Lecture: Stem Cell & Gene Therapy for Ocular Genetic Disease: What Technologies are Already Transforming the Ophthalmic World?

This live webinar will focus on state-of-the-art development of treatment technologies for genetic eye diseases. All subspecialties will benefit from learning about how ocular genetics is (and will be) transforming eye health as well as the patients, families, and communities we serve. A live question and answer session will follow to address clinically relevant pearls for practice with open chat available to all those who attend.

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


[Alex] Nice to see everyone. Thanks for joining us today at this Cybersight Orbis webinar. I’ve been asked to talk about stem cell and gene therapy for ocular and genetic disease. I’m the chief of pediatric ophthalmology and ocular genetics here at the University of Rochester and the chief of pediatric genetics. And I was thinking about how to do this talk. And at first they said, what do people want? I could sit here and I could go through trial after trial and tell you what the protocols are and what the actual results have been so far, what’s available. But you know, I think that would just do this, it’ll get you all sleeping. And instead what I’m going to try and focus on is more about the basic principles that are operating, bring you up to date on how they’re being applied, what general concepts about some of the trials. And the tribulations, what’s working, what’s not working, where we’re going, how we’re thinking about this, what are our challenges going forward? And since this is an international audience, I’m going to spend some time talking about how this technology can be translated to the entire world.

I know that many of you are, maybe, signed into this talk hoping that you can get gene therapy for your patients tomorrow. You want to know how to get access, you want to know what’s going on? Again, I’m not going to go trial by trial, but I’m going to give you enough information to get you in that direction so that this will hopefully be applicable in the near future to your patients.

I’m going to give you an idea of where we’re headed. Where are we going, where is this all taking us? How are we going to make it accessible to the whole world, as well, and affordable? And then we’ll have time for a question and answer period at the end.

Why do we bother finding genes? We bother finding genes, and by the way your questions and answers can go in the question and answer function of Zoom. We find genes because if we know a patient’s genotype, that leads us to appropriate diagnosis, which leads us, in turn, to appropriate counseling of a family, recurrence risk, and things like that. But knowing the patient’s gene also helps us understand how the disease happens, how it works. And that’s, in turn, going to lead us to cures for some of these disorders.

The eye is a perfect organ for gene therapy. First of all, it has immune privilege in many ways. Some of you may remember the case of Jesse Gelsinger, a patient at the University of Pennsylvania over a decade ago who got gene therapy for hepatic disease and subsequently died. There’s a lot of ethical issues, a lot of concern, but it’s unlikely that the eye is going to be a place where we’re going to see gene therapy spreading to the rest of the body and giving untoward side effects. And of course the eye is very accessible. We can put injections in and around the eye, we’ll talk about that. And the target cells can be visualized. The only place in the human body where we can actually see living organ: living tissue, nerves and blood vessels. That’s why we’re all in ophthalmology anyway. So that helps us with these therapies.

There’s hard ways to do it and easy ways to do it. Here we see a schematic. It’s nice to see that it’s somehow got flipped around backwards, but that’s okay. Where we take a needle, after doing a vitrectomy, through the pars plana, hope you can see my pointer. And it goes into the sub retinal space, where it injects a bleb of the delivered treatment agent, in this case a virus that’s been modified to carry the appropriate gene. That infects the retina and delivers the cargo of that virus into the retinal cells, in effect gene therapy. That’s hard, any retinal surgeon can do this. It’s not really that hard. There are technical challenges that we’ve learned over the years to make this easier. 40 gauge needles so on and so forth, technology that can help us do it. But there may be even easier ways to give gene therapy. For example, what about eye drops and the idea of using gene therapy in the form of eye drops for corneal dystrophies is something that’s being worked on right now. There’s been a clinical trial using it for the PAX6 gene for anaritic keratopathy. Putting the gene directly onto the surface of the eye to treat one form of mutation in that gene.

There’s a wide variety of delivery systems available to us. We can inject around the eye, into the anterior chamber, into the vitreous, sub retinal space, all of these routes are technically not that challenging for us. And in fact, if you’re on this Zoom and you’ve ever prescribed latanoprost or a prostaglandin analogue for glaucoma, you’re doing gene therapy already. Because these drugs work in part to altering the transcription of metalloproteinase genes. It’s not so far-fetched that we could deliver gene therapy topically to an eye because, in fact, we’re already doing it.

