Lecture: The Clinical & Surgical Considerations of Gene Therapy in Retina Patients

During this live webinar, we will discuss the current state of gene therapy for retinal diseases. The indications, mechanism of action, and delivery routes for this novel class of therapeutics will be briefly reviewed. The latest efficacy and safety data of leading gene therapy candidates will be presented along with areas of continued exploration. The participant will leave the webinar with an improved understanding of retinal gene therapy and its potential applications. (Level: Intermediate)

Lecturer: Dr. Christina Y. Weng, Ophthalmologist, Baylor College of Medicine, USA


Good morning, good afternoon, or good evening to everybody who has joined today wherever you are in the world. Thank you so much for being here. I want to thank Cybersight and Orbis International to be part of this webinar. I joined many other webinars and it’s a stellar line up of speakers and experts in their field. So I’m humbled and honored to be part of this line up. I’m going to talk a little today about a really exciting area in the world of retina and ophthalmology. Because I think this is going to be spreading across our entire field and has the potential to help an incredible number of patients. I hope you’re excited. I’m Christina Weng. I am on faculty at the Baylor College of Medicine in Houston, Texas in the United States. I’m a professor of ophthalmology there. I also serve as the fellowship program director for the surgical retina fellowship training program here. I’m going to talk today about the clinical and surgical considerations of gene therapy in retina patients. I dabble in many areas, but thanks to my chairman, Timothy Stoudt, when I started my career a decade ago, I started getting involved with gene therapy and Fortunately, the timing was just right. It was the beginning of a lot of important candidates coming through the pipeline, and I even saw one of those drugs see approval here in the United States. So we’ll talk about all of that today for about 45 minutes. I will save 15 minutes towards the end for questions. Feel free to type in any questions that you have into the Q&A function. These are my disclosures. I serve as a consultant to several companies that have gene therapy candidates and I’m a sub investigator for gene trials. This is an article from 2020. This is from the FDA. That is the Food and Drug Administration. It’s the regulatory authority here in the United States. It’s organization that approves our drugs for patient use. In 2020, this release was given by the FDA that just really highlighted what a burgeoning space this is. At that point, four years ago, there were 900 investigational new drug applications sitting on the desk of the FDA. So just a lot of interest in this area. In fact, that year, the FDA had to hire 50 new personnel to join their team just to be able to review all of these applications. And now that we’re four years down the road, I’m certain that number is even greater. So lots of interest and lots of research that’s going on in this area. As you probably know, if you pay attention first at the middle column. There are many different types of gene therapy that exist. We’ll go through these in a short bit of time. But the type of gene therapy that any patient needs depends on the type of genetic disease that you’re trying to treat which is in the first column. Let’s look at the first row together, for example. Autosomal recessive. Known as loss of function inherited retinal diseases. A patient has a mutation that they’re not able to produce a protein that our body needs to function. It’s an autosomal recessive loss of function inherited retinal disease. The gene therapy type to treat that is gene augmentation. Sometimes referred to as gene replacement or supplementation. This is the most common type of genetic disease, the loss of function mutations. So gene augmentation was the earliest Fourier into gene therapy. One example of this type of gene therapy is our one and only currently approved gene therapy in the United States which is Voretigene neparvovec. What about autosomal dominant or gain of function diseases. This is where there is a mutation of overproduction of a certain type of protein. These are notoriously a challenging class of diseases to treat and we haven’t had as great luck treating this class of diseases. Not only do you need to inactivate or suppress the gene that is over acting, we need some level of that protein. You can’t just suppress it completely. A lot of times that is done concurrently with a low level of gene augmentation as well. It’s trickier. We have made great strides in this area for technologies that might be able to treat these gain of function diseases with small interfering RNA or antisense oligonucleotides. There is also gene editing. We’ll talk about that later in the deck. But this is one example of this is the CRISPR Cas9 technology. That is being looked at for a variety of diseases including LCA10. And finally in the bottom row we have multifactorial diseases. Diseases where you can’t necessarily attribute the disease to a single locus. For example, macular degeneration. We know there is a root in genetics there but we don’t know, there is not one single gene that can be pinpointed for macular degeneration. It’s a combination and there is a large variety. What about that type of genetic disease? We’re able to now leverage progress in the gene therapy world in the sense of bio factory approaches. So if you think about N for macular degeneration, we treat them with anti-VEGF injections. We give these as frequently sometimes as every month. It’s a lot for the patient. What if we can give a gene therapy to allow their own eye to produce their own supply of anti-VEGF protein. That is what is happening. There are several programs in different stages. Like the ABBV-RGX-314 and more. The last type I want to touch on that is excellent for all of the different types that you see listed here is a gene agnostic type of gene therapy called opto genetics. This allows the cells that are remaining in the retina to potentially take over the function for the photoreceptors that are often damaged in inherited retinal diseases. And one example that is coming along in the trials is MCO-010. Bottom line, a lot of exciting areas that are happening now for all of the different genetic disease types. How does gene therapy work. Let’s take a 10,000-foot view. Essentially, this is a little oversimplifying but you create a trans gene that codes for the protein that you desire. That trans gene is packaged into a vector. The vector is going to carry that into the host cells. The vector can be viral like adenovirus or adeno associated