Lecture: Past, Present, and Future: Treatment of Inherited Retinal Diseases (IRDs)

In this highly interactive webinar, we will review the history of gene therapy including its past and present successes and challenges. With this historical perspective in mind, we will then describe the ever-expanding field of genomics and genetic testing related to inherited retinal diseases (IRDs). The webinar will stress the importance of clinical judgment, patient-centered care, and the critical role of a genetic counselor. We will end the webinar by detailing current, approved gene therapies and their impact on patient outcomes, while looking ahead in the not-so-distant future to new treatments.

Lecturer: Dr. Alex V. Levin, Ophthalmologist, University of Rochester Medical Center, USA

Funded by an unrestricted educational grant from Janssen.


Hello, everyone. So nice to see you. Let me share my screen with you. It’s a pleasure to be here. I want to thank Orbis Cybersight for the opportunity. We’re going to be talking today about past, present and future. Where are we with treatment of inherited retinal disorders?

In particular, we’re going to have a pretest first, and then we’re going to go through the plan. So here’s question number one. What is required to do gene therapy? Is it a genetic diagnosis, a delivery mechanism, a target, or all of the above? And we’ll get some audience feedback. There we go. strong preference for all of the above. And the next question is, all the following retinal disorders currently have clinical trials for gene therapy, except which one? RPE 65, clinical trials rpgr, PDE6B or CLN5? Which one does not have a current clinical trial for gene therapy? Little tricky question. Okay, CLN5, we see does not. Let’s keep going to the next one. Concerns about gene therapy include all the following except ?off target effects, efficacy, surgical ability, or incorrect diagnosis, which one of these is not really a current concern. And we’ve got a slight leader in surgical ability. Well, very good.

So thank you for joining us. We’ll get started. As I said, I’m Alex Levin. I am the Chief of clinical genetics and the chief of Ocular genetics here at the University of Rochester in New York. And happy to be here. Thank you from all around the world, to everyone who’s joined us. In today’s talk, we’re going to focus on the history and current status of gene therapy for inherited retinal disorders, and gene therapy in general, and how to get there. How to get to gene therapy, how to get to treatment for these disorders. We’ll talk a bit about phenotyping clinical characterization, genotyping, genetic testing, the importance of genetic counseling, and clinical trials. And where are we headed? Where is this field taking us where we going? And then we’ll have a q&a at the end. I’ll go for about 45 minutes. And at the end, we’ll have our question answer. And I’ll be happy to answer whatever you can put your questions in the chat. That’s something in advance. So we’ll have an open dialogue.

Well, believe it or not, most people don’t believe it. It was 60 years ago, almost 60 years ago, 55 years, that the first gene therapy was attempted. This was not for an eye disease. It was for systemic disease, arginase deficiency, where a guy named Rogers and his team used a shope papilloma virus to infect the patient, hoping to correct their arginase deficiency. But sadly, that failed. But it’s really amazing that it was so long ago, that we realized that viral vectors were capable of delivering material to human cells.

In 1972, as this was all emerging, there came a call for some ethical standards, there was concern about the ethics of all this. And in 1980, there was a trial, Thalassemia, two trials without institutional review board, without ethics board approval. This was an ex vivo, that is they took cells out of the patient, and viral infected them hoping to deliver the DNA. And that really raised some concerns and lead to a President’s Commission in the United States for the study of ethical problems in medicine and biomedical and behavioral research, called Splicing Life, a report on the social and ethical issues of genetic engineering. So early on, we see the 1960s when technology was really changing medicine, things were going a little bit too fast. There was this concern about the ethics of all this and the need for some oversight and some regulation. This report really dealt with stem cell that is, I am sorry, germ cell, that is cells which correct all the cells in your body, gene therapy versus somatic or tumor type of correction.

In 1999, Jesse Gelsinger was a patient at the University of Pennsylvania, he had ornithine TransCarbamylase deficiency. He was treated with an adenovirus vector to correct this and four days after his gene therapy, he died due to cytokine storm. And this really, really changed the landscape of gene therapy. And in fact, in 2000, the FDA, Federal Drug Administration, United States issued a moratorium saying we got to stop this, we got to like, whoa, we got to step back. And really think about what we’re doing here. And this was due to off target effects. Right. So we didn’t expect the cytokine storm, the reaction to the virus as it spread through the system, and this patient died.

Nonetheless, a trial that had started in 1999, two trials actually, for severe combined immune deficiency syndrome, five of 20 patients wound up with T cell leukemia of whom die, another off target effect of an oncogene. So here we have the situation, right, we’re taking gene therapy, where we take a virus that normally causes the common cold adenovirus, it gets in your nose and infects the respiratory epithelium in your nose, it delivers its contents, it takes over those cells, and causes the symptoms of the common cold. In these situations of gene therapy, we remove the guts of the cell that cause the common cold, and instead put in, what we’re trying to deliver. And we then infect a tissue either ex vivo outside the body or enVivo, where we are delivering it directly to the patient. And we hope that it affects only those cells, and it delivers the treatment that we need. That’s a phone that has never run ever in my history in this office.