What is gene therapy? What do we mean when we’re talking about gene therapy? It actually means many different things. The bottom line is that gene therapies are therapies that are initiated and based on an understanding of the genetic knowledge of a disease. For example, we might use gene therapy to replace the protein that is not being made by a gene. Instead of fixing the gene itself why not just deliver the product of that gene that isn’t being made? We can up regulate or down regulate genes. That may be in the case of up regulating beneficial genes or down regulating genes that are harmful. We can actually replace a gene, or its function, or lastly we could fix a gene. These are all forms of gene therapy.

Here’s an example. We could regulate apoptosis. Apoptosis is the final end route, a genetically programmed route for cell death. It’s the pathway by which patients with retinitis pigmentosa lose their vision, it’s the pathway by which patients with glaucoma lose their vision. We could up regulate genes which are anti-apoptotic: bcl-2, bcl-x. Or we could down regulate genes that are pro-apoptotic. We’re not treating the disease per se, we’re affecting the end organ effect of that gene defect.

We could regulate other steps. For example, PR1 is a gene which down regulates NR2E3. It’s been shown in animal model, we know that NR2E3 is a gene which when mutated is associated with a variety of phenotypes. Intraretinal cystoid spaces, pigmentoid retinopathy, enhanced S cone syndrome. And this gene is involved with promoting the differentiation of cells into cones as opposed to rods. If you have a rod disease, you could down regulate this gene to promote cone function. You could use these genes to alter this pathway without actually fixing the gene itself or replacing the gene itself.

Different inheritance patterns are going to demand different approaches. An autosomal recessive disorder where both copies of a given gene are dysfunctioning or malfunctioning or no mutations. So you’re getting no gene function, you have to replace the entire gene function. You don’t have to replace all of it, you could just replace one copy of the gene to turn that patient into a heterozygote carrier as long as it’s a disease where being a carrier has no functional deficit.

If it’s an autosomal dominant disease where one gene not working is enough to make you not be able, make you can’t function, you get the disease. We could increase the expression of this allele. So now that we say double the amount that this is making to cover for the haploinsufficiency of this copy not working. Some autosomal dominant diseases work because this abnormal allele makes a protein that’s defected and binds to the protein made by the normal allele, thus causing what we say a dominant negative effect where both that combination causes there essentially being no functional protein. If we could inhibit this allele from making its bad stuff, then this in itself may be enough to prevent the disease. Different inheritance patterns are going to affect the approach that’s necessary to treat a disorder.

In order to do gene therapy, there’s going to be some prerequisites. Number one, obviously, the genetics of the disease need to be understood. The treatment has to be efficient and non-toxic. We have to make sure that it also does not cause off target effects, like what happened with Jesse Gelsinger. We want this to only treat the end organ of concern and not to create other problems in the eye due to manipulations of other genes with expression of the target gene in another tissue. Lastly, it helps if we have an animal model for testing. Some way to make sure that we’re on the right track.

Most gene therapy uses viral vectors. Adeno-associated viruses of many types, two, nine, et cetera. And these viruses are essentially the viruses that cause the common cold. Those viruses, when you get the common cold, infect our nose cells and deliver bad genes into our nose cells that cause the symptoms of the common cold. If we take the guts of that virus out and replace that only with the cargo that we want it to deliver, say normal copy of the gene with the mechanism that will allow that gene to be expressed, and put it under the retina, it will infect the retina and deliver not the common cold, but deliver the therapeutic agent, the gene that you want it to deliver.

There are problems with this virus and the other viruses that are used. Sometimes they have a limited capacity. If you have a big gene that may not be able to fit into a virus or adenovirus, let’s say, we have to come up with alternate strategies. Also, different viruses have different efficacy in infecting target tissues. Again since AAV9 can go through the entire retina better than AAV2. All of these have to be taken into consideration.

In 2008, “New England Journal of Medicine” was a landmark study for Leber’s congenital amaurosis, patients who have the autosomal recessive disease, RPE65 mutations on both copies of their gene that causes LCA2. They injected three patients in the UK, three patients in Philadelphia. They were young patients. UK patients had no improvement and Philadelphia patients, one had a macular hole and we’ve learned how to reduce that risk a bit. There were slight vision and visual field improvement and one had a change in function. But the key thing here was ocular gene therapy had started. The door had been opened.

