has RP when they’re born, X-linked occurs at a later time in life, dominant is later in life. So there are some features that will help you define the patient. Make sure it matches, rod versus cone. You should lose your peripheral night vision first. If your cones are affected, first your central vision goes first, then you’re thinking of macular involvement, even though it still looks like RP. You want to look at intraretinal cystoid spaces. They can occur from cystoid macular edema, leaking of fluid, but more commonly they occur as a breakdown, so to speak, of the retina, not from leaking. If you do a fluoro angiography, these are non-leaking spaces. We want to look at cataract, because that’s another cause for worsening vision. When central vision is getting worse in a patient with RP, why does that happen? Doesn’t happen quickly from a natural history, although it can eventually happen. There’s four reasons why a RP patient will have worsening of vision …: You want to consider the ocular history. Was there trauma or drug exposure that might be causing a pseudoRP? But ask questions, like what other doctors have you seen? What other diagnoses were you given? Have you had any testing and what were the results? Often misinterpreted as we’re going to talk about. When you had your cataract surgery, did it help? Pregnancy is a big syndrome. Just stress in general can bring in those cystoid spaces and pregnancy even without so cystoid spaces. I’ve lectured in rooms where there’s 100 people with RP and you say, how many of you have had weird symptoms like strange colors and weightiness? We don’t actually know the biologic correlate, but those kind of odd symptoms are common and it’s important for you to be able to reassure a patient that those are common. And then you’ve got to get the systemic history. If you ask a patient do you have any medical problems, they say no, you say have you had any medical problems and they say no and you say, did you have any surgery? And oh, yeah, I had an open heart bypass surgery. You have to ask the right questions to get the right answers. What medications are they on and for every medication you should have a reason that you’re taking it and I ask are there any other parts of your body that weren’t formed correctly? You can pick up an extra finger that was removed in childhood. Maybe the patient didn’t even know they had that, the parent didn’t want to let them know growing up, so you have to ask these questions, because these are going to be important in characterizing the RP. So these are some of the things we ask: polydactyly, hearing, I had a patient yesterday who has a retinal and I asked, do you have hearing loss and he said yes, but I was shooting a gun and that’s not a medical condition that’s related to the disease. Kidney problems, obesity, liver, now you’re thinking of ciliopathies, there’s a lot more common reasons for obesity and if there’s a liver problem, is the person a drinker and it’s important to ask them if they drink for reasons that will become apparent. Are there cardiac problems? In particular cardiomyopathy is associated with RP. Ataxia. Position sensors, a form of RP due to a specific gene where patients are unable to button their buttons, and they can’t feel their pulse. Hm, an interesting symptom, how often have you asked that? Have they had a stroke or other neurologic conditions like we might see in one of the myopathies? Have they had cancer, in particular, melanoma, or autoimmune disorder that might mimic RP, cancer-associated or autoimmune-associated retinopathy. See, these questions are helping us narrow down what we’re getting to to get to a diagnosis. When you ask systemic questions and they depression, anxiety, always ask, is that related to your vision, that’s an important question in what help might be useful. How are they doing functionally? Are they still driving? Many patients are still driving, but shouldn’t, depending on where you live, what the laws are in your country. Are they working and why aren’t you working? Is it because of your RP? What accommodations can we get you back working if you want to be working? We don’t just treat the eyeballs, we have to treat the whole patient and the whole family. And that takes us to family history. This is a critical part of understanding what you’re dealing with. You know, family history is really just a story, you’re told a story and you have to ask questions about that story to get the details. Sometimes we have to examine family members, see what the details really are. When a family member said, oh, he has macular degeneration, well, when was he diagnosed? At 40? That’s not age-related macular degeneration, that’s likely a macular dystrophy. Take a three-generation pedigree, that’s the minimum that’s required. You want to ask systemic stuff on every family. You see, it’s not sufficient just to say, is there anybody else in your family that has RP. That doesn’t put it. We need to look for signs and symptoms that are going to