viruses, lentivirus or nonviral as well. Antisense oligonucleotides. DNA compacted nano particles. That is a way of getting the trans gene into the eye. Whatever you package, you put into the vector and the vector is taken with an endosome into the cell of the host and breaks down that, that vesicle releases the vector. The vector injects that new trans gene into the nucleus of the host cell and that ray lows the host cell to begin producing whatever protein is dictated or encoded in the trans gene. That can be a native protein like RPE65 or a nonnative protein that our bodies don’t typically produce like an anti-VEGF fragment. We become really sophisticated in these technologies such that the trans genes you can play around with and modify and you can actually modify the promoter, the enhancer, the terminal repeats. We have become more advanced in engineering the vectors. All of these modifications allow for different behaviors and characteristics of the gene therapy and opens the door to the applications that we’re able to turn to compared to 20 years ago. As you can see here in this non-comprehensive list, ocular gene therapy targets many different diseases. Traditionally when we talked about gene therapy we thought about the orphan, really rare diseases. And those are still on this list. We have made great strides in achromatopsia. Stargardt. They’re still on the list and a wonderful application of gene therapy. What is interesting is you’ll see on this list a lot of the most common diseases. For example, diabetic macular edema and diabetic retinopathy and wet and dry macular degeneration. This is by no means a comprehensive list but a snapshot published at the end of 2023. These lists change by the day. There are always trials that didn’t work out and new trials being added. A small glimpse of the clinical trials happening now in this space. You can see a lot are in early stages. This doesn’t include the preclinical trials of which there is even more. There is a lot of phase one and phase two studies. But you’ll notice a lot of studies in phase 3, some pivotal studies. We’ll hear a lot of buzz about this in the forthcoming years. How do you get gene therapy into the eye. The eye is incredibly fortunate because it’s relatively immune privileged. It’s a great space. Our eyes are this compartmentalized area of the body and it allows different types of gene therapies to do quite well. We’re fortunate in that we have that advantage over potentially different parts of the body where gene therapy is also being looked at. How do you get the gene therapy into the eye? There are three main routes of gene therapy administration. Look at the schematic to the right of this slide. Back in the day we used to think that we would need to put the gene therapy as close to the target cells as possible. So for example, for LHON, labor hereditary optic neuropathy, we thought an intravitreal injection was best because the cells we’re trying to target in that disease are the ganglion cells. For a disease like, labor congenital amaurosis, a disease where the disease cells are at the RPE, we thought, hey, maybe put in a sub retinal injection for that condition because those disease cells are closer to that space. But because of the advances I showed you on the last slide, we’re able to modify the vectors better and play with the trans genes, this rule of thumb really no longer holds. In fact, all three routes of gene therapy administration super choroidal, sub retinal and intravitreal are all being looked at and all have validity and all deserve a good look to see which is the optimal approach. We may find the optimal approach depends on the disease we’re trying to treat. Most of you are familiar with intravitreal injections where we put the substance into the vitreous cavity. Supra choroidal is the newest route. This is given by a short needle near the pars plana into the space between the sclera and the choroid. It’s shown in animal and human study to penetrate quite deeply across all of the ocular tissues even the posterior part of the eye. And sub retinal has two different subtypes. There is a trans-vitreal approach and a supra choroidal approach. The top left image that you see there is the trans-vitreal approach where you go through the vitreous cavity and inject into the sub retinal space. Contrasted to the bottom, that’s a supra choroidal approach where you tunnel a catheter through the supra choroidal space and when you hit the targeted area, there is a little needle that emerges and enters the sub retinal space. One of the benefits of that approach is you avoid disturbing the vitreous which is advantageous especially in the younger populations. All three are being studied actively as we speak and all three have their advantages and disadvantages. If you look at the first row, intravitreal injections. Those are generally safe and convenient to give. You can do it right in the clinic. The draw backs of intravitreal are they tend to be more immunogenic and incite a greater inflammatory reaction when we give them. Something we need to look out for and that’s happened in some of the studies that we’ve seen. Additionally, the transduction efficiency of the more common recombinant adeno associated viruses, viral vectors that we use, AAV2 and AAV8 for example, seems to be less. Might be limited by the internal limiting member and difficult to penetrate the deeper cell layers but that is not a fixed statement because of the advances that we made in terms of vector technology and the trans gene engineering itself. The next two rows are talking about the sub retinal approaches, the trans-vitreal and supra choroidal routes. These are less immunogenic. The sub retinal space is the most — tend to be not as inflammatory as other routes. If you go through the super choroidal approach, you avoid the need for a concurrent vitrectomy as I mentioned on the last slide. The drawback is if you go trans-vitreal-ly it requires a surgery for the patient and concurrent vitrectomy. If you look at the supra choroidal route, one of the disadvantages of that form is it does take, require greater technical demands to tunnel through the choroidal space and penetrate the membrane and it’s not easy and carries some unique risks. Lastly, in the final row, the supra choroidal approaches to delivery. One of the advantages of this type is it can be given in the clinic and is fair whether I well tolerated by the patient. It may offer better transduction efficiency compared to the intravitreal route. The drawbacks of suprachoroidal is there isn’t as much study as the other areas. So the immunogenic response is not quite as well understood. And injecting into that space has proven to be somewhat challenging in certain populations