Anyway, meanwhile, what’s happening? We’re finding that there’s all these effects, these concerns, these ethical concerns, so on and so forth. Meanwhile, things are kind of marching ahead. In the year 2000. In China, intratumoral gene therapy, two agents, gendicine and Oncorine, are approved, this becomes the first governmentally approved study anywhere in the world, to have an approved gene therapy.

While these concerns are being generated in United States, in 2000, Cerepro was approved in Europe. And sure enough, that goes on to be withdrawn from the market in 2010. The feeling being that the studies were inadequate to show an effect. So we have these competing interests, we have the basic concept, take a virus that is known, take out its guts, put in what you want to deliver, we can do it. In fact, that’s been approved now in three countries. But meanwhile, the US is saying well, we’ve got some ethical concerns.

In fact, since the 1990s, there’s been almost 2000 trials of gene therapy. And what’s happened in the last 20 years, is we’ve developed TALENS and CRISPR/cas9, which is not only the idea of delivering a new gene, it’s the idea of gene repair, some way of fixing or altering the expression of a gene that’s present. So it’s actually openes up our toolbox to do more. And we began to recognize the ethical concerns. So that bringing this all together full circle, along comes the eye.

And the eye is a unique place because we could do all these things from eyedrops gene therapy, to intravitreal, to subretinal, to super choroidal to even putting an implant in the eye, which could continually deliver or other nanoparticles, whatever, so that we can continue to deliver the virus with its contents to do gene therapy. So now we’ve got experience, tools, and it’s actually not the surgery that’s the problem. All of these techniques, if you have the right tools can really be done fairly easily, with all due respect to our retinal colleagues.

The eye also offered us the ability to have an organ, which had immune privilege, unlike the treatment that was done on Jesse Gelsinger. Things that are injected in the eye should pretty much stay in the eye and not be recognized by the rest of the body. The accessibility was a big issue, and we can see what we’re doing. The eyes the only place in the body where we can see live cells live neurons. So we’ve taken all this past experience, and we can apply it to an organ. Jessie Gelsinger’s was a liver problem, you can’t see the liver. So some of the ethical concerns get diluted out with our advantages that the eye brings us.

It’s no surprise we’ve been doing topical gene therapy for over 20 years. The use of prostaglandin analog eyedrops is really a gene therapy, because these drops changed the transcription of what’s called Metalloproteinase genes in the eye through an eyedrop. So this is actually a form of gene therapy that we’ve been doing all along. It’s not as fancy as it may seem, as taking a virus and changing it. And really, we should ask the question, you know, what is gene therapy, which we’ll get to.

More recently in 2008, in New England Journal of Medicine was the RP 65 clinical trial, where they reported subretinal injections in three young adults from the UK, and three young adults from Philadelphia. There was no improvement in the United Kingdom patients who had biallelic mutations in each copy of their RP 65 gene, which causes labor congenital amaurosis type two. In Philadelphia, one patient had a macular hole. So larger volumes of injection. Were just learning the technique. They had some slight vision and visual field improvement, and one had a change in function. So this was really the start of a more invasive gene therapy approach in the eye.

In 2009, in Lancet, they reported 12 patients ranged eight to 44 years of age, four children that were done in Philadelfia in Italy, they did the worst eye in each patient, they used the sub retinal viral vector carrying a new RP 65 Gene, to the retina. And in 2009, we see this report with one fovea hole, all say their vision got better. Actually, seven had better view visual acuity one was worse, four the same, didn’t correlate with age, the author said all the visual fields are better, but not really. And none of the ERGs changed. And follow up over time, they were stable. Not the most impressive three papers, right. But there were some really dramatic improvements on the obstacle course in dim illumination, these patients made a big difference. So let me show you what we’re talking about.

So here’s a video, and we’re gonna watch a boy, he’s got one eye cover, that’s the untreated eye, he’s got one eye that he’s using, he’s basically hand motion count fingers vision, we’re going to inject a virus under his retina, carries a normal copy of his RP 65 Gene, because both copies of his gene are abnormal. All he needs is a new gene to start making some protein to essentially convert him from a disease to a carrier. Just a few weeks after surgery, we’re going to look at them. So here’s before surgery, we’re asking him to navigate this, this obstacle course. And you’re going to see as he goes, he’s going to start going, and he’s really tentative. He’s got using the one eye we’re going to treat, he can barely do the course, he goes forward a little bit, then he’s going to get lost. He just can’t do it. We’re going to come in, this is research done at University of Pennsylvania. He’s going to go forward, and we’re gonna see that, redirecting him he walks right off the course. So now let’s treat him. A few weeks later, he’s treated few weeks after the surgery, we’re going to look at the right side of your screen. I’m going to see what he can do. Watch the right side of the screen. And it’s amazing. He can immediately do this course, he sees a step he steps up, goes forward, he’s going to step over an obstacle. He’s going to keep going. The same kid who’s on your left he could see still struggling and goes out the door at the end? Well, that’s amazing, right? And in 2017, nearly 50 years after the original gene therapy, it was done by Rogers.We approved the first FDA gene therapy for patients who have biallelic RPE 65, who are one year or older for this treatment.

