Lecture: Gene Therapy and Delivery Strategies for AMD and Diabetic Retinopathy

DR HO: Hello, everybody. I’m Allen Ho. And it’s a pleasure to be with you. I would say good morning, but I know it doesn’t apply, since as is typical of Orbis, this is a global event. Let me share my screen. Today we’ll be talking about gene therapy and cell therapy, and specifically as a retina surgeon, some of the delivery strategies. That’s kind of my interest. And how to get some of these novel treatments to the back of the eye for patients who have unmet needs in common retinal conditions. Gene therapy really has been born in the retina space with a lot of credit to doctors Gene Bennett and Alpert McGuire in Florida. Who in combination with Spark Therapeutics really established the first approved in-human gene therapy. And there’s a couple of ways to think about gene therapy. One is a gene replacement. And we see that for inherited retinal diseases. And another way to think about gene therapy, the second way, is to insert a gene that then encodes for a therapeutic in the eye itself. A biofactory approach. We’ll dive into that. This is a disclosure slide. And we do a lot of clinical research at Wills Eye Hospital. And these are companies involved in cell and gene therapy. And I’ve highlighted them for you here. A lot of credit to many of the collaborator teams at a variety of these — in this ecosystem. Including my partners at Mid-Atlantic Retina and Wills Eye Hospital, RegenXBio team, Gyroscope team, Lineage/Cell Cure Neurosciences, Clearside Biosciences. I would like to give a shout out to RegenXBio, who are sponsors of this program today. It’s been a pleasure working with all these groups. And as we think of gene therapy for common retinal diseases, actually we’re on the second generation of gene therapy clinical trials for wet AMD, for example. We’ve improved viral vectors and improved which trans genes we’re selecting. And our obligation is not only to improve the vectors in the trans genes and the protein products that are therapeutic and the biofactory approach, but also to improve our precision and consistency in delivering these medicines. And that’s maybe surgical in the operating room, or as you’ll see, there’s some promise for in-office use as well. The strategies involve getting interventions to the back of the eye. And the familiar way is to do a vitrectomy, like you see here on the left. And then use a small microcannula to deliver to the back of the eye a therapeutic, whether it’s a cell or gene therapy. That’s the most familiar way. That’s a surgical method. Another way that we developed to try and obviate the need for creating a hole in the retina — when you create a hole in the retina, there are two things that can happen. One is precision of dosing can change. And also you can get egress of the intervention out. And, for example, in some cell therapies, we’ve seen membrane formation on the macula. Finally, there’s an evolving technique that has a very big advantage to being office-based, instead of going to the operating room. And this is a suprachoroidal injection. And there are a couple companies working on devices and some companies that are working on therapeutics. I’ll talk about a few of the programs, and I think my take-home messages are: There are a number of ways to get to the back of the eye, as I just described. Some in the operating room. Some in the office. And this biofactory approach is being validated. And we have validation in this particular study for neovascular AMD. This is a RegenX 314 wet AMD study. I’m gonna show you the phase I/IIa results. And because this is a development talk, we’ll show you some of the videos. This is one of my colleagues working on heads up 3D glasses, working on surgery to the subretinal space. So this involves using a vitrector to remove the vitreous, and then using the MedOne MicroDose cannula syringe so we can deliver 200 microliters to the retina. No special steroid or immune suppression is done. If you think about the volume of viral vectors, we’re talking about 10^10 or 10^11. So we’re talking about 100 billion viral vectors. These eyes in a RegenXBio study are amazingly quiet. On the right, you see evidence of the biofactory approach working. That is, dose dependent in these cohorts, in the initial phase I/IIa, dose dependent protein production of the trans gene, essentially ranibizumab, and on the bottom right is a swim lane graph of some of these previously treated patients, who, on the left of the vertical there, you’ll see the frequency of their need for anti-VEGF injections, and then on the right, you’ll see a marked reduction, clinically meaningful reductions in the need for injections. That is, durable treatment effect. Let me show you a video here. This is in the operating room, and what you’re seeing here was… We’re drawing some fluid out of the eye to test for antibodies for the viral vector. Turns out whether or not you have antibodies to this AAV8 vector is not relevant. Probably because the subretinal space is immune privileged. Here you see a vitrectomy being performed. And those white particles are steroid particles that we use to help identify the clear vitreous gel. This is the microcannula. That we test outside the eye. And we put it in. Through one of our trocars. And as we come down, you’ll see the shadow of the instrument get closer to the instrument itself. And then as it touches down, I’ll hit on the surgeon controlled foot pedal, and a very slow controlled infusion of the trans gene, 200 microliters, 10^11, so 10^9 is a billion. 