and they’re working on different approaches to that and individualizing the needle length. So in the next section I thought we would talk about five gene therapy candidates. There is no way I can go through that entire list. There was an incredible number there. I thought I would pick out five that are in late phases of clinical trials or that you’re probably hear ago lot of buzz about now in the news. So all of these you may have heard of or will hear about soon. I’m going to breeze through these quickly to highlight the top characteristics and features to know and we’ll talk about each of the five in more detail. The first is ABBV-RGX-314. This leverages the biofactory approach and is being looked at for wet macular degeneration in the sub retinal form. This codes for a nonnative protein. An anti-VEGF antibody fragment that is similar to ran business microbiota. We are also looking at this gene therapy to be give the supra choroidal approach. We’re looking at that for wet macular degeneration and diabetic retinopathy. The next one is ADVM-022. A modified vector-based intravitreal therapy encoding for a molecule similar to Aflibercept. Of note, it was being looked at for diabetic macular edema but unfortunately there were some adverse events noted and that trial was halted in 2021. It’s only moving forward for wet macular degeneration at this point. There are two on the third row. And these are both similar therapies in the sense they’re both sub retinal gene therapies being used to treat RPGR associated X-linked retinitis pigmentosa. We will talk about that more shortly. Two more on the list. The first is MCO10. An AAV2 based intravitreal gene therapy that is gene agnostic. I talked about this briefly on that one slide. This introduces trans genes that produce proteins that are light sensitive called opsins that use the cells that are remaining in the retina to act as photoreceptors. You can think of it that way in an oversimplistic description. This is being studied in retinitis pigmentosa and Stargardt disease. The next one is edit 101. A sub retinal treatment being looked at for LCA10. Starting with the first, ABBV-RGX-314. It’s a vector based single dose gene therapy producing an antibody fragment similar to ran business microbiota. In the studies there were encouraging efficacy signals. They looked at 42 patients with wet macular degeneration and divided them up into five cohorts as a dose escalating design. These were not treatment naive eyes. These 42 patients were high demand patients that required between nine and ten injections in the year prior to entering the study. They required a lot of treatment. So they gave them one time gene therapy with ABBV-RGX-314 and watched how they did. The visual and anatomic responses remained stable. They were stabilized entering the study because they had gotten so many injections. They remained stable. What was impressive is the reduction in injection burden was almost 80 percent in cohort five at two years. It was well tolerated. There were some pigmentary changes that we saw. We’re still actively learning about that. Otherwise, patients did quite well. This has moved onto the next phase, two on going studies called atmosphere and Ascent that are looking at this for wet macular degeneration. This is also being studied in a supra choroidal form for wet AMD and diabetic retinopathy. Let me show you a highlight slide from this study that I think is impressive. On the bottom on the X axis, these are the different cohorts and different doses of gene therapy. As you go towards cohort five, the gene therapy doses are becoming higher. You can see in the gray bars, that was the number of injections per year that on average the patients were getting in each of these cohorts. To the right of those gray bars are the number of injections they were getting after the gene therapy. So for example, in cohort five, you can see that at the two-year time point, there was a 78.1 reduction in the annualized injection burden for these patients. A meaningful difference. The next gene therapy I want to discuss is ADVM-022. This is an intravitreal gene therapy using an adeno associated virus 2 serotype but it’s a modified AAV2. It penetrates deeper layers of the molecule. It’s studied in a phase one study called OPTIC. This had encouraging finding. They took four cohorts, two high dose and two low dose with wet macular degeneration. A high need population. They were treated many times on average per year before entering the study. They found similar findings. There was a stable to improved visual and anatomic response at two years but the most impressive take away was the reduction in treatment burden by 80 percent in the low dose cohorts and greater than that in the higher dose cohorts. In fact, more than half of the low dose patients remained injection free at two years. Imagine you were requiring nine to ten injections on average of anti-VEGF and get the gene therapy and suddenly half of them don’t need more injections for two years and that might be going on longer because the follow up is still ongoing now. Unbelievable. There were some patients effected by inflammation in this study, in fact, quite a few. This tended to be low grade and responded well to topical steroids and no cases of severe inflammation like vasculitis. But it is something to be aware of. As I mentioned, these intravitreal gene therapies tend to be more inflammatory. Certainly, that was seen in the DME study called infinity. There were such serious cases of inflammation and hypotony in that study that the trial was halted. While ADVM-022 has progressed to phase two, luna study, they have taken precautions. They took the lower dose from the optic study to continue on. A 2E11 dose they’re moving forward with and incorporated an even lower dose in the phase two Luna study to lessen the inflammatory effects. They’re looking at a 6E10 gene therapy dose in that study. We’ll learn more. The second thing they’re doing is they’re incorporating prophylactic steroid regimens that are being tested that we’ll learn a lot about. Here is one of the slides from the phase one optic study that is impressive. At the top is the high dose cohort. The bottom is the low-dose cohort. The vertical line in the middle where the syringe is, is the time point the gene therapy was given. Each dot represents an injection of anti-VEGF. To the left of the vertical line, these patients were requiring a lot of injections in the year before they entered this study. To the right of that vertical line, after they received the gene therapy, you can see a dramatic reduction in the number of anti-VEGF injections that were required by these patients. So pretty impressive once again. I will talk about this