So what is this gene therapy, we’ve just covered 60 years of gene therapy, but it’s really a lot of different things. And Gene therapy can mean replacing a protein. So if your gene makes a protein and we just replaced that protein, that’s a form of gene therapy. We can upregulate good genes, downregulate bad genes, we can replace a gene like we did with the RPE65. Or we can change or replace the gene function, but we can fix genes CRISPR/ cas9, that kind of thing.

For regulation control, think about apoptosis, apoptosis the death of programmed death of cells, a genetic event. If we upgrade related genes, BCL2, or BCL X, that’s going to encourage the prohibition of apoptosis. Or if we downregulate pro apoptonic genes like P53 and Bax, will resist apoptosis. NR2E3 is a gene in the retina that promotes cones over rods, when you have disease, NR2E3, you will get more rods differentiation than cones. So if you have rod diverse disease, we can manipulate this right? These are ways that we can change the gene regulation that’s so important for our body function.

Gene therapy is going to be something different for every inheritance pattern, like RPE65 disease, all you have to do is give new gene function because you have no working gene, both copies of your gene in autosomal recessive disorder aren’t working. In autosomal dominant disease, you’ve got one working copy of the gene, one nonworking copy of the gene, your haploinsufficient. So you have to increase the production. So that you can get a full complements work that’s a little trickier, or some disease you are dominant negative where you have one working one not working. But working copy makes a protein that interferes with the residual protein from the not working side. So if you could block that protein from being made, you will be fine. So again, the mechanism by which it occurs, is going to be important for deciding how to treat.

So not only we have to think about what we’re trying to do here in terms of gene therapy, what kind of manipulation, we have to think of some things need to be happen. So we’re gonna have to understand the genetics of the disease, number one, can’t do gene therapy, unless you know the genetics and the disease. You’re going have to have a treatment that’s efficient, and non toxic. You can’t make the person more sick by your therapy, like what hapenned to Jesse Calsigner. You have to control gene expression, you don’t want to overexpress a gene, at the same time you want the gene to express only where you want it to be expressed. Some diseases, let’s take axenfeld-rieger syndrome, right, if you have a mutation in the gene that downregulates or upregulates, you’re still going to get the disease. So you have to figure out what do I want to do here to control the gene expression, having an animal model is very helpful, because then you can test them in advance, as we’ll see. And you need a method of delivery, viruses can deliver genes. But some viruses like the AAV virus can’t take big genes. So we have to look at other viral models like lenti virus and other viruses that can carry bigger genes or look at other ways to do it. Or you can have small particles, liposomes and other things that you put in the eye to allow transfection, not using a virus. And of course, you need to have cells that you can transfect, putting gene therapy in where there’s no cells to take up the gene is not going to be helpful.

So let’s look at a patient with RPE 65. This is from the literature. And we see this patient. And what you can see on his OC T is look at this. He’s got all of this outer nuclear layer. These are great cells. He’s got all of this ellipsoid zone. So his rods and cones are sitting there, they just don’t work. This is the perfect disease, for gene therapy, because all the cells are sitting there waiting to get the virus. Well, let’s take that, as opposed to this patient who’s got another form of retinitis pigmentosa. What we see here is from this point at the edge, there’s basically no outer nuclear layer, very little outer nuclear layer and no ellipsoid zone. This patient is not gonna get a lot better outside of his fovea, we think because the dormant cells and cells are not working or low in number. In fact compare that to this patient who’s got an atrophic lesion in his macula from an ABCA4 mutation. This will get infected out here. But there’s no cells to infect in the atrophic area and this patient at all, who’s completely wiped out. This is actually his inner nuclear layer laying on the retina there on what was the outer layers of the retina which are gone. He’s got maybe a couple of little photoreceptors. So doing gene therapy and expecting a cell to recover when the cell isdead, you can’t revive the dead, you might be able to revive the dormant, but not the dead atrophic. So this gets us to our expectations.