10^11 is on the order of hundreds of billions of viral vectors are delivered. We’ve learned that we should be delivering these vectors inferiorly to avoid pigmentary changes that you can see. That have been observed in a variety of gene therapy trials. And what do we see? In 42 subjects, we saw… Stable to improved anatomy in cohorts 3, 4, and 5. Where there was a meaningful effect. In protein production. We saw — and we have data now out to 3 years — we saw stable to improved anatomy. We measure the macular thickness with an OCT. And we see on the bottom right, in gray, bars that showed pretreatment, frequency of injections annualized. For example, in cohort 3 in the middle, there were seven injections, annualized. And subsequent to the treatment, the reductions in the need for rescue injections went down to about 2 to 3 injections. And because of these positive data, this was really the first clinical trial to really validate this concept of a biofactory approach. Gene therapy, not to replace a immunity gene in an inherited retinal degeneration, but a common disease, using gene therapy techniques in surgical delivery. And there are two pivotal trials comparing RegenX 314 to monthly ranibizumab or to bi-monthly aflibercept, and this is an ongoing trial and very exciting, across the United States and Canada. That’s one delivery method. And the other delivery method that we developed really was born from a cell therapy clinical trial sponsored by Jansen. And what our aim was — was to deliver to the back of the eye, without creating a hole in the retina. Well, how do you get something under the retina without creating a hole in the retina? Well, if you come from the front, like we did with the technique on the left, of vitrectomy and retinotomy, you’re gonna have a hole in the retina. But if you come from the back, take a microcatheter, pass it along the suprachoroidal space, and then come up under the retina, you can deliver something subretinally, without creating a hole in the retina. And that’s what we aimed to do. Here’s a cartoon showing the traditional vitrectomy approach, showing the idea of some of the intervention escaping there. Creating imprecision and dosing and also the potential, for example, for cells to come out. And cause epiretinal membrane formation. Here’s a cartoon animation. So it’s a scleral cutdown and then a catheter in the suprachoroidal space. And then you come up under surgeon visualization with that microneedle that you see on the slide right. Inject in the subretinal space. And then retract the needle and come out. It’s a concept that we did a lot of iterations with, a lot of design engineers, a lot of surgeons, animal surgery, testing, and this is an evolved system that has now been FDA approved. And this was one our original ideas of access to the subretinal space without creating the retinotomy. This is a suprachoroidal microcatheter approach. Sclerotomy up in the center. Cannulation into the suprachoroidal space, sliding that microcatheter to the back of the eye. Needle advancement in the subretinal space. And then cell delivery and then closure. I’m gonna show you a side by side video of an animation and a surgery I did for a patient with geographic atrophy. So now we’re moving to other common conditions. That are potentially amenable to the biofactory approach. Here you can see a cutdown through the sclera. And we’re not going into the eye. We’re going into the suprachoroidal space. And passing the microcatheter through these sutures that serve as kind of stay sutures. And the catheter goes into this potential space. And as we see it go back, we see it kind of like a groundhog under the retina and RPE. And then we advance a microneedle. Inject saline first, to create a bleb, and then switch the line to your intervention. In this case, it was a cell therapy. There’s an air bubble to know we’re in the correct space. The instruments on the right, where you can switch from saline to cells, and then voila. You’ve got subretinal delivery without a hole in the retina. This device has evolved, and a lot of credit goes to the Orbit Gyroscope team. Now affiliated with Novartis. And it’s FDA approved. Has been used in one cell therapy trial. It’s also being used in a gene therapy trial. For atrophic AMD. Not wet AMD, but the advanced dry form. And in this gene therapy trial, in the Gyroscope program, this is the FOCUS gene therapy trial. What we’re seeing is: Really a whole variety of strategies, trying to manage atrophic AMD. And in this particular strategy, it’s leveraging the observations that geographic atrophy may progress as a function of dysregulation of the immune system that’s hyperactive. And so this strategy uses an AAV2 vector. Recall that in the RegenX program for wet AMD, we used an AAV8 vector. This AAV2 vector encodes for a complement factor I, which is essentially a brake on the complement system alternative pathway. It does this by sequestering this key component of the pathway, C3. And this is… We can measure bioactivity by measuring some of the breakdown products of C3, and if CFI is… The gene product is sequestering this key player, we see less breakdown products as an indicator of biologic activity. In this FOCUS geographic atrophy trial by Gyroscope, phase I/II open label GT005, there