In 2009, in “Lancet” 12 patients were reported from a variety of ages and they had either LCA or later onset retinal dystrophy. Again, to biallelic RPE65 gene mutations. And keep in mind, we get questions all the time from patients about this treatment. It only works if you’ve got both alleles of your RPE65 gene mutated. It’s not going to work for another gene. One eye that is the worst eye in each situation was treated with this subretinal viral vector. Results, one had a foveal hole again. All said their vision was better but when you look at their acuity: seven were better, one was worse, four was about the same. The improvements were small but they were real. The authors said that the visual fields were better but not really when you look at them. The ERGs did not improve and in follow up they’ve been stable, three, five years down the line and longer. But here’s the key. Using an obstacle course, we saw some dramatic improvements. And the obstacle course is designed to test the patient in lower levels and varying levels of illumination. And let me show you how this came out.

Here’s a boy, he’s going to be treated, we’re going to patch the eye that is not going to be treated. So he’s asked to navigate this course with the eye that is going to be treated. Let’s see how he does. Oh, hold on, there we go.

He gets on the course, he’s very hesitant. Remember he’s using the eye that’s going to be treated. He’s going to wander off the course. You see, there he goes, wandering off. Someone’s going to come in and reorient him, get him back on. And he’s going to try again and he just can’t do it. He can’t do it. Right off the course.

Now we’re going to treat this kid and he’s going to be on the right screen. And a few weeks later after injection, let’s see how he does. He’s using the same eye to navigate the course. Right side of the screen. Right on target, same kid, very good. He’s going to step up over the step, down, step over another hurdle, keep going. It’s amazing. That is impressive. That is really incredible. That’s a kid who went from essentially hand motion vision to riding a bicycle, going to normal school, hitting a baseball, incredible functional improvement.

And in January of 2018, two years ago, three years ago, this was approved by the FDA in the United States for children over one year of age, one year and up, for treatment of biallelic RPE65 disease.

Since that time, there are many, many, many trials going on around the world, gene therapy in the eye. We have other LCA genes under trial. And the strategies have been different. What I showed you was a gene replacement trial. There’s a trial going on for CEP290, another gene that causes a form of LCA. Where you have a specific mutation, this is a hotspot mutation, in an intron of the gene we can use a molecular mechanism to block that mutation so that that intron which when mutated causes abnormal splicing, is now skipped over and normal splicing occurs. That’s an alternate strategy. We don’t have to take the whole CEP290, we essentially are fixing the defect or masking the defect to let the patient’s own CEP290 transcribe.

Retinitis pigmentosa genes. USH2A is a difficult one because it’s too big for adenovirus. One of the trials that’s being developed is to take the gene, break it into two, put two viruses in at the same time, and then their product will reconnect in the eye after the injection to create a functional gene.

XLRP has several trials going on around the world. These trials are moving into the phase three and are showing some promise as well.

Choroideremia. Choroideremia’s been a little bit of a challenge. There’s been some, a little bit of success but some disappointment as well. We have to consider what it is about choroideremia that makes it difficult? We know the gene, the gene codes for protein REP-1 protein. But one of the problems is that in choroideremia you only have a tiny polygon of vision left in your fovea and you have to raise a bleb under this small remaining healthy part of your retina. Number two, although the mechanism is not well understood, we have choroidal loss, vascular blood supply loss. I think we need to learn more about choroideremia as a disease to get a more effective treatment. Although trials are ongoing.

Juvenile X-linked retinoschisis has been very promising in the mouse model. Less promising so far in the human model with problems due to vitritis and inflammatory approach to the agent which is injected intravitreally. This is just a smattering of the many trials that are being developed. There’s trials for Bardet-Biedl, trials for Batten’s disease, which we’re involved with here. And many other genes that are under investigation for retinal therapy. If you’d like to get a list of all the current therapies, if you go to the AAPOS, American Association of Pediatric Ophthalmology and Strabismus website, the genetic taskforce for that, genetics committee now for that, we put on there and update every month a list of all the active trials in the world. And there’s many more.

For Stargardt disease, we have another problem again. The gene is too big for an AAV virus. Maybe we could break it up. But there’s other ways to approach Stargardt disease. Not only gene-base, but how about regarding lipofuscin removal. The basic pathophysiology is you get the accumulation of lipofuscin under the retina, which for lack of a better term, poisons the retina. If we could remove that lipofuscin, or if we could prevent lipofuscin accumulation, those would be effective therapies for this disorder. And there are several trials that have been underway to try and use medical treatment to limit accumulation or increase clearance of lipofuscin. Again, the genetic defect would not be fixed in those cases, but the downstream effect of that would be attacked.