pair for X-linked retinitis pigmentosa. The first is AAV-RPGR. It’s an AAV2/5 based sub retinal gene therapy used to treat XLRP associated with a mutation in the RPGR gene. This was studied in a phase 1/2 study. At 6 months they found nice efficacy. Mean retinal sensitivity in the treated versus untreated eyes. Also, a visual function test where patients had to navigate a mobility maze and there were improved in the treated versus untreated eyes. The phase three LUMEOS trial is underway. The AGTC-501 is sub retinal and used to treat the same disease. In the phase 1/2 trial at one year all patients treated showed a positive microperimetry response and it was well tolerated. The first patient was enrolled for the phase 2/3 trial at the top of 2024. So enrollment is actively underway. I’m going to move to MCO-10. This is an AAV2 based intravitreal gene therapy that is mutation agnostic. No matter what type of mutation you have, you potentially could have benefits from this type of gene therapy. I really am interested and intrigued by this class of diseases. For a long time, we had monogenetic treatments. We find a disease, we find where the mutation is and we see how we can address that mutation. That is great and we’ve had our first FDA approved therapy is a monogenetic type of treatment. But it’s very limit inning the sense of resources and time and progress. Because you can only look at one mutation at a time in those types of approaches. And yet we know there are thousands and thousands of different mutations out there causing ophthalmologic diseases. So looking at the gene agnostic type of therapies is a very important and could be very promising in this space. This intravitreal gene therapy is injected and allows the patients to produce opsins. Those are light sensitive proteins usually found in the photoreceptors that sensitize and convert light into electrochemical signals that are transmitted to the bipolar cells and the ganglion cells and eventually what we see as vision. In these eyes, the photoreceptors are no longer functioning well. What MCO10 does is introduced a trans gene that produces an opsin that allows the eye to be sensitized at the bipolar cell level. While their photoreceptors are not working, the bipolar cells might be working well. And they allow the bipolar cells to then function and detect light. This’ the goal of this type of therapy which has fast track and orphan drug designations from the FDA. It’s currently being studied in a trial called RESTORE. A phase 2B/3. This is a 100-week study that had some preliminary readouts showing encouraging findings. The primary end point is a functional mobility test where patients had to navigate at different light levels through a maze. That was met. But one of the secondary end points looking at best directed visual acuity, they found improvement in the patients that were treated with MCO10. Both doses. They found improvements there at week 52 compared to SHAM. MCO10 is being studied in phase 2 for star guard disease. Stargardt is the most common macular inherited retinal disease. These two are encompassing a lot of patients around the world. The phase two starlight trial is looking at various outcomes as well. So far, they have seen encouraging findings at week 24 where patients on average had a BCVA improvement of five and a half letters. With a magnifier, that improvement was 15 letters. There was improvement on the visual field perimetry test in terms of mean sensitivity gain. And the results are promising enough that a phase 3 trial is now being planned. The fifth and final one that I’m going to talk about is edit 101. It’s a CRISPR Cas9 sub retinal treatment. A gene editing system that you can think of as sort of molecular scissors. CRISPR Cas9 is truly science fiction turned true. But it’s actually — some of you may have heard recent buzz about a trial called Brilliance that was just published last month in the NEJM. But what this type of genome editing system does, it is able to find a sequence of mutated genes, cut it out and replace it with a functional sequence. So cool. Like I said, this is being actively studied in several different areas but one that I wants to highlight for you is the phase 1/2 brilliance trial that included 14 patients, two children in that group. For a disease called Leber congenital amaurosis. It’s a mutation in the Cep290 gene. They looked at best corrected visual acuity, full field stimulus testing, patients performance through a maze, a visual function navigation maze. And visual function quality of life assessments. They found that 11 of those 14 patients experienced improvements in one or more of these visual and quality of life measures. In fact, many of these patients had improvements in two, three, or even four of the measures which is really exciting. 4 out of the 14 patients had clinically meaningful best corrected visual acuity improvements as well. A lot of promise in this area. Still early and warranting study but it’s been encouraging to see that it’s well tolerated with no dose-limiting toxicities in this small cohort. One of them that is not in this list of five because it’s already FDA approved and our only FDA approved gene therapy. This is the one I have the most experience with Voretigene noparvovec is trademarked as Luxturna. It became our first FDA approved ophthalmic gene therapy. It’s administered in 17 sites of excellence in the United States. Baylor is one of them. We were one of the first to start giving this. Which is why I have more experience in this area. It’s an AAV2 based sub retinal gene therapy. Consisting of 1.15E11 vector genomes. It’s indicated for patients with a biallelic RPE65 mutation associated retinal dystrophy which clinically manifests as labor congenital amaurosis type two and certain variants of retinitis pigmentosa. They must have viable retinal cells to receive this. One of the interesting facts about this drug that I want to touch on because it has implications from a social standpoint when we’re talking about accessibility and care as these gene therapy products become more widely available is the cost. It’s an incredibly expensive drug. The most expensive drug that we have in the ophthalmology space now. It’s almost half a million U.S. dollars at this point. It’s incredibly expensive and I hope that future gene therapies forthcoming have lower price tags and we’ll find creative ways to ensure that as many patients that need these types of treatments are able to get them. The outcomes of Voretigene. You have given a lot of these patients gene therapy, how are they doing. It’s a great question to ask. We’re so used to talking about outcomes and improvement in terms of Snellen letters on an eye chart. We bring the patient