have been seven cohorts of subjects, some of which have been done — and delivered this viral vector AAV2 CFI trans gene, by the transvitreal approach. The approach I showed you before. And others are being done with this suprachoroidal approach to the subretinal space in the operating room. Here’s an animation showing you some of the evolution of the device. This is the second generation. And it’s pretty cool. There’s a magnetic pad that allows you to hold the needle advancement knob in any position that you want, so that the microcatheter is oriented correctly for coming into this — through the sclerotomy, into the suprachoroidal space. There’s a syringe with precision dosing. And a lot of little refinements. A microneedle geometry. Initially, the microneedle was coming up, and we weren’t getting into the subretinal space. So we changed the launch angle of the microneedle and materials to improve that. So let me show you another suprachoroidal video. This is… The first one I showed you is for cell therapy. This is for the Gyroscope gene therapy. These are some sutures we’re working on, using a hardware device instead of sutures, which would make it a little more efficient. We’re cutting down through the sclera. Remember, we’re in the operating room. Our goal is to get into the suprachoroidal space. And you use this blade. It’s about a 3 millimeter incision across. 8 millimeters posterior to the surgical limbus. And this is something to make sure that there are no scleral fibers that will inhibit passage of the microcatheter. And then we orient the device outside the eye. You see side by side simultaneous video. Check that there’s patency of the line. Feed it. From external view. Put in a chandelier light. So we’re not doing a vitrectomy here. We’re using a chandelier light to view the back of the eye. You need lighting. Orienting the catheter. And there you see the needle emanating and magnification coming through the subretinal space. It’s a little scary. Looks like it’s perforated the retina. But that’s what it looks like. And then we inject saline to make sure we’re in the right place. And then we switch the line over to the gene therapy to deliver this complement factor I inhibitor. Of that overactive complement system. And this is a patient with geographic atrophy that you see down on the bottom left with an autofluorescent image showing basically a black hole. Where the macula should show some fluorescence from RPE. And we close. And we pull out the chandelier light. And close the external of the eye. And this is a phase I/II study that’s led to evidence of safety. And bioactivity. We’ve seen by less breakdown products of C3. And we’re looking at this in two groups of patients, in a phase II larger trial. 75 subjects with the particular CFI mutation. And 180 subjects that are geographic atrophy, irrespective of the mutation, with different doses being looked at. And that’s ongoing now. The EXPLORE and HORIZON studies. So gene therapy, suprachoroidal to subretinal approach, FDA approved. Operating room. Finally, I’d like to talk a little bit about one technique that would have a big advantage, because it could be done in the office. And that’s the suprachoroidal approach. And this is with an injection in the office. As you can see on the image on the right. Where you see the teal green. This is an idea to use a specific suprachoroidal injector with a short needle to deliver an investigational agent into the suprachoroidal space that will then dissect posteriorly towards the target tissue, which is the macula region. The delivery advantages of suprachoroidal injection are that: Number one, it’s office-based. Number two, it’s targeted. Because you’ll be adjacent to the tissues. You’ll be adjacent to the choroid, the RPE, and the macula. It’s compartmentalized, kind of like a depot. And it seems to be bioavailable. We’ve seen this with steroid studies in uveitis, and we’ve seen it in some preliminary gene therapy work as well. I’ll show you some evidence of that from a RegenX program. This is a cartoon showing suprachoroidal injection. This is an animation… Excuse me. A live video of a clinical trial patient. There are two needle lengths here. You try the short needle length. And try and orient the syringe perpendicular to the globe with some gentle pressure to dimple the globe and then inject. If the short needle doesn’t work, you go to the longer needle. This is the design, a refined design, of the suprachoroidal injection system. This is the ClearSide system. There are others. This one is very nice. And allows injection of up to 100 microliters capacity. It’s calibrated so you can see 25 microliter increments. Down below in the teal box, you can see the short needle. This is more nuanced. Retina specialists are… We do a lot of intravitreal injections, which are quick. This is a little bit more nuanced and takes a minute or two, to get this done. So it’s a different experience for the patient. But the patients have done really well. Very safe. Very good safety profile. Hold the syringe perpendicular. This is my partner, Mike Klufas, doing a suprachoroidal injection in the RegenX trial. A little audio by Jesse. It’s an infrared camera, so you’ll see if it’s in the suprachoroidal space, as spread of that purple temperature, colder. Gene therapy in this RegenX 314 suprachoroidal injection. And we’re looking at suprachoroidal injection in a RegenX wet AMD program. And also in a diabetic retinopathy program. Now, this is a really interesting idea. I think particularly for the diabetics — we’re in the midst of the other pandemic that’s going on. It’s not an infectious pandemic. Like SARS-CoV-2. But this is a diabetes mellitus pandemic around the world. 