The other thing that has to be considered is is targeting and should not only have the cell, but lo and behold this, the I may be isolated. But if we look at this article from the literature, we can see that if you give the gene intravitreally, subretinally, or superchordially, you do get some expression. Here we go, if you look, the third one down, this is egress into the circulation, you do get the gene therapy in the circulation. So, it’s not 100% Slam Dunk, that’s going to stay in the eye. And we have to consider these off target effects. Easy to do the surgery, that’s not our concern. Our concern is what happens afterwards. Not to mention the fact that different viruses infect the retina differently. So it depends on which virus, some viruses like AAV9 can go through the whole retina, they may be better for intravitreal injection, as opposed to AAV2, which won’t go through the whole retina. So different viruses, in different diseases, with different routes of delivery, have different exposure to the immune system, different targeting, and perhaps different longevity. So it gets a little bit more complicated in the science.

So what do we expect from gene therapy? Well, will it slow the progression? For Sure, if we can get gene therapy into the residual cells, we should stop progression. Will it restore function? Well, it did an RPE 65 in some patients, not all patients, because the cells were there, right? They were just turned on again. You needed in a retina as well. So you put your outer retina, you correct the gene therapy, the inner retina still has to be okay. We’ll see how that comes up later on. Will itrestore vision? Well, it may restore that central area. And how much will it restore? In RPE 65, some patients get better, some patients don’t. Will it restore the visual field? While you’re giving an injection under the fovea in the macula, you’re not doing a peripheral injection, at least not yet. Will it restore the ERG? It didn’t do that for RPE65, who cares? You don’t decide whether someone can drive or not based on their ERG, It’s based on your vision. So we have to modulate our expectations for gene therapy.

And now there’s many other trials going on. If we take a look at some of these, we’ll see how these have different ways of getting to the problem. SEP290 trial done out of Boston in this year. They took one specific mutation, one specific mutation, they mask that mutation with a silencing kind of RNA. So you can skip over the mutation essentially, and have normal reading frame. And that’s been done in some patients with that specific disease. For retinitis pigmentosa, it’s going to be a little harder, USH2A for example, the most common cause of Usher syndrome. And the second most common mutated gene, the retina is too big for the virus. So the current work is trying to break the gene into two, deliver two separate viruses, each with half the gene that would reunite in the cells in the retina. XLRP has two studies, one by Janssen one by AGTC. These are studies to try and fix that genetic disorder severe form of retinitis pigmentosa, X linked recessive RP, RPGR Is the gene.

Choroideremia and Juvenile X-linked retinoschisis were disappointing gene therapies. Choroideremia was an injection under the small residual area of central macula. Juvenile retinoschisis was an individual injection. Why were they disappointing? Maybe in Choroideremia, just that you got too small of a retina piece that you’re detaching with your gene therapy fluid. Maybe we just don’t understand the mechanism of that disease. Well, we really don’t know. Is it the choroid is getting sick. Is it the retina getting sick, we don’t know that mechanism of that disease well enough. The next step is to try a suprachoroial injection maybe that’ll be more helpful. But we just don’t know enough. And in JXLR, the problem was inflammation and injection into the vitreous because you have to get through the whole retina to treat that disorder. Inflammation was a problem. So these are challenges that we have to face, we have to face the challenge of something like SEP290, while you’re treating one mutation, the challenge of the two big gene, the challenge of residual random mechanisms of disease, understanding the challenge of inflammation, and there’s many more trials underway.

Stargardt disease has also a big gene, does it fit in any virus, but there are gene based treatments that people are trialing. But another way to affect that disease may be just to remove the excess, lipo fusion that’s been formed under the retina, the deposits as the flex we know, maybe if we could clean that out, it will help or discourage it’s, continually to remove various drugs therapies which are trialed. That’s another way to try and get it the disease, it still have the disease that is the gene. But we can modulate the after effects of the gene variant that’s causing the pathology.

Neuronal ceroid lipofuscinoses is a terrible disease, children go blind and die. We’re currently one of two sites involved in a CLN5 treatments study, where we’re giving this viral vector into the vitreous and into the brain, into the intraventricular region to try and treat both aspects of the disease. Two patients have been injected. CLN3, we’re starting a study where we’re going to inject it subretinally but not in the brain. So therefore, at least the kids won’t get blindness before they die, increase their quality of life. And you can see that becomes to be an ethical concern, right? If the kids still going to die, why use the resources to just treat the retina. And here we hear these are our clinical concerns or ethical concerns coming back from as early as the 1970s when that first call for ethical consideration was made.

Achromatopsia is another gene therapy. I’ll show you this video. We’re going to do sheep here. This is a sheep that has achromatopsia, and you can see he just stuck in his pan, he doesn’t know where to go. And then we’re going to inject him, the same anterior subretinal injection, and he carries out and navigates perfectly fine. So what we can see is, gene therapy can be effective. We saw in RPE65. We see in animal models, but we’re not sheep, right? we are not dogs. Although RPE65 started with a dog model and made its way to humans, there’s no guarantee that any other study is going to translate into humans, not to mention the other considerations we have about targeting, off target effects. So on, we just don’t know. But these therapies are all in development. And we just have to keep doing the research to bring these to the fore.