Leber Hereditary Optic Neuropathy, intravitreal gene therapy for the 11884 mutation has been tried. It has shown some promising effects, although it’s still to go into final trials. And again, the neuronal ceroid lipofuscinoses, the Batten disease, so to speak, these are the CLN genes. CLN5 therapy is going to be starting here with both an intraventricular treatment as well as a subretinal treatment. CLN3 is going to be into clinical trials soon as well, as other CLN genes.

Achromatopsia has been a gene of interest. Basically based on the animal treatments. I”m going to show you the animal work that’s done here by a company, Neurogene, which I am a consultant for. Here’s a sheep, you can see he cannot, sheep doesn’t know, can’t find his way out of his pen. If we treat him with the virus, we’ll see what he can do thereafter. Here he goes. He gets right out and can see the barriers and follow along. Gene therapy packs strong potential for disease.

Will it work in humans? We’re not sheep, we’re not dogs. Animal models are helpful, we will have a lot to learn as these trials unfold. And the answer is we just don’t know. And it’s important that patients know this as well and we’ll get back to that in a little bit as well. How do we figure it out? You have got to do the research. If you do the research, you have to enroll the patients. But managing expectation, which we’ll talk about, is very important.

All of the therapies I’ve showed you so far are therapies which are gene mechanism dependent. Another way to approach retinal dystrophies, for example, is gene agnostic approaches. That is approaches that will silence any gene or many gene defects with the same therapy using small interfering RNA to bind products. To preserve the rod derived cone viability factor. As you lose your rods, you in turn lose your cones because of the loss of this factor. If we could preserve this factor or deliver it in another way, we may be able to preserve central vision. We already talked about retinal rescue, the anti-apoptosis genes.

And lastly, there is optogenetics. The idea of using photo pigments, largely from the animal kingdom, that can be injected to infect ganglion cells or bipolar cells through an intravitreal injection and turn them into photoreceptor genes. Remember that in the outer retinal dystrophies like RP, the inner retina stays intact for a long time. And if we could stimulate that directly, the very basis, by the way, for things like the Argus implant, through optogenetics make them photosensitive, perhaps vision could be restored. And that has already been done as well.

Stem cell is another way of delivering things like rod derived cone viability factor. The only stem cell trials that have gone on so far are genetic trials, sub retinal intravitreal, to try and deliver factors or get differentiation. But we’re early in the game and I’ll tell you more about that.

One way to do stem cell would be to take a three millimeter skin punch from the patient, to convert fibroblasts from that skin into potential stem cells. And then convert those stem cells into photoreceptors. You could CRISPR correct ex vivo the genetic defect in those cells and then you could reimplant what is essentially the patient’s own cells, we can reimplant the patient’s autologous cells back under the retina, now corrected for the disease. CRISPR has been used in vivo as well, in a study centered, I believe, in Boston to correct gene defects in the photoreceptors proper. But if you don’t have photoreceptors in your eye, say on an OCT, to take up a viral vector then gene therapy isn’t going to work because there’s no cells to be cured and you would need stem cells to accomplish that.

This is a robot at the University of Iowa where we’re collaborators. And it’s an amazing system because what happens is this robot is capable of plucking from cell culture one photoreceptor at a time. And placing those photoreceptors in the correct polarity into a 3D printed grid. Each one of these would hold one, some studies have used more than one photoreceptor, that gets placed under the retina, delivering 500,000 cells in a disk. And you can imagine the benefit it would have for someone with advanced RP. It would get you central vision. Now is it going to cure the whole disease? No. But it will preserve or restore central vision in these patients.

And you might even ask, do we even need to know a gene? Because let’s say you get RP when you’re 40. Now you’re 75. Well, if I give you the same cells back, healthy RPE cells made from your skin fibroblasts, I don’t need to fix that gene. Because if you’re 75 when you get the injection, it’s unlikely you’re going to be alive 40 years later when those cells will begin to get sick with RP. It gives the opportunity to give autologous cells without even doing the CRISPR correct in the gene defect. And then, again, using them agnostically to provide other factors that are missing because of the gene defect.

Let’s take, we used to think this was all dreams and science fiction. But I assure you this is very, very much real and very much happening now.