help us diagnosis this patient. For example, is there a lot of psychiatric disease in the family? A lot of our mitochondrial signs in the family? And then when we see if there’s segregation in the family. So for example in I have several families in which the patient has deafness and retinitis pigmentosa, but when you ask the family history there’s multiple people that are deaf without the retinitis pigmentosa. So that’s a failure of segregation. two things are likely unrelated. The patient has retinitis pigmentosa incidental to a family history of deafness. The same with polydactyly. You want to know the age that people die. If somebody died in a car accident at 20 then you don’t know if they were going to be affected with the disorder that has an onset of 30 or 40. Was there a history of miscarriages? That’s often a sign of a genetic disorder or a balance translocation in a family where there’s multiple miscarriages. And lastly geography. And ethnicity. How did your parents meet? Oh, my parents grew up in the same village next to each other. What religion? They will to the same church? This is ways of saying do I have a constricted gene pool that might be contributing to the increased likelihood that this is an autosomal recessive disorder, as opposed to a non — two people meet in college in University, it’s unlikely that they’re sharing the same genes as carriers. So although that can occur and anyone can get an autosomal recessive disease, and even if you’re consanguineous in your marriage, these things are helpful in trying to narrow down what you’re dealing with. And then you do a complete exam, and refraction is critical. You know, a patient has a blinding eye disease, if you can help them see better, gosh, you’re going to change their quality of life and I’ve had patients who were high myopes that weren’t corrected because the doctor said oh, you’ve got RP and I correct them and they’re much better. And that’s huge. not to mention Leber mononucleosis strategically not RP, check the pupils. Is there a paradoxical pupil, a pupil that gets bigger in response to light, we see that in advanced conditions. Check the eye movements for ptosis, check carefully the a the slit lamp, look for a posterior subcapsular cataract. And you have to look at them systemically, look for polydactyly, check the hearing, neuro exam, look at the palate, you know, a person can look very much like RP with radio lattice that might be confused with had RP. So you guys still have your license. When you became an ophthalmologist, no one took away your license to examine the rest of the body. You have to do this, or get someone to do it for you, to make sure you’re not missing a key clue that can help you genotype your patient. And then after the exam is done and all this history and family history, we’re going to do some testing to help us understand the state of the patient and to confirm the diagnosis of what I’m looking at and what I think is RP really is RP. Full-felled electroretinogram. Multi-field electroretinogram is important. It may be macular function that’s still present and families who really want to know how am I doing, doc and when the ERG is stable after two or three years, that is reassuring to them, as it should be. I put the G in yellow on the visual field because Goldman visual field is really the gold standard, excuse the pun, is real it is so much better than Humphrey visual field in demonstrating these defects. Here we see an early Goldman visual field in a patient with moderately advanced RP. We see constriction of these isopters in the middle and then we have this peripheral vision that’s going to progress later. Here’s the other eye to a temporal island that’s slowly going away, giving just this central visual field. This is important for driving regulations in some jurisdictions, but it’s also important to monitor patient progression. You always want to do an OCT of the macular, looking for intraretinoid cystoid spaces, but also. D15 or some color vision test to say what’s the cone function left in this patient. And I always take photos, because photos you often see things that are hard to see on exam because the patient’s moving or they can’t tolerate bright lights. Remember, these patients when you shine a bright light in their eye, their recovery time is much slower than others. Here’s some typical pictures when you see the typical RP on the left. The very thin vessels, and notice how in the fundus auto fluorescence on the right, you can also appreciate the arteriole attenuation, we see the blocking, also the blocking, you can see there’s more black there than this is pigment because a lot of it is dead retina in the periphery. And sometimes you see the hyperfluorescent. Sometimes you can be seeing 2020 and have a ring in your macula. Fairly characteristic. There are other tools that we use, but these are more research tools, micro-perimetry, FST, quantitative FAF. These are not routine but they’re very helpful in trying to narrow down