Another way of doing gene therapy would be, what’s called gene agnostic therapy. That means you don’t have to know the gene mutation. You’re not treating the gene specifically, right. So in SEP290, you have to know exactly what mutation having the gene, but in retinitis pigmentosa, which is largely a death of rods, rods make something called rod derived cone viability factor. That’s why they keep their excellent vision in that central tunnel. As the rods die, cone viability factor is being lost because made by those rods. What if there was another way to create a source of this factor and prevent the central retina from dying? You’re not going to cure the disease, right? But what you’ll do is you’ll prevent the further progression. And there’s a trial being developed by a company from France, looking at three forms of RP, rhodopsin, PDE6B and PDE6A, a recessive disorder for two of them and autosomal dominant for the other. They’ve picked these two diseases, not because you’re treating the disease, but you’re treating the byproduct of generic retinitis pigmentosa, theoretically you could treat any form of retinas pigmentosa. We talked about anti apoptosis or retinal rescue. And another form of gene therapy is optogenetics, where you would deliver a protein which is photosensitive to cells in the retina, which are usually not photosensitive, like the ganglion cell layer, and turn them into photon detecting cells and hopefully creates a vision. And there’s been some work done on this, particularly in India, where there’s been some success. There’s many companies looking at this approach. The problem with this approach is that you’re sure you’re invading the inner retina. And that’s a risk. Because if you eventually want to cure the disease, as opposed to replace the function of the dead photoreceptors, and treat the outer retina, where the photoreceptors lie, and you’ve ruined or sickened your inner retina by an optogenetic treatment, will it still transmit the messages from the restoring photoreceptors, this is a concern.

And then we can get back to those original studies where we could do gene therapy ex vivo. And this is a system where you would take stem cells, you create stem cells from the patient, take a three millimeter skin punch biopsy from their arm, convert the fibroblasts to stem cells, then convert the stem cells to photo receptors, use CRISPR/cas9 to correct the gene defect, and re implant those cells. So here’s the robot that can pick out individual cells from culture. This is at the University of Iowa, you could put those cells into a 3d printed grid, so they have the right polarity up and down. And you can place them under the retina, 500,000 cells, slide that grid and let those cells reconnect. And there’s been shown some affect in retinal models. And why not do that, in patients, for example, with those atrophic lesions, or other lesions where there’s only a few cells left, in other words, you’ve lost your target, give new cells instead. And you may not even need the gene therapy part. Because if you’ve got a disease that has an onset, when you’re 60, or 50, or 40, and you’re already 80 years old, maybe it just gives them brand new retinal cells without even correcting the gene. Because when you’re 60, you’re gonna be lucky if you live another 40 years before you start that symptoms. So you may not even have to do the gene therapy. Or you could do this agnostically. And people are trying this now, give stem cells to deliver, for example, cone viability factor without worrying about the gene defect itself, maybe even intravitreally.

So a lot of lot of options here, we’ve gone a long long, long way, from the beginning, we’re just learning in the 60s, through the 90s, when many trials are been underway to the 2017 gene therapy approval for RPE 65, no longer a clinical trial, that is now a clinically approved treatment being given all over the world at designated centers, to the future, which is the increasing approaches to varying different ocular genetic diseases, very different inherited retinal dystrophies. through varying means. We can even dream really big. If you consider Aniridia, which is due to PAX6 gene mutation. While the PAX6 gene is in every cell in your body, it’s just only used in your eye. If you turn the PAX6 gene on, where it’s not usually used in the antenna of a fly, it grows a new eye, or on its wing, it grows new eye, pretty good looking eye, maybe someday we’ll even be able to gene therapy, gene engineer a new eyeball. So this is all exciting, right? It’s really great.

We’ve come a long way in 60 years, we’ve started to deal with some of the ethical concerns, which we’ll get back to. But it’s exciting. But there’s a problem. questions still remain? When do we treat? Is it better to treat earlier or later? Should we put a subretinal injection under the retina of a 20/20 person who has yet to experience any symptoms from their disease but will eventually, that’s an ethical dilemma to take that surgical risk. Does treatment place limits, so if you enroll a patient in a clinical trial now and something better comes down the line? Does that take them out of the other study. What’s the durability of treatment? We know 15 years later that the RPE65, all but one study seems to still be working pretty well. What about the ultra rare genes? How are we going to resource diseases where there’s only four people in a world affected? And who should do the treatment? While any retinal surgeon surgical ability is not the question, any retinal surgeon can really do the treatment with a little bit of training. And who should pay? These are expensive treatments, right? And we have to define success. What’s our expectation? What’s our goal going to be? And of course, there are the ethical issues that remain. Like, what about eugenics? We can make flowers without stamens and chickens without feathers and breed weird animals. Could that happen in the eye? No, no, no, you say, Oh, here’s a study, 2009, gene therapy corrected red green color deficiency in adult primates, very effective. This is a very important study, because it showed us that even cells that hadn’t been working your entire life, if you make them work in adulthood, the brain can learn to use them, can be trained to use them. So this always, this old thought of one’s never seen never will see, it’s not true. But his red green color deficiency a disease? Should we be spending time energy and money? Or is this just a form of eugenics, we’re trying to make the world more perfect.