Let me give you some small examples and some big examples, just to give you an idea of what the potential is of gene therapy. If we take this cell with albinism in the top. It has a TCT instead of a TGT in the tyrosinase gene. And as a result of that mutation, that sequence change, doesn’t make pigment. If we were to transfect that cell with an oligonucleotide, DNA-RNA oligonucleotide, that has the correct copy of that gene with liposome transfection, that C will be changed to a G and we’ll get a cell that makes pigment. Well, big deal, we fixed the cell. If we take this oligonucleotide, make it into an ointment, rub it onto the back of a mouse that has full-blown oculocutaneous albinism from this very mutation, that mouse will start to grow black hair in the area that this is rubbed in. Who cares? To make mice have black hair. This person cares. Here is a woman with albinism. She’s got white hair, she’s been made fun of all of her life, she’s been stared at on the subway. You can’t dye hair with a patient with albinism well. But if I could give her a shampoo that would make her grow black hair, I would change her life.

Let’s take another bigger example. The problem with albinism is that the RPE is the first cell to pigment in the human body, at five to six weeks of pregnancy. If we want to prevent the retinal effects of this gene defect, we’d have to get in at a time when a mother doesn’t even know she’s pregnant. But there has been postnatal study underway, we don’t know the results, using gene therapy to see if we could restimulate pigment expression and foveal development postnatally in albinism.

Likeways, patient with aniridia with a mutation in the PAX6 gene. WE know that every cell in the human body contains every gene. There’s no cells in the eye that just have eye genes. The cells in your nose have the same genes, you’re just turned on. If we go to a fly who’s PAX6 gene is over 70% the same, identical to a human’s, and we turn the PAX6 gene on in an area where it’s normally not expressed, like its antennae, it will grow a new eye. The PAX6 being the master control gene for the eye, it’s not hooked to the brain. But think of the enormous potential. We know the mechanism to make an eyeball. If we think from the shampoo to this, small to big and inbetween, all the retinal therapies that I’ve talked about so far. The possibilities really become quite endless.

It’s very exciting. All of our patients should be excited. You should be excited. But let me ask you this. Is this a success? We have one FDA approved treatment right now. The RPE65 gene. We can treat one gene. This is treatment I’m talking about, not research, treatment. It took 20 years to treat one gene.

In the United States, there’s probably 250 eligible people. Maybe a bit more depending on how you count and who’s really eligible. It only works on some. Most patients have some improvement but those dramatic effects don’t happen in every case. There are only 10 centers in the US, we are one of the centers here in Rochester, who are allowed to deliver this treatment. So it’s hard to get to. And it costs 425,000 US dollars per eye. $850,000 to treat both eyes and most treatments with patients who have one eye want their second eye treated. This is not sustainable. If every gene therapy costs $850,000 we are not going to be able to sustain this treatment, let alone deliver it to the third world. Keep in mind that the quality of life years that you gain by not being blind, and that’s how they’ve offset this. And insurance companies are paying, so far, for this. But as treatments get more and more, either the cost has to come down, certainly the 20 year span is coming down. We have to get the pipeline to move faster, which it is. Cost is going to have to come down. Somehow, someway, we’re going to have to make this better accessible.

And questions remain. When do we treat? We treat early, do we treat later? Is it better to wait until a patient’s? Well obviously we treat earlier you’re going to prevent a disease from happening. But at the same time, that means you wind up treating patients with better vision. If you had a treatment for a disease that’s going to come 10 years down the line, should we take that patient when they’re 20/20? When they haven’t expressed the disease yet and treat them and take those risks of surgery? Do we treat them before they’re even symptomatic?

Does treatment place limits? If a patient gets into a trial, one trial, does that limit their ability to get into another trial or to get treatment when it’s approved? That is an unknown question. What if you have a medical treatment for Stargardt’s, and then there is a gene therapy? How do those conflict, we don’t know that answer? The durability question still remains. There’s been some conflicting data about RPE65, but in general, it is a durable treatment. But will it be durable for all these diseases? For example, choroideremia.

And what about the ultra rare genes. There are some diseases which we know of only four patients in the world that have this disease. These ultra rare genes, how are we going to afford? Companies are delighted to get involved with Stargardt research, it’s the most commonly mutated gene in the human eye. They see dollar signs. They’re not going to be interested in the gene therapy development if there’s only four patients to treat.