in and have them read the eye chart and that is what we consider the outcomes for patients. That is true for a lot of diseases like macular degeneration and diabetic eye disease, et cetera. It’s different when it comes to inherited retinal diseases. A lot of these patients may have low enough levels of vision that you can’t assess their outcomes objectively on an eye chart. There is more to vision than just being able to read letters. There are lot of areas of visual function that are actively being studied now that we don’t typically measure in the clinic day to day. That was very true of these trials. One thing that was super interesting is and landmark in the phase 3 registration study is the primary outcome was not visual acuity. That is not how this gene therapy became approved. It was based on patient’s performance on a multi-luminance mobility test. A human maze. You set up an obstacle and let them walk through it and see what their time is and their successful rate of completing the maze is. You test them at different light levels. These patients have a difficult time seeing in slightly dim light not to mention in darkness. They have a very difficult time navigating. That was the primary outcome in phase 3 and that was met which led to the approval of this drug. The point is we need to look at visual function more holistically in this class of diseases. In fact, that type of finding has persisted. So those patients in the phase 3 program, a lot of them rolled into the post approval phase 4 study called PAS. In the interim analysis of PAS, we saw that patients treated in the real world actually, excuse me, this is a real world study. Patients were treated post marketing. There was no significant change in the visual acuity of patients. Similar to what we saw in phase 3. But there was a mean FST decrease. Meaning that patients were able to detect light more sensitively and able to essentially improve in that aspect of visual function. Additionally, myself and some colleagues after this drug was approved pooled our cases and published this a couple years ago in a multicenter case series of 77 eyes in 41 patients. We looked at various aspects, various factors that could impact mean visual acuity change at one year. Including baseline visual acuity, whether we detach the fovea. The patients age, et cetera. None of these seemed to have a statistically significant association with the patient’s visual acuity change at one year. However, what we did find is that those high gainers, those who gains two lines or more of vision, 16 out of the 17 eyes belonged to pediatric patients. One of the important lessons that we’re studying makes sense, with these types of inherited retinal diseases that are progressive and degenerative, it’s better to treat them as early as possible and treatment them when they’re younger. In addition to age, who else should be getting these gene therapies especially when we have limited resources. We want those patients who are going to have the greatest likelihood of graining visual function and having some of these benefits. We don’t know. It’s an unknown area that is actively being looked at. In fact, there are many working groups and bright people in this space developing consensus recommendations for who should be eligible for gene therapies. I just want to show you this multi-luminance mobility test. This is really need to see but you set up all these cushions in a very darkroom. The room has to be totally blacked out. All the windows are covered and underneath the door is covered so it’s pitch black. And we have different ways to adjust the light to different levels like in the scale below. The patients are asked to navigate through the human maze. There are many different versions of this being used in different trials. This one was the one used by Spark Therapeutics for the Voratigene study. We have talked about that. I want to show you one video of a patient that I treated with voretigene noparvovec, and in fact, this is the very first patient that I treated. A 4-year-old with RPE65 deficiency. As I mentioned before, these kids have a very difficult time seeing in these types of darkrooms. This is my exam room in my clinic. Those are his two parents with him. In this level of light, he was not able to see his mother standing in front of him before treatment. This is one week after treatment with voretigene, you’re going to watch as he counts his mother’s fingers as she walks back along the 20-foot lane. >> Five, four … You can see. These types of gene therapies can enact changes very, very soon. This was one week after the treatment of the left eye. He can already count the fingers as his mother is moving. I want to show you some of the challenges that we face in this area. Let me show you two patients that I treated with voretigene. Both have similar ORTs and the 6-year-old boy on the left had a significant visual acuity improvement. The patient on the right had a more modest improvement. And yet again I couldn’t see any difference preop. This is where we need help identifying which candidates are going to gain the most from these types of interventions. I want to use this example to point out that vision goes beyond just the visual acuity reading. We look at functional outcomes. In children, especially, these functional outcomes might be things you don’t even think about. For example, the patient on the left had a very hard time going to sleep at night because when it got dark he wouldn’t want to go to sleep and he wouldn’t be able to wake up for school the next day. He wasn’t doing well academically. After the gene therapy, they saw a night and day transformation. He was able to sleep at night and do his homework and go to school the next day and did a lot better in that setting. The boy on the right didn’t have a significant improvement in visual acuity, he was for the first time in his life able to go trick or treating and his parents were thrilled that he was able to do that which was about a month after the gene therapy treatment. If you’re not familiar, trick or treating happens for a holiday called Halloween which is celebrated in America where kids go out at nighttime to collect candy for different houses in the neighborhood and he was never able to participant because he couldn’t see at night. For the first time after his treatment he was able to do that. Here are just some surgical considerations when you’re thinking about performing a sub retinal gene therapy. I’m not going to run through this in the interest of time. These slides will be available for you. There are certain preop things that you may want to do. For example, most definitely you want to make sure you have genetic confirmation before you treat any of these