10%, 11%, 12% of the population having diabetes mellitus, and maybe 35% of the population prediabetic. And anti-VEGF strategies for diabetic retinopathy have shown efficacy for reducing a mechanism of vision loss that is diabetic macular edema. But they’re also showing the ability to take a stage, a more advanced stage of diabetic retinopathy, with a lot of hemorrhaging and findings, and reversing that, at least from a fundus photograph appearance. And this is one of the scales that we use to grade diabetic retinopathy. On the left, you see mild changes to moderate. And they’re numbered. 35 DRSS 43, DRSS 47, DRSS 53, and so on. As you see more severe diabetic fundus manifestations. Bleeding. Leakage. And we’re attuned to showing patients pictures of their eyes. They may come in and say… Dr. Ho, I’m not having any problems with my eye, but they may show up with a DRSS 53, like you see towards the right. Where they’re on the edge of a cliff. And they’re at risk for significant vision loss. And the problem with a diabetic working age patient is that it’s hard to sustain injections and injections and injections. It’s hard to take off work. It’s hard to pay that co-pay. It’s hard to make a retina appointment when they’ve got other medical comorbidities and have other medical appointments. It’s hard to get child care. Because they’re working. These are the many issues that cause loss to follow-up with diabetic patients. And therefore a durable enduring biofactory approach is particularly attractive for patients with diabetic retinopathy. And in the preliminary… These are small numbers in the RegenX program on the right. We’re seeing two-step regression turning the clock backwards to less severe disease on photographs in the RegenX suprachoroidal program. That’s similar to what has been seen in the ranibizumab or Lucentis monthly and the aflibercept bi-monthly programs. 40% to 50% reductions when you have significant diabetic retinopathy at 3 and 6 months. So very kind of encouraging. Good safety profile to date. And the summary of the phase II ALTITUDE RegenX suprachoroidal program, office-based, very well tolerated, no inflammation… And we’ll see. We’ll see how this goes. We’re excited about this. A one-time in-office injection of gene therapy, to have durable, long lasting improvement in diabetic retinopathy severity. Reducing risk of vision threatening complications. Would be very attractive in light of all the things that make it hard to be compliant when you have diabetic retinopathy. And so at least for our sponsor again, I would like to thank RegenX. There are multiple programs going on. Including a pivotal subretinal operating room delivery of RGX314 for wet AMD. We’re seeing a suprachoroidal approach for… In the office, for wet AMD and also diabetic retinopathy, and the suprachoroidal to subretinal approach for cell therapy programs, and for geographic atrophy, gene therapy program, the Gyroscope program. Just to show you that… Nothing really stands still when we’re talking about delivery. One of the fun things is looking at and evaluating different new devices. This is an Oxulumis device, that has an illuminated catheter so you know when you’re in the suprachoroidal space. It emanates when you’re doing the injection so you can see it. This is Marc Desmets showing the illuminated microcatheter. We’re working on a couple of programs with them. You can see the suprachoroidal space. And there it is. Verification that you’re in the correct space. So precision and consistency of dosing is one of the themes today that I’m highlighting. And that is continually being evolved in this ecosystem of instrument makers, design engineers, surgeons. And of course, the patients. That allow us to do this. So we’ve talked about gene and cell therapy. I can tell you that I think gene therapy for common retinal diseases and the biofactory approach is promising. We need to do more work in larger trials, randomized trials, but we have multiple companies that are looking at this. RegenXBio, Adverum, and others. The traditional standard vitrectomy retinotomy approach is time tested and the most familiar. The suprachoroidal, the subretinal microcatheter approach is more nuanced, it is FDA approved, more surgeons are learning this, and it may be particularly amenable for cell therapy delivery, in my view. Because there’s no opportunity for egress of the cells in the intraocular space. The suprachoroidal injection I just showed you has a really potential advantage, because it’s office-based, and the instruments are still evolving. It’s really fun to be involved and to see us moving to new therapeutic options, hopefully not too much in the distant future for common diseases. I would like to really thank Hunter and Larry, who I have been communicating with at Orbis. I would like to thank Ron Palanki, who is a colleague and friend who encouraged me to get more involved with Orbis. And I think this is historic. And I appreciate the opportunity to be here with everyone. Thank you very much. I think we’re gonna move to an opportunity for me to answer questions that I see. Maybe, Larry, you can tell me if that’s correct.