And who should get treated? Do we treat one eye, do we treat two eyes? Do you treat patients who have cancer and you don’t know how long they’re going to live? Do you treat patients who have immune problems? We have so many questions you have to answer. And lastly, who’s going to pay? That’s a big question.

And of course with all of these questions, we also have to define success. If an ERG stays the same and a patient can navigate a mobility course better, that’s a measure of success. Do we need visual acuity get better? What is our measurement? And there’s all types of studies, natural history studies going on for many different genetic disorders, to try and define what are the parameters that are going to be used to define success? Let alone the parameters I just showed you are: is success defined in time, money, and resources, and eligibility?

And of course there’s ethical issues as well. We now have the ability to make flowers without stamens, featherless chicken, unusual animals. We say, eugenic gene therapy, come on, that’s World War II kind of stuff. Should we be spending resources to treat red-green color deficiency, which really isn’t a disease, so to speak. People who have it function entirely normally in their lives. Yet people are doing research into primates that has shown that we can successfully restore color vision descrimination to primates. Do we want to be doing that?

And we see this all the time. This is from 2011, not long ago, redheaded donors not wanted at world’s largest sperm bank. Is red hair a mutation, is it a disease? This is all the kind of issues that really do confront us as we tread into these waters.

And then we’re faced with the desperate patient. Our patients with these disorders, these blinding eye diseases that are currently untreatable will do anything. They will do anything. I have patients that come to me and say, “My son’s got this disease, can I donate my eye? You can take my eye right now, donate it to my kid.” They are really prone to being misled and we have to respect that. We have to really have a healthy respect for that.

Patients ask us, does it apply to me? Will it ever apply to me, what can I do to get gene therapy? Let me answer some of those questions. The process for all gene therapy is going to be adults first unless it’s a child onset disease. Poor vision patients usually go first. Check for safety. We have our phases, phase 1, safety 2, dosing 3, et cetera. There’s usually an observation period and the FDA, for example, can make that quite long. They can say we want to wait two years before the next patients get enrolled. And we have limited enrollment, they’re saying out this number of patients can be enrolled. And in many places that do gene therapy, they already have a list. When they open up their door their list is filled and your patient can’t get in.

And there are always inclusion/exclusion criteria. Have they had prior surgery, do they have systemic disorders, what’s their vision, what’s the vision difference between the two eyes? These are all things that come under consideration.

And of course, every family, every patient, I should say, every mutation is different and that makes the results somewhat unpredictable. Some of these therapies are geared to stop progression. Others are for vision reversal and patient’s expectation has to be managed.

How do I know if there’s a study going on? The best place to go is clinicaltrials.gov. But keep in mind that not every child that’s registered here, as all trials must be in the United States, are good trials. There’s been some very bad, dangerous trials, particularly with stem cell injection, that have been listed on clinicaltrials.gov that you wouldn’t want to have your pet involved with because they’re so dangerous and have blinded eyes. But this can tell you what’s out there, who the study contact is, gives you a minimum of details about the study, some of the eligibility criteria to tell if your patients are eligible.

Really what you need is someone in the know. Going online and trying to sort this out on your own is not very helpful. You need someone who understands this process, who understands how to get enrolled, has the contacts to make this happen.

It isn’t the treatment that’s really the hard part. It’s the gene diagnosis that comes first. That’s the stumbling block. Except for the gene agnostic treatments, you’re not going to get in unless you get a gene diagnosis. And that is what I tell my patients. I say look, the first thing we’ve got to do is get you a genotype, we have to have a diagnostic answer before you can even think about a therapy. We need an extensive workup, which is OCT, and fundus autofluorescence, ERG, et cetera. We have to define your clinical phenotype. That allows us to do DNA testing to get your genotype, that’s the entry point into most studies.

The holy grail would be if we could do this for everybody, right? Every disease could have gene therapy to restore vision. These studies are going on in the gray portions of this graph. Not a lot going on in these other counties. And in fact when we’re thinking about therapy, we have to ask how are we going to access the rest of the world?

Most of the world remains poor or low- income. If you look, over half the world, or the majority of the world, is in the low-income or poor group. 71% of the world lives on less than $10 a day. Luxturna costs $425,000 per eye which is $1,164 a day for one year. How are we going to get this treatment out there? Can they get gene therapy in that 71% of the world? What does it take to get it there? It’s going to take a local method of diagnosis, clinical and diagnostic testing and that’s for sure. You have to have the machines to do the diagnostic testing, and the ability to do genetic counseling which is required for gene testing. You have to have access to genetic testing and then comes the treatment. There’s a whole bunch of steps before you can even think about enrolling a patient.