And here’s from the internet, 2011 Redheaded donors, not wanted at the world’s largest sperm bank. I mean, it is a slippery slope, and there is some difficult considerations of what we’re going to treat, and what we’re not. There’s the issues in gene therapy, we often hear, Oh, there’s a trial open, you get all excited, and all of a sudden, you find out all the spots are closed, because the FDA will only allow a certain number of patients to be treated in the early phase of the trial. And maybe those spots fill really quickly by the patients at the own center. Are they really open? What are our expectations we talked about? Genetic counseling is an absolute critical piece of this whole formula. Cost is an issue. Accessibility is an issue. How can people from underdeveloped countries get that. Having the teams that deliver the holistic care that’s important, and then the egos, the conflict of interests, and trying to make money and wanting to be the first, sometimes get ahead of us? And this is all in the face of desperate patients? Who asks does it apply to me? Will it ever apply to me? What can I do to get gene therapy, and they have to understand the process. adults get treated before kids usually, poor vision gets treated before good vision. These are the clinical trials. There’s the phase one, the two, the three. Number one just being safety, you have to observe the patient for a certain period of time to make sure these off target effects and other side effects aren’t happening. But limited enrollment, the inclusion criteria, exclusion criteria, which apply. Many patients who would love their gene therapy, but they don’t qualify for the studies because they’re excluded for their vision or for their age, or asymmetry. And every family patient is different, which makes the results even more unpredictable.

And back to expectations, are we stopping progression? Are patients expecting to be cured? We have to realize that clinical trials are not treatment. There are clinical trials, the research, only RPE65 is out of clinical trial, where it’s a treatment. The hope is that other things will convert from clinical trials to treatment. And we might even ask, is this a success? RPE65, we’ve got one treatment, 60 years later, one gene. 20 years it took to develop it. Maybe 250 eligible people in the United States. In fact, we think that almost every patient United States who’s accessible has been treated already. It only works with some patients.

There’s actually 14 centers now we’re one of the centers that are able to give this treatment and it costs $425,000 US per eye, 850,000 per patient that is not sustainable. If you look at the rest of the world of low income countries, you know the world remains a poor low income place. Look at this, the left side of this is the real world income. And if you look at 71% of the world living on less than $10 a day, let’s turn his $425,000 per eye. That’s $1,000 per day for a year. It just it just doesn’t compute it’s not going to work. So how can they get gene therapy? What does it take to get there? You need to be able to make a diagnosis. Phenotyping is the key first step in getting the gene therapy. Diagnostic testing, you have to have OCT, ERG, fundus, autofluorescence, all those things, you have to have genetic counseling to interpret testing, before testing, after testing, a key piece of the puzzle. And then you have to have access to genetic testing, which is expensive and not accessible in some countries. And then you have to have accessibility to treatment.

You know, here’s the list of genes in 1990. With the eye, we only had one gene, rhodopsin. Over the years, the number of genes has gone up, gosh, who knows how high it’s going to go right? The 40,000 genes if you include the non coding genes in the body, here’s the membership of the International Society for Genetic Eye Diseases. What happens to that, it hasn’t grown. There’s only 80 to 100 ocular geneticists in the world. And for gewnetic counselors, it’s even worse. There’s maybe 30 or 40, dedicated ocular gtenetic counselors in the world, we don’t have the resources to cure all these diseases. We need more ocular geneticists, thefellowships that are very few, some are funded, some are not. They vary in lengths, some have a research components, some don’t. It can be done though, these are fellows that I’ve trained or are in training ocular geneticists, we put them all over the world. So we can put ocular geneticists into community, we have a program here where we can pay genetic counselor, or who want to learn ocular geneticists or ophthalmic technicians who want to learn to be a genetic counselor, six month period learn to be an ocular genetic counselor, we can populate the world with people. So if we can populate the world with people, what if we had open access, that is, didn’t matter what centre you are out of, if you could do it, there was no patents involved? No profit, remove the ego, we remove the conflicts of interest. We have accurate low cost genetic testing, maybe free genetic testing, maybe we have low cost treatment. Maybe we are not for profit system. That’s like a dream, right?