the effects from treatment as we go forward with treatment. So let’s move on to that, and which would you say is correct now? Retinitis pigmentosa is untreatable, we’re talking about today. It’s a blinding eye disease. It’s treatable now. Or it will be treatable some day. Very interested in your responses to this question because this is going to tell us where your head is at in terms of RP. What would you say? Untreatable? Blinding? Treatable now, or will be treatable someday? Will be treatable someday, that’s certainly sure for all of RP and it is treatable now in many ways. In fact, I would have put treatable now for all patients with RP and I’m going to show you why. Can we treat this disease? Yes. It depends on what you mean by treatment. There are things that we can do for patients now, and I think this is part of, you know, we have to change the narrative of this disorder. No longer are we going to be saying, sorry, see ya later, nothing we can do. There are things we can do now that are really quite simple. Take for example a person who has RP, who’s got this restricted visual field, 10 degrees of central vision. Well, if you take a small cataract, tiny PSE, a cataract that wouldn’t bother you or bother me, and you put that in the middle of this field, it is devastating. So early cataract surgery can be a huge, huge advancement to these patients. That is if their macula is not involved and they have the potential for good vision. We have to keep in mind, though, that patients that have cataract surgery with RP have a much higher chance of getting CME and sometimes that’s responsive to treatment and sometimes it’s not. And I always tell my patients this risk in advance before I recommend cataract surgery so they’re aware. Sometimes they try one eye and see how that goes before going to the other eye, but if it works, they’re the happiest cataract patients you can imagine. It totally changes their life. If they have — you can treat with carbonic anhydrase inhibitors. And in adults or kids you can add oral can Qam and get an added affect. We have many patients where the symptoms have completely gone away, with visual improvement today. That’s not research, this is today. Some patients that works early and then it starts to wear off and when you stop the medicine they get a paradoxical response and it starts working without the medicine, so we have things that can make life better for these patients. You know, first things first: Before we talk gene therapy and all that, optimize the patient’s vision. Make sure they’ve got the correct glasses on, for goodness sake. Send them to a low-vision doctor if the macula is involved and they have low-vision problems. Now, there aren’t not much we can do for peripheral vision, but some people have found assistive technology, even dog, very helpful for that legal blindness of a constricted visual field, or a cane. Sunglasses we recommend, because you don’t want the extra added burden of the rays from the sun pounding on a sick retina. No smoking whether as’ smoker or second-hand smoke. We may be eye doctors but we got to get our patients to help for smoking because this has been shown it can slow down the progression of the disease. Eating fish two or three times a week has been shown to slow down the progression of the disease, better than the tablet forms of fish oil because those are unregulated and for patients who don’t eat fish, algae tablets have a concentrated version of the substance that helps the retina. And prior to recent research, you don’t go and buy 15,000 IU, big doses of vitamin A, those studies many years ago really were very poorly done. They had some flaws, they weren’t done with genetics, and so we don’t recommend that anymore and in fact, some forms of vitamin A can get worse from taking vitamin A. And treating RP is about employment and depression. Treat the whole patient. Address these issues. Use social work, nursing, other resources in the community to help the patient’s quality of life. There is hope. And yes, in the future, many forms of RP will be treated by ways I’m going to show you, but we have to give hope to these patients. We cannot be taking away hope, because hope is very powerful. Did you know that less than 1 in 1,000 patients actually go blind, completely blind from RP? That’s an incredible figure, and I encourage you to read this book, The Anatomy of Hope. It will give you insight into many patients. We don’t want them in desperation try things that are crazy. We want to help them with their disease. What about treating and actually curing RP? Depends on our goal, right? Are we going to slow down the disease or are we going to stop it cold? And when we talk about reversing, are we talking about reversing the central visual loss? Now, to do gene therapy, we’re taking usually some form of viral vector containing the correct copy of the gene or a CRISPR mechanism to fix a gene or another mechanism to skip or read over a mutation in the gene. You gotta have cells there