patients. There are several different programs that allow for gene therapy testing. Two of them that I really like because they are no cost are Invitae and Prevention Genetics. You can order the kits and test the patients for a variety of gene therapies. This is important for a number of ongoing trials and potentially for different treatments. It’s more important now than ever for patients to understand what their mutation might be. Patient counseling is important. Prophylactic corticosteroid treatment is a reality for a lot of these trails. Ancillary testing to look at ERG, FAF, FS T-testing. These are types of tests that we don’t maybe typically do every day but are very important for this group of patients. On the day of operation, I prefer general anesthesia to make sure they don’t move. Especially for gene therapy treatment. And, especially, since a lot of these are younger children. And in postop, you’ll want to taper corticosteroids. Often, we use the standard postop topical drops. For certain sub retinal gene therapies, I like to position the patients supine for 24 hours to let gravity work and hold this gene therapy in the macula as much as possible. The supplies and instruments needed are not that different than what we usually have in the OR. You need a 41 gauge cannula to enter the sub retinal space. I like the bevel the cannula so they enter the space more easily. You need some tubing to connect the cannula to the gene therapy contained in a 1cc syringe. I’m going to show you videos now so you can see me performing this. This is a patient with RPG65. I do a core vitrectomy. We’re going to place the gene therapy into the sub retinal space, so we need to elevate the hyaloid. If you don’t elevate it, it makes the subretinal bleb hard to raise. That is why we do this. When you inject the gene therapy, you can self-inject with a foot pedal or you can have someone manually assist and inject the syringe while you’re holding it. I’m touching down along the supra temporal arcade and you see blanching and the subretinal bleb raised. It’s .3ccs. Not that much. But this bleb looks huge under the microscope. I was amazed when I gave this for the first time to see how large of a volume that was. You don’t need to laser the hole that you made. That will self-seal by the end of the case. There is no reason to do anything there. We deliberately try to elevate the foveal center in this type of gene therapy. But it varies. Different types of gene therapies you don’t necessarily need to give it in the macular and raise the fovea. I like to suture to prevent egress of the gene therapy product to extra ocular spaces. Here is another video in slow motion so you can see the blanching of the retina that I’m looking for. When I see the blanching, that is when I have my assistant start injecting. That propelling of the injection opens up that sub retinal space. Here is another video showing the injection speed so you can get an idea. It takes about 60 seconds to inject the entire .3ccs into the sub retinal space. As I cross the foveal center, I slow down the injection velocity a little bit just to make sure that we don’t create an iatrogenic full thickness hole that has been reported in sub retinal injections. After I finish giving the injection, I will keep inside the bleb, I will stay there for a few seconds before withdrawing to avoid reflex and let the gene therapy settle. You want to minimize the amount that comes out into the vitreous space. Some people considered pre-injecting with a bleb or air. I want just the drug product to enter the space. We don’t know what happens with drug concentration or localization of the therapy. But some people have done that. Staying there for a few seconds before I withdraw and that entry site made with the 41 gauge cannula will self-seal. Here is my injecting an older patient. You can see by the pigment they’re an older patient. I’m using the help of a cool technology called intraoperative OCT that can tell you exactly where you are to confirm you’re in the sub retinal space. That is important because in these older patients it can be easy to penetrate into the sub RPE space which you don’t want to be in for these injections. That’s one really important application of intraoperative OCT. I just wanted to show you that. What are future directions as I wrap up here? Intraoperative OCT is incredibly helpful to confirm the space you’re in when treating these patients. But another cool application of intraoperative OCT is with volume metric measurements of the blebs. You don’t really know how much is coming out into the vitreous cavity. And some of my colleagues at Duke did a test in an animal model asking the surgeon to estimate how much ended up in the subretinal bleb. Surgeons were bad at estimating how much was in the subretinal bleb. As we become more sophisticated and refine our dosing, I think that knowing exactly how much is being delivered into the sub retinal space is going to play a key role in the treatments in the future and intraoperative OCT can help us do that. Another exciting area is robotics. This sounds like science fiction but again, it’s another area that is being studied now. In fact, just last year there was a first in human application of using robotics to deliver sub retinal therapy. It wasn’t gene therapy, it was tissue plasminogen activator but it was put into the sub retinal space. As you know, entering the potential sub retinal space is challenging and you have to be careful in that delicate area. If we have something like robotics that can assist in being more precise, it can be a game changer in this area. So I’m very excited about learning more about that as the study continues. There are many questions that we main. This is a bustling area with a lot of studies and it amazes me as far as we’ve come, there is still a lot of questions that we need answers to. What the optimal delivery approach is. I told you intravitreal, sub retinal, we don’t know yet. Finding a good surgical candidate. How come some people improve more than others. We need to identify the best candidates to be treated. We need to know what the ideal age to treat is. We should be treating when patients are younger but how young is that. Should we be treating newborns with these inherited retinal diseases. We don’t flow. What’s the best surgical technique. Does the hyaloid need to be elevated. We don’t know. The location and the volume of the bleb is also being looked at. I talked to you about some of the sub retinal treatments, below was published in a case series, are associated with pigment changes. This happened not right away but down the line after the patient was treated with the voretigene, you can see all of the pigment changes. Most seem