Then we could get this out to the world, we can actually do RPE65 technically, for $20,000. We can make the virus for $500 per patient. This surgery if the institution would agree to do it not for profit, $20,000. They do that through philanthropy. And philanthropy supported our mission. And our academic center supports that mission. That’s a way to get into third world. We work with Ed stone in Iowa, we have two gene therapies CLN3 and MAK. These are therapies that are going to be within the next year out there in use. And the education to fellowships and Orbis Cybersight, we have a genetics curriculum, the first module is out there on Cybersight. Please go take that course. And you can learn how to manage this information. And then we develop an information pipeline to help with diagnosis around the world, and post aftercare treatment pipeline. So what we do is we say where’s the money to fund all this? We don’t live in a world where money flows out to holes in the bottom of the Earth into the universe. There’s rich people everywhere. And we have international NGO support. And together we can support bringing these treatments around the world. They can underwrite the effort to diagnostic technology, the training and then maybe we fly it, put on Orbis plane, put a retina surgeon, some vials of viral vector, fly them to a country where we’ve pre selected patients by telemedicine, then teach that country how to do the surgery again, the surgery is really not the the obstacle. And then what we can do is leave, followup the patients by telemedicine and we delivered for free with the help of philonthrophy.

And so our world is changing. We can do this. We’ve come a long way in 60 years, we still have some ethical issues, we still have some challenges. What I tell my patients now is the first thing you got to concentrate on, is getting a diagnosis that no one’s got. 30% of the patients who come to see me have the wrong diagnosis. Many patients have no diagnosis. The average number of physicians that a patient has seen before they see me is four or five. We have to shorten the diagnostic odyssey. And we have to make it more precise. Then we have to do DNA testing. Now there’s a large panel testing that creates all these variants of unknown significance, hard to interpret. But if we get more specific, more targeted testing, then we’ll have better more precise diagnosis of better genotype to explain the phenotype?

How do you know if there’s a study going on? This is one thing, one site, trials in the United States ought to be registered. But keep in mind that not everything on this site is good. There is some bad stuff out there, stuff I wouldn’t recommend to my pet dog, you got to be careful. And you have to have the knowledge. And that’s where getting to someone who’s in the know, who knows people who know people who knows how to interpret information, we screen these channels for all our patients, to tell them what we recommend and what we don’t recommend. All we can do is we’re no longer saying I’m not sure what you have, we can make a diagnosis on 80% of patients. We no longer say you’re going blind see you later, nothing we can do. I tell my patients, there’ll be a treatment in your lifetime, you will be cured. I’m not exactly sure what it will look like, depends on the disease. I’m not exactly sure what form of therapy will be stem cel,l gene therapy, ex vivo in vivo. I’m not sure if it will stop progression, or restore the vision. But the bottom line is, we’re now 65 years after the first gene therapy experiment, able to say there will be treatment in your lifetime, 55 years after there will be treatment in your lifetime. And it may be sooner than you think.

Okay, let’s get back to our pretest. I’ll take some questions. What is required to do gene therapy? Well, why don’t you take this test? We’ll see if we do any better? We need a genetic diagnosis, a delivery mechanism and a target. Which of these do you think we need? Or do we need all of them?

And the answer is you got it. So you’re correct, 80% All the above, you need to have … Now it’s a little tricky because you don’t officially need genetic diagnosis need a phenotype right? And the phenotype, so retinitis pigmentosa, you don’t have to know your gene. You could do it. But really what we need is all of those things. And if we ask question, all the following retinal disorders, which one does not have a clinical trial, which of these three genes is second gene is RPGR. Third gene is autosomal recessive RP. The fourth is CLM5, I told you about. Which one does not have a clinical trial right now. So the correct answer is RPE65. Because that is not a clinical trial anymore. That is now clinically approved for treatment. So you don’t need a research trial. And that’s the difference, a research trial versus approved clinical therapy. So RPE65 is the one that currently does not have a clinical trial because it’s approved. And lastly, our last question. Concerns about gene therapy include all the following except which one is no longer much of a concern? And you’re right surgical ability is the one that is really less of a concern today, at least in countries where we have that available.

So if you have any questions, I’m going to answer some now. I’m going to look at the q&a and see what’s in there. How often do we need to repeat the injections is a question? The answer is we don’t know. For RPE65, we have not had to repeat the injections, it seems to last but for others we may need to. And that’s one of the advantage of intravitreal versus subretinal. If we can do it intervitreal treatment, if it will work, then repeating it is not a big deal.

Question between AAV9 and 2, which one is difficult to treat with gene therapy? It’s not a question of difficulty. It’s a question of targeting. Right? It’s the same technology to deliver the treatment. But it’s a question of where’s it going to go? Where’s it going to carry this gene, is it going to carry the gene to the target cells, which are different in RP for example, versus CLN3, where it’s the whole retina that’s diseased, where as in RP, it’s the outer retina. AAV9 does better penetration of the entire retina.