to take up that virus. So we look at this patient on the left here, this is a typical RP, OCT. We see this residual subfoveal ellipsoid zone without a nuclear layer that tapers out here and here. So this patient has a central visual tunnel visual field, the periphery being lost. But look here, the inner retina is basically sitting on the RPE, that means the inner retina is there and available for treatment. We’re going to talk about that. But if I’m putting a virus under this retina, it can infect these cells and maybe there are some cells that are dormant out here that could respond, but in areas where the cells are dead, like this patient with advanced RP who’s really lost all semblance of an outer nuclear layer, has very few cells left, he’s more than likely going to need a stem cell treatment than a viral vector. But even here in this advanced case, the inner retina is preserved. Now, in 2008, New England Journal, we saw this publication, RPE65, I presented that to you in a former webinar where they took dogs who were blind from Leber congenital amaurosis, and those dogs were running around catching frisbees instead of sitting around a table. But the process had started although it was not perfect. Some of the patients had dramatic improvements, I’m going to show you one here. This patient we’re going to cover his right eye, we’re going to be using the eye that has been treated. And he can barely do anything, right? He’s going to start to walk off here and someone’s going to have to come on and get him reoriented. He just can’t do it, about 10 or 11 years old, we get him back on the course and he walks right off the course. Now what we’re going to do is we’re going to treat him by treating the eye that was not patched in the first trial. Give him a subretinal injection of what’s known as Luxturna and a virus caring the RPE65 gene and we’re going to put him on the same course and see how he does. On the right side we’ll watch him and he does it with flying colors. Look at this. He keeps going. He steps over a step. He avoids another obstacle. I mean it’s really remarkable. And on the left, you can see he’s wandering off the course, right? And there he goes. So that is incredible. I mean, this was approved by the FDA, in January of 2018, for biallelic RPE65, you have to have two variants of the gene on separate copies of the chromosome for kids over 1 years of age. It’s really amazing. And this opened the door for many gene therapies and now there are many other trials involving other LCA genes, retinitis pigmentosa genes, X-linked RP. Some other trials for various different genes, specific genes for specific types of retinitis pigmentosa. thus the reason we went through all of that to get you to a gene diagnosis, right? And in fact some are even specific for certain mutations in certain genes. Usher’s is going to be tackled, lining up for clinical trials, and many, many more. Other options I spoke of are stem cell. We would take a 3mm punch biopsy from the skin and you would convert those skin cells to fibroblasts, from fibroblasts to stem cells. There’s a robot that can pick cells one photoreceptor at a time, put them into a 3D-printed grid one or two photoreceptors per grill and slip that under the retina and those cells can grow to ones that are perfectly healthily in a retina, right? Reconnecting what’s sitting there, waiting to be used. We restore central vision, it will not correct the mid peripheral problems here, but we can get central vision back and this is something that we expect within the next ten years and I tell my patients, for all the genes we expect treatment within the next ten years. And you might not even need to know your gene. Because if you had your onset of RP when you were 30, and you’re now 80, if I put those new cells under your retina, you’re not going to live 30 years for them to become sick. We need to do the gene fix part. The other approach to treating this disease are gene-agnostic approaches. For example, the reason this is a rod-cone dystrophy is the rods secrete a cone viability factor and as the rods die, that viability factor is no longer made, right? And that’s what keeps them alive. What if we use gene therapy or stem cell therapy generically to deliver rod code viability factor, to at least keep the center from getting worse? And that’s going on right now. We have a study we’re about to start here using disulfiram, Antabuse, that’s the drug used to treat alcoholism. Well, that drug as it turns out inhibits a process that occurs when the photoreceptors die and retinoic acid is released in abundant amounts. That causes the inner retina, although it’s anatomically normal, to become kind of scrambled in its ability to transmit messages and we’re hoping by giving Antabuse to patients, even patients who are not alcoholics, that we can unscrambled the retina and at least get the residual cells to transmit more through the retina. Ophthogenetics trials are going on around the world. In fact, if you go on