You make a diagnosis by having an ocular geneticist. If we look at what’s happened over the years as the number of genes have grown dramatically and who knows where it is going. This is the International Society of Genetic Eye Disease formed in 1975, the first gene in eye disease for RP was Rhodopsin in 1990. What’s happened to the membership of ISGED? Not very much. Our genetic knowledge is outstripping our providers. If you’re out there and you’re not a geneticist and you’re not an ocular geneticist, and you’re thinking well, I’m a retina doctor. I’m an ophthalmologist who sees patients. Are you going to be able to do this? It’s going to be hard to get those resources.

Ocular genetic counselors, there’s only 30 or 40 of them, we have to train those as well. I will do an advertisement. Orbis Cybersight is opening up an ocular genetics consultation service, I’ll tell you more about that in a second. Where you can send in your questions about a patient and we can help you find routes for testing and ultimately get patients we hope enrolled.

How do you make an ocular geneticist? Fellowships. There’s not a lot of fellowships in the world. We have two funded fellowships here at University of Rochester, we welcome applications from around the world. Depending on where they are in the world, they can be one year, two year, with or without a research component. But it can be done. These are the fellows that I’ve trained over the years from around the world. Brazil is coming this January. There is a way to get people out there so we can populate. Our current fellow from Nigeria will be the first ocular geneticist in Africa.

We also have a training program for genetic counselors where individuals can come. It’s fully funded, we pay them a salary for six months, we’ll take an ophthalmic tech, even an ophthalmic nurse to train them in genetic counseling aspects. Or a genetic counselor to train them in the ocular genetics counseling. So they can go back to their home country to provide these much needed services.

There’s been studies that have looked at the availability of testing itself and they’ve all come to the same conclusion, we need more testing elsewhere in the world. This one says despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathway exists. You can’t even think about gene therapy unless you can do this basic element first.

This is from Canada, access to genetic testing for rare diseases, another gap in care. This is in the developed world.

Ed Stone has done some work, there’s an important paper I encourage you all to read. In 1,000 consecutive families paper from “Ophthalmology.” The second paper is the policy statement from the American Academy of Ophthalmology. And this has to deal with how do you test for these diseases?

We all have free panels and many of you from around the world are sending free panels with 300 genes, 400 genes, 800 genes that are company sponsored, they’re not really free. The company’s paying, they’re paying because they want to have access to the patients to get their $850,000 per treatment. But when you order these big free panels, you create what’s caused a large false genome rate. All this information, variance of unknown significance, that make it even harder to understand what the patient has. I get these patients all the time who’ve had this test and they come to me to sort out the test. They haven’t had genetic counseling. Who owns these patients? The company or the doctors? And there may be cultural and political barriers to blood leaving your country to do these panels.

You have the technology challenges that we’ve talked about of treatment and diagnostic technology. What if there was a way, what if there was open access treatment, no patents, no medical industry involved? Anybody can have it, all you have to do is send an email, we’ll send you the treatment. What if there was a way to do accurate low cost testing? What if there was a way to do low cost treatment? We can do the same treatments that we’ve shown here today, gene therapy, sub retinal injection for $20,000, not $850,000. Stem cell would be about $40,000. Commercial stem cell’s going to be much, much, much, much more expensive.

What if it was not-for-profit? It would lower the cost of testing by tiered testing. Sometimes I order one mutation and one gene if I know what the disease is, instead of a big panel. The smaller tests, and then we back off in the tiered system, the most common genes first, the less common as we go. We may eventually do whole genome sequencing to find an answer, but we get an answer in 80% of the cases. But we can save so much money doing it this way. Longer turnaround time, for sure. But there’s no urgent need to know in these patients what their result is until treatment is there. The average cost is less than $1,000 this way, but it’s free. The way we do it is completely philanthropically supported. My patients pay nothing for tiered testing.

Gene therapy is going to be cheap, $20,000. How do we do this through philanthropy? And you say, well, where is the money coming from? Well, guess what? We’re doing it right now in our collaboration with Dr. Ed Stone at Iowa. We’re totally philanthropically supported. And we’re taking it international through fellowships, through