How does the gene therapy spread throughout the world? Or has it spread and it’s starting to spread. There are trials in multiple countries around the world. And I’ve given you some idea. Well, it spread to Pakistan, it’ll spread everywhere. Once we tackle some of the barriers that I’ve talked about.

Can CLN5 and CLN3 be treated by Gene therapy? CLN5 is in clinical trials and CLN3 will soon be in clinical trials.

There’s nothing right now for Prph2 related disease in active trials. You know, there are animal models, which is a good first step. And many genes are under preclinical or pre clinical trial work of a PRPh2 is not in human trials right now.

What do you think about the time when people actually start to take these therapies for the better version of themselves? Is that actually possible? And that’s where we get into, I am glad that question got asked, you know, that gets into this whole question of eugenics and what are we trying to do with gene therapy? And do we want to change our human race? We have the ability to do gene to clone people, we have the ability to create babies with changes in their germline. And these are difficult questions that we’re going to have to ask over time. Does restoring vision make you a better version of yourself? Some patients I say I come to this a you know what? I can blind for 20 years? I don’t really want vision back. I’m happy the way I am. And these are difficult issues that we’re going to need to ask.

Won’t new viral delivery systems reduce the cost? Are there any advances? That’s the gene agnostics that I spoke about? And, you know, cost is a relative thing. Certainly, the cost is higher in the medical industry model, regardless of the treatment than it is in the academic model that we’re using. And it’s just a matter to see over time, things will get cheaper over time. But it’s hard to know right now, what treatment is going to have what cost?

What are the top priorities, the most commonly mutated gene in the retina is ABCA4, RS2A is second, depends on what country you’re in of course, the smaller the genetic pool in a country, the higher a certain gene may rise to prominence. For the United States,I encourage you to read the paper by Ed Stone and his colleagues, a 1000 families paper and published an ophthalmology that gives you the frequency for all genes in the United States.

And there’s a great question here. Does the choriocapillaris need to be good to support the new cells on the grid? Yeah, you need to have blood supply. That’s one of the challenges with choroideremia.

And then, what other resources do you recommend for learning ocular genetics? Well, other than the Cybersight? Well, Cybersight has several resources. They have webinars that I and others have given. They have courses that you can take, the handbook of ocular genetics is something that I wrote with Mario Zanolli and Jenina Capasso. That’s a book that takes you disorder to disorder. If you want something more weighty, there’s Eliah Trabolsi’s ocular genetics textbook. That’s the more kind of larger version. But ultimately, training on site is the best. You can bring ocular genetics into your country to do on site training. You can have people outsourced to countries. We’re now training for LV Prasad, their first ocular geneticist is training with us. So there’s many ways to get the information. But I think it’s important to recognize that this is a subspecialty, a recognised subspecialty. This is requires a special knowledge. You know, you don’t want me to treat your ptosis, I don’t do ptosis surgery. You don’t want me to figure out your diabetic retinopathy. I don’t do that. I do what I do, ocular genetics. And I learned that after years of practice, and this is something that is a unique niche. And we need more ocular geneticists for sure.

Is there any trial for was split gene therapy for USH2A, it’s not going on now. This is, many of us have USHA2 patients who have a limited time having viable retina to treat. That is true. But there’s something really important in that question. You know, RP, let’s take RP. Rp is not a disease where you’re here with your vision and you fall off a cliff. That’s more like CLM3, disease where people rapidly lose their vision. In RP, It’s a very slow progression. So we have time. Patients vision is now I plan to drop dramatically in five years, maybe not in 10 years. And we see our patients every two or three years, and reassure them that not much is changing. So we do have times and I think within the next five to 10 years, many of these changes are going to come to gene therapy trials, many of them and will start to have some clinical approval going on. So the patients have more time than we think we have. We have the time, not unlimited. A patient whose 80 has less time than a patient who’s eight. They just have to be functioning and working on their current lifestyle being followed in the system, so they have access.

Lastly, someone says about learning more about the chemistry behind all this, and that’s a little bit harder, right? There are also programs and ocular genetics fellowships in Iowa and elsewhere that are more focused on the science, PhD postdoctoral training, or for ophthalmologists who want that science training that’s available, as well. So I think that’s the end of our gene therapy related questions. That will bring us to a close. I want to thank all of you, 254 of you who joined us. It’s been a delight to chat with you. You have my email there. I’ll share with you one more time so you can see that, feel free to reach out by email with any questions. Remember, to take care of your patients one day at a time, get their genetic diagnoses and treatment is on the way. Thanks very much. Take care

3 thoughts on “Lecture: Past, Present, and Future: Treatment of Inherited Retinal Diseases (IRDs)”

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