this website, clinicaltrials.gov, there are 241 studies ongoing. Some interventional. Some are interventional, some are testing — cannabis, all kinds of things. And then we have the bionic chips. I thought I would include that, the idea of putting a chip on or under the retina, the Argus II device approved by the FDA in the United States. It doesn’t really do much, it gets a patient from total blindness to kind of light perception with projection. This is a device where the patient wears glass, the video and and sends it to the eye. And if you ask the patients they’re only turning it on about 20% of the time, it’s not really that useful. There is something in Germany with some more functional vision for that. We also see advances in low-vision aids that will help these patients as well. So you say, let’s start ordering gene tests, right because if we can get, if we can start from the very beginning of this talk, we went from phenotype, to genotype. That it lead us to specific treatment which may not be necessary as I’ve shown you, more treatments are coming down the pike. So let me ask you, the best gene test for a patient with RP is: Large panel, whole exome sequencing, phenotype based gene hypothesis or microarray? What do you think it is? And the answer is phenotype based gene hypothesis. That’s good, you’re listening, that’s where I’m going and I’m going to show you why that is. So it’s not just a gene test, right? You’ve got to get the right gene test first, you have to examine family members, define pheno subtypes as I’ve told you. Who’s going to pay for it? And then you’ve got to interpret the results. Is it polymorphism or mutation? Does it segregate the family? And you need to do pre- and post-test … The key is narrowing your hypothesis. Sometimes we order just one mutation in one gene or just one gene in a patient. And that’s going to be based on, is the macula involved? I gave you some options. What inheritance pattern am I expecting? Is there systemic? Does ethnicity help? An Ashkenazi Jew, the MAC gene, you’ve got a high possibility of getting that with one test. Anal of onset? All of these things are you say, oh, they’re free, right? Well, you get what you pay for with a cheap test. The bigger the test you order, the higher the false genome rate, the more noise you get, the more stuff that’s hard to sort out and then you’re spending more money, time, and effort and you’re not helping the patient. That’s why narrowing the gene hypothesis will get us to a treatment soon. Why do we bother with all this? Well, if you get a gene, you get a patient diagnosis, sometimes you can look at a gene mutation and say patient with this gene are going to be driving or not driving. You give them the correct counseling. You give them the power, and the support and the information that comes from this. And it gets us to the cause of the RP and eventually to a cure. In addition to all those generic things we can do, now the more specific things. And every patient I see gets a when we get a gene diagnosis gets a clinical trial search for what’s available for them. We’re not saying he’s going to go blind, see ya later, we don’t do that anymore. We don’t say nothing we can do, see ya later. We don’t say, I don’t know what it is. If I see a patient that looks like this, a 12-year-old with RP, a 20-year-old, a 40-year-old, I say you’re going to be cured. In fact, I say I can do some things now for you. Patients are so used to being told there’s nothing we can do. I change the narrative I say I can do these things for you now. What? Cataract surgery, carbonic anhydrase inhibitors. I can tell you what you can do. I can tell you what clinical trials you can enroll in. Times are changing right? It’s not just RP. These are specific disorders that your phenotyping will get to help the patient by recognizing the unique nature of their condition and unique nature of each patient and that’s the way we can treat them. So I’m going to stop here as instructed. We’re at 45 minutes. I have chats in the chatbox, I’m going to go through some of those, and I’m going to go through some other questions, but if you put your questions in, I can go through. The first question is can snow syndrome and blue field in RP be cured? I think what you’re asking is visual snow. Visual snow actually is more common in RP and these other weird symptoms. Visual snow is a very, very tough thing. Many drugs have been tried, most times without success. I often refer to a neuroophthalmologist, and this kind of green vision or red vision or wavy vision, these are odd symptoms and there’s no specific treatment for those unfortunately. They tend to get better with time, sometimes, patients get used them with time. But those are frustrating injections. What self-protein injection is suitable? I’m not sure what that is referring. You can see those in Leber congenital amaurosis early on and that would change your diagnosis. Let’s see, what is the cause of … I covered that. Lets let me just keep going