>> Yes, thank you, doctor. So you can go ahead and stop your screen share. We have three live questions as of now. So you can open up the Q and A.

DR HO: Okay. We have a few questions here. Suklengmung Buragohain has asked: How much would be the cost difference between these novel methods in comparison to traditional anti-VEGF injections? When can we see these methods coming into clinical practice, especially in a developing country such as India? That’s a really good question. Now… I think that when you’re talking about gene therapies, let’s go to what’s out there now. The Luxturna gene therapy program for Leber congenital amaurosis is very expensive. On the order of hundreds of thousands of dollars. More towards a million dollars per dose. These kind of therapies, I think, let’s say, for wet AMD or diabetic retinopathy, will be less expensive than that. And they’ll have to come in at a point where cost of injections over time will be similar to cost of maybe a one-time delivery. So if you take 750,000 for Spark Luxturna, and bring that down to… I don’t know what the number would be, to be honest. I would be just purely guessing. 100,000? 200,000 for delivery? That would still be very expensive for a developed country. But we need to establish these things first. And then figure out how to get them everywhere. The next question by Nehal Youssef. As an ophthalmologist in a developing country, how could one be involved in advanced trials? That’s a really good question. And as some of the trials go global, I would say to be in touch with the companies that are doing these programs, and to try and get involved in that fashion. Shola Dada has a question. A vitrectomized diabetic patient had routine intravitreal Ozurdex injection in an eye with DME of around 400 to 500 microns thickness, second injection. The Ozurdex was misdirected to the macula with a subretinal hemorrhage developing immediately. The OCT scan, however, showed a significant reduction of the macular edema by the second day. Unfortunately she had long-term poor vision to which the vision returned with the hemorrhage clearing up within a few days. What are your thoughts? We don’t like to see an Ozurdex hit the macula. But I’m happy that the macular edema went away. So when you’re directing an Ozurdex injection, I’ll often direct tangentially, rather than straight to the back of the macula. I’ll have the patient seated up and then delivery inferiorly, so that gravity will undermine the ability of the Ozurdex missile, if you will, from going towards the macula. Chee Ming Lee asks: Is intravitreal injection for gene therapy a possibility? And the answer is yes. There are a couple of programs working on that. Adverum is working on that for macular degeneration. They stopped for diabetic macular edema. Because of inflammation and some safety issues. They’re going to lower doses. Morteza Mortazavi Fard asks how many times gene therapy are needed in such chronic diseases? The hope is one and done, but we’re not sure. Boniface Mandishona asks: Anti-VEGF strategies don’t seem to address the primary driver of neovascularization, ischemia. I think you’re right. You need to think about going higher on the pathway, above VEGF. Like the HIF factor, or other ways to strategize, to affect the microvasculature, that gets undermined in the capillary beds, when you have diabetic retinopathy. Olalekan Aremu asks: There are a number of genetic research going on in Africa right now, especially through H3 Africa Initiative. Are there ways these genetic research in ophthalmology can involve the African population? We definitely need to continue to diversify those patients that have access to all these novel therapies. Not just novel therapies. But diversity in access is important. And I agree with that. Pat Otieno asks: How old is the youngest patient you have treated with these new therapies? What are the rates of clinical success, compared to the traditional treatments? Well, some of the treatments that I’ve treated in the young patients are the inherited retinal diseases patients. We’re doing some collaborative work with University of Pennsylvania on patients with Leber congenital amaurosis. Not the Luxturna, the Spark mutation, but others. And I’ve treated teenagers. Is unilateral gene therapy effective for the contralateral eye? From Morteza Mortazavi Fard. That’s a good question. People have made that observation in the GeneSight trial for Leber’s hereditary optic neuropathy, of the gene therapy affecting the other side. Fascinating. Not well understood. Systemic transfer? Or through the visual optic chiasm and pathways? The answer… Your question: Is it effective? The answer is unknown. But there are some observations of contralateral effects. So… Wow. That’s a lot of questions. And Larry, thank you for the opportunity to engage. I wish I could see everyone. It’s a little… Challenging without that.

>> Thank you. I believe there are four more questions, if you see them. If not… You can let me know.

DR HO: I don’t see the chat anymore.

>> If you could reopen the Q and A… If not, I can read the remaining questions.