to be clinically insignificant. There is no visual impact. But some of them are. So are these clinically meaningful. Why do they happen. We don’t quite know yet. It’s an area that is actively being investigated. One of the questions I had is what happens as you have constitutively active trans gene end product. You put in a gene therapy, for example, take one that’s a bio factory approach. The patient is continuously producing anti-VEGF theoretically indefinitely. You can’t control how much or shut it off. Are there consequences to that. What does that mean. What would happen if we needed to shut it off. Those are all very important questions to answer. Theoretically because retinal cells are non-replicating, the durability of treatment should be forever but is that true. We don’t have a long enough runway of study yet because these are new treatments but it’s a question to be asked. If it’s not forever they last, is retreatment possible. And finally, the accessibility question. As more and more gene therapies become available in the upcoming years, how do we ensure that all of the patients that need these types of treatments with able to access them. Very important. In summary, retinal gene therapy has the potential to transform the treatment of rare and common diseases. We only have one FDA approved ophthalmic gene therapy in the form of voretigene. But there are many candidates in the pipeline which is exciting. And we’ll learn more from the slew of trials going on and real-world experience. From these we will gain additional insights. I want to conclude by showing you one set of videos that I find inspiring. These were shared by my chairman and good friend Dr. Tim stout. This is a boy in a phase 3 study for voretigene. And he had RPE65 deficiency. These kids have a very difficult time seeing at night. So even though there is a light in the background on this baseball field, these children can’t see where the ball is in this type of low contrast setting. And his mother took this video in between the two eyes that were treated. So when we treat patients with voretigene, we treat both eyes and separate the treatments by two to six weeks apart. He took her son to the ball field in between the eyes that were treated. The first video is his untreated left eye. He is going to throw the baseball and he can’t see it against the dark sky. It’s very difficult for him to see where it is at any given moment. You can see his treated eye is currently patched up. >> Trying to catch it with his non-treated eye. >> And compare that now to his treated eye just two weeks out from the treatment in this video. And look at that incredible difference. You can see that ball and again these are outcomes that we’re not able to measure in the clinic on a day-to-day basis. But have very meaningful implications for patients and their quality of life. In fact, you might argue are the most meaningful benefits that patients are able to gain. I think it’s a remarkable era that we’re in today and this video always inspires me because it shows the capabilities and what we’re able to do today with gene therapy. Thank you so much. I’m going to move onto questions now. I left my contact information there. If you have any questions, I know this is a limited amount of time and we weren’t able to cover everything but I’m more than happy to talk with you or answer further questions that you have. I appreciate your attention in joining us this morning, afternoon, or evening. I’m going to look at some of the questions that came through now. Please continue to send in your questions if you have any in our final ten minutes. Let me take a look here. I’m going to start with a safety questions because it’s an important question to ask as you venture off into these novel treatments where you’re not sure. And we don’t have a long enough run way to grasp safety over a period of decades, for example. One person asked, has there been a documented case of unanticipated dangerous genetic modifications from ocular gene therapies? That’s an excellent question. There have been some off target effects in animal models as well as in some other types of gene therapies outside of the eye. However, to my understanding and knowledge, there has not been any dangerous genetic modifications from ocular gene therapies that I’m aware of at this point. I think there’s a couple things to say about that. First of all, the most common viral vector that you see being used is an adeno associated viral vector. One of the benefits of an AAV vector is it doesn’t integrate into the host DNA. It’s episomal. So that minimizes the chances of mutagenesis happening. That is unlike a Lente viral vector. That integrates into the host DNA and that has a greater potential for mutagenesis. That’s a really important question. And additionally we’re going to learn more. That is one of the potential concerns of technologies like CRISPR Cas9 where you’re looking at gene editing and that’s why they’re looking at other ways of gene editing, prime editing for example that may have minimal chance or no chance of mutations being introduced into the host genome. Really excellent question. Thanks so much for it. Let me take a look here. Let me see. So I’m not quite understanding this question. Does age matter to apply laser on the blade for sub retinal injection. I’m guessing the question is whether age plays a role in whether or not laser treatment needs to be done for the retinotomy site. It does not. And I treated patients as young as 4 and old as 39. The retina is very elastic to some extent and able to Lucille the holes up nicely. By the end of the surgical case that takes 30 to 45 minutes, I can’t find the retinotomy site most of the times. The cannula is very, very tiny and I have never had to laser that opening. Thanks for that question. How long before gene therapy will be clinically available? Thank you very much for that question. As I mentioned, in the United States and in certain parts of Europe, voretigene and I believe in Japan, voretigene is already commercially available. We already have gene therapy clinically available for RPE65 deficiency, retinal associated dystrophy patients. But you’re correct, there are many other types of gene therapies being studied that are still in early phases or phase two or phase three studies but we don’t have results yet. For those types of treatments, it could be many years if ever that come to market and become commercially available. I have heard that one of the farthest along is APPV-RGX-314. They’re prediction is 2025 or 2026 where we have top line data and potential approval. However, that is a speculation at this time. Because their full phase 3 study readouts have not been done yet. We don’t yet have