here. We talked about measures to slow down progression. Had genetic testing, we covered that, do you recommend yellow-tinted glasses? So I think there’s very little to this whole blue light filter. I mean there is some evidence that blue light is important for your circadian rhythm and your sleep cycles, but outside of that, the real tint that patients need is photophobia when it occurs with RP, the Corning filters, the 527, 530, 511 range, that yellow to rose color tend to be most helpful in helping patients symptomatically. Really I tell any patients unless you’re really photophobic any sunglass will help. So let’s keep going down here. Is gene therapy unilateral or bilateral? That’s a great question and the answer is tricky. You know, if you’re a patient who’s got RP in both eyes, like when we take the Luxturna experience, it was a unilateral treatment at first. Of course the company has a financial incentive, they want it to be bilateral, because goes from $475 per patient to double that. But it turns out that patients really found that they wanted the second eye, and they do better with the second eye treated and there’s much data to show that and therefore it has been considered, although not mandatory bilateral treatment, patients seem to like having both eyes done better than than you might expect otherwise from one eye alone. How often do you recommend follow-up for RP and what to look for? So I tell my patients, so I’m an ocular geneticist in large and I tend to tell patients to have a checkup yearly, they check in with me every two years to see how they’re doing. I repeat those tests, because as clinical trials are coming up, I want to make sure they’re like in the starting gate ready to go with all of that data already collected. But otherwise, I think an OCT annually, fundus auto fluorescence annually, are the — and pictures annually are the best things to assess, to tell the patient how are you doing. In most patients you’re going to say hey, not much change and that’s really reassuring to them and really helpful. We can change that narrative So how do we treat in the developing countries? I was hoping someone would ask that. I talked about this before in an earlier webinar, can you it look for on the cybersight.org website. Everything I talked about except for gene therapy is available in almost every country. Gene therapy, we have to figure out a way, and in my work with doctor stone in Iowa, we’ve been, working, we can do Luxturna, $820,000, we can do it with 20,000. Philanthropy can support bringing gene therapy for tree to developing countries, something we’re working on right now and we hope to bring in the future. As far as how long do I continue topical and oral carbonic inhibitors. We’re really good at knowing when to start. We’re not very good at knowing when to stop and I see these patients every three months. They get an OCT and visual acuity and I ask them three questions. What do you think the vision is: Better worse or the same? I measure their vision, better worse or the same. I look at their quantitative retinal thickness on OCT and the qualitative appearance of their cysts. Now, those four things on their own are not related to each other. But if I see any sign that the patient is getting better or not getting worse, I continue with those treatments. And I continue with those treatments until they stop getting better, or more importantly, until they’re getting worse, at which time the first thing I do is stop the oral, then stop the drops. Looking for that paradoxical response to see if they’ll paradoxically get better. Otherwise, I keep them going as long as the patient is having no side effects. The oral is 50% of the oral treatment. Patients who still get side effects, I’ll switch them over to methazolamide, you can sometimes get a response with that, as well. I would use topical and oral if needed. Sometimes it doesn’t work as well as it does before cataract surgery, but it’s always worth a try. It cannot hurt to try it. Can micropulse laser therapy help treat RP? I’m not aware of any evidence that micropulse laser helps RP. In fact, I’m not aware of any trials of laser treatment in RP at this time. There’s a question I have a patient with enhanced S cone syndrome, wanted to know any recent updates. Well, the gene which causes that disorder, we now know how that gene works in the pathway of cone and rod differentiation, there are some gene therapies in the works to it treat those patients in the future, I think we’re going to see treatment for that disease within the next ten years. Hold on, there’s a question here … One second. I skipped over something. Here it is. So there’s a couple questions about slowing down juvenile RP, and really everything that I said about regular RP, adult RP a is the same for juvenile RP. Obviously it would be better to treat patients soon. We have a gene therapy trial that we’re going to start soon with the MAC gene in which case we’re going to try to treat patients before they