DR HO: Why don’t you just go ahead and read them?

>> Sure. So the next one is: As the sclera thickness might vary for a suprachoroidal approach, how can one adjust or actually avoid getting deeper towards the peripheral retina?

DR HO: There is variation in scleral thickness. So the needles that are used are 900 microns. And then if you can’t inject… In other words, you feel resistance… You go to the longer needle. It’s a good question. Thousands of patients have been injected, or thousands of injections have occurred over I think hundreds, maybe thousands of patients. And really the idea of perforating an intravitreal injection has been rarely seen. The Oxular cannula that I’ve shown you, that illuminates, is a nice way to know you’re in the right spot. I kind of like that. But using just the needle lengths themselves and the techniques… Have been pretty safe for suprachoroidal injection.

>> All right. And the next one is how old is the youngest patient you have treated with these therapies.

DR HO: Teenagers.

>> And what are the rates of clinical success, as compared to the traditional treatments?

DR HO: For some of the treatments in the youngsters, it’s been… There is no alternative treatment. Because they’re inherited retinal degenerations.

>> All right. Next, is this gene therapy effective in AMD with advanced geographic atrophy?

DR HO: We’re working on that. That’s what I was trying to show in the Gyroscope program. Is it effective? Not sure yet.

>> Next is: What is the material injected in the subretinal space in AMD and what is it in DME?

DR HO: Anti-VEGF trans genes.

>> Next question. Is this gene therapy effective in cure for colorblindness?

DR HO: No.

>> All right. Next is… Are there oral gene drugs for the retina?

DR HO: No.

>> All right. And the last open question is: Seeing into the future treatment possibilities, we hope cost will allow us in the developing world to access these treatments. So more of a comment than a question.

DR HO: Very much a theme. And a focus for Orbis, most certainly. So I agree.

>> All right. And that seems like all of the open questions as of now. So we’ll give it about 30 seconds. If not, we can close the session.

DR HO: Great. You know, the videos… That I’ve shown were collated across a variety of clinical trials. And it’s just a reflection of how much activity is going on for unmet needs. We have some treatments for wet AMD, for example. But trying to get better, in terms of even better vision. Better in terms of less burden of treatments. Since patients have to come in all the time.

>> Thank you. And just two more questions I see. If the patient has cystoid macular edema with macular traction, can this be effective?

DR HO: No.

>> And another is: Did you encounter any allergy/reaction or side effects?

DR HO: Side effects are a very important part of the initial assessment of these therapies. And some of the intravitreal gene therapies have seen inflammation. The eye has some immune privilege as compared to the rest of the body. And I think there’s some relative immune privilege, probably greatest in the subretinal space. That is, you can inject something foreign there and not elicit an inflammatory reaction. Then maybe in the suprachoroidal space it would have some relative immune privilege, but maybe less than subretinal. And then finally, intravitreal… I think… May have the least immune privilege. And we’ve seen some programs where there have been inflammatory responses. So we monitor that carefully. I can tell you that in the RegenX subretinal program, where we’ve had the most experience, those eyes are amazingly quiet. They do not require systemic steroids or immunosuppression. Just the usual topical postsurgical drops.

>> Thank you. And then one other one that just came through is: How to get in touch with companies conducting such trials. And how could you guide fellow ophthalmologists in developing countries.

DR HO: I think education is one way we can guide to give people a sense for what’s going on. Programs like this, through Cybersight, that are focused, more globally focused, defocused, is one method to keep people up to date. Communicating with the companies themselves… A lot of programs are focused kind of where they are. So it makes sense that they might focus more on, for example, sites — clinical research sites in North America. But some programs will need to go global, because they’re looking for approval globally. And that’s when having your name in there, by communicating with the companies themselves, could be helpful.

>> And any unexpected proliferation of cells or rare possibility of metaplasia or tumors?

DR HO: Yeah, no tumors. But we have seen in cell therapy trials epiretinal membrane formation. And more. Even on rare occasion traction retinal detachment. So cell therapy has its own challenges. Because the cells can — not form tumors, but can form membranes on the surface of the retina.

>> And then a follow-up question was: How about endophthalmitis following these treatments?

DR HO: Have not seen that to date. But that is obviously a possibility. It’s something we consent for. When we’re doing invasive procedures.

>> All right. So that seems like all of the questions.

DR HO: I really want to thank everyone again for the opportunity. I wish I could see you all. And Larry Hunter, Ron, specifically, my contacts there — thank you so much.