confirmation of their efficacy and safety. So good answer to that question is it will still be a number of years I think before we have a number of gene therapies that are commercially available for ophthalmic patients. However, a lot of these patients that we’re treating are still very young and it just takes that breakthrough. So it’s very likely in their lifetime there will be opportunities to treat the most common IRDs like retinitis pigmentosa. Let me take a look here. I’m going to take one of the questions from Fabian in Spanish. My Spanish is a little rusty, but I think you’re asking which types of ethnic groups is genetic treatment most effective. That’s an excellent question because we know from other diseases, even our most common injections that we give in retina anti-VEGF, we know they can potentially have different pro files and effectiveness in different ethnic groups and it’s so important to understand that when talking about therapies like gene therapy. They can have different effects and profiles in different races, in different genders and different ages. Unfortunately, we don’t have a great answer to that question at this point because the phase 3 studies for voretigene were quite small. So we don’t, we really need larger-scale studies and need to make more conscious efforts of recruiting diverse populations in these types of trials to better understand that type of question but I’m so glad you brought it up. Let me take a look here. One question about sub retinal injection models. There is a manual and auto-injection. Which is better and what’s the reason for the difference. When giving a sub retinal injection in the OR, you can either have a manual assistant injecting the syringe of gene therapy for you or you can connect it to a foot pedal and use the pedal to inject the gene therapy on your own. There is pros and cons to both. I have mostly done the manual injection. The manual, what is nice about that, is it’s very simple. You don’t need any additional equipment. You just hand the syringe to your assistant and as long as they inject slowly and are well and familiar with the injection of sub retinal gene therapy which you don’t want to suddenly inject forcefully, it goes smoothly and is very effective and efficient. The drawback is you need an assistant and we don’t always have that. Not just any assistant, you need a trained assistant who has given gene therapy before. That is what is nice about the auto-injection. You have full control over it. If you want to slow down or stop you’re able to because it’s your own foot pedal controlling it. I like to set the injector around 12 to 14psi. It should be a slow drip of the therapy into the space. Having that control and not depending on someone else is very, very nice with the auto-injector. But you do need special equipment to use that. You need an adapter to put the gene therapy into it and attach it to the same part on your vitrectomy platform where you hook up the silicone oil. These are readily available in the kit so it’s not that big of a challenge. Both work well and it’s probably split evenly across the community. Half of us probably auto-inject and half of us inject man Julie. How has insurance coverage played a role. This is an important question. When you see the price tag on gene therapy that we have now, half a million dollars in the United States, I don’t think anybody would be able to afford that. But we develop these treatments because we want to get them to patients that need them. It’s a really important question. Through spark therapeutics they had a robust investigation through the — that was arranged at the time of approval before it was commercially launched. They had a lot of agreements in place with the payers. All I need to do is I just work with spark therapeutics to initiate the patient investigation process and there are actually people who know a lot more about that whole, all the steps and the process that it entails to negotiate with the payer and make sure that all of the ends are tied before we’re able to deliver this. It’s an area that I think is going to need to be built on, especially if we do end up with more gene therapies down the line. Because we need to figure out a way to make sure there is coverage for these patients and coordination for those processes that can be resource and time intensive. Thanks for that question. Let me take a look here. I will take one more question. Let me scan this list really quickly. Give me one more moment. Thank you for all the questions. I’m sorry I’m not going to get to all of them. But I left my email there. Please feel free, I welcome questions, email me after the program today. All right. I’m going to take one more about sub retinal and supra choroidal injections. This person is asking which one will be the future trend. Which one is better. Like I mentioned before, we don’t have an answer to that question yet unfortunately. Sub retinal has been studied more extensively than supra choroidal but both have their pros and cons. Sub retinal injections seem to be so far the most effective when I’m looking broadly across all trials. They’re very effective. Very safe in general and well tolerated because it’s an immune privileged space. But they are more challenging to give because you need a vitrectomy. You need to tunnel through the supra choroidal space or perform a vitrectomy that can be a disadvantage in younger patients. Supra choroidal injections are really promising and we have an approved agent to give steroid treatment in the United States for uveitic macular edema. It’s being done. You can give it in the clinic and it’s very straightforward. And for the most part, however, we’re not yet sure, we don’t fully understand the efficacy profile of that in comparison to sub retinal gene therapy approaches. I think the ADBV-RGX-314 studies will be important because they’re taking the same gene therapy and looking at it both ways. We’re going to learn a tremendous amount as far as safety and efficacy from that trial. I think all of these routes deserve continued treatment so we can learn what the optimal approach is. And like I said earlier, it may vary depending on the disease itself. You may want to give certain treatments subretinally and others supra choroidally. We’ll find out. Thank you so much for all of the interest and being on and spending part of your morning, afternoon, evening or late evening with me today. All of the engagement with the questions. Please feel free to reach out with additional comments or questions that we weren’t able to get to. Thank you to Cybersight and Orbis International for inviting me to come today. Thank you.

Last Updated: June 17, 2024

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