get signs of the disease. Now, there are some risks there, right? Before you get symptoms or do you wait to the symptoms and that’s something that we’re getting good enough, fortunately to have to think about that, but only the future will tell. Is RPE65 gene therapy a single shot? So far it has proved to be a single shot. The effect has been lasting in the eyes. There’s one paper that shows otherwise, but almost all papers are showing that the effect is persistent, which is very encouraging, we hope with all of these gene therapies, but heck, if it’s not, you give another injection. And some of these may be treated by intra — I think subretinal is going to be the way to go, and doing that more than once is a little bit more tricky, but it can be done. What foods should be avoided? There’s no foods that I know of that should be avoided, other than supplemental vitamin A. And there’s a great question here, what if you have limitations in ordering a gene test? In some countries, gene testing is not available, not affordable, those are cases — and there’s an editorial that our team wrote in the Oman Journal of Ophthalmology that talks about what do you do if you don’t have those resources. It should be coming out in the next couple of months. Well, you have cybersight.org where you can ask questions and they’ll be answered often within 24 hours and there will be helpful in the phenotyping. Sometimes if you have really got phenotyping, No. 2, we all have partners and colleagues, especially in research labs that may be able to help get free genetic testing available. No. 3, consult. Use your molecular, your clinical nonophthalmic genetics, I’m working with one country now where we’re trying to use their clinical genetic service to work as ocular genetics fill-ins by teaching them how do it. So it’s kind of like phone a friend by using your colleagues and friends, you can get answers and hopefully by phenotyping really, really well, that genotyping may be less necessary. In rural south India we see a high incident of neonatal deaths. In RP does that have any significance? Well, the question is, are those deaths occurring in the patients with RP or without RP? If they’re occurring in patients with RP, that has a huge significance, that lets us think that those things are segregating together and we have to think of what disorders systemic might be associated with RP. You can get RP changes in the mucopolysaccharidoses, so we have to think about things jax cardiomyopathy causing sudden death, maybe they’re going to get it, but if the deaths are in the siblings without RP, then those two things are not segregating together, and they’re unrelated in the family. But of course, certainly worth pursuing for the purpose of helping these people: There’s a question about new technology for low-vision patients with RP. There is a lot of incredible stuff going on. There is tongue vision, you can look up tongue vision on Google. Your tongue is incredibly rich in neural receptors. And you can teach your tongue, with a little thing, kind of like a pad that goes on the tongue, to read visual stimuli. That’s a form. There’s now a like a bat — a sonar device that patients withhold in the palm of their hand instead of a white cane, to help navigate. That are devices where a person can wear an ear phone with glasses and the glasses is connected to a live person on board who can tell the patient what’s in front of them. Technology is taking us really, really, really far in treating low vision that can help the quality of life in these patients, and I see that question is coming from my friend Niko Ye in Guatemala, hello, Niko, I’ll see you soon. I think next we’re talking about the intraretinal spaces in retinoschisis, that there is no role in any of the disorders I’ve discussed today. That isn’t going to represent RP, or intraretinoid spaces, because they’re not leaking from — which is what anti-VEGFs are designed to treat. A couple more questions as we’re going overtime. Is there a clinical in — there are a clinical trial for two genes that are involved in that disorder, another one that’s developing, it’s going to be here, as well, and one more question, I think that’s it. And we’re at the top of the hour, so I’m going to say thank you to all of you. It’s been a great pleasure. I forgot to put my email address out there. I’m going to put it in the chatbox so you have it, so you can feel free to give me an email if you’d like, if you have any questions further. Feel free to email but feel free to use Cybersight. You can get information on any topic in ophthalmology and we’d be happy to help you. Take care, have a great day, with pleasure, be well.

Last Updated: February 23, 2023

7 thoughts on “Lecture: The Past, Present, and Future of Retinitis Pigmentosa (RP)”

  1. Awesome good news. I was at work in the theatre so I missed it, but listened today and was thrilled. When teaching I can include clinical trials and new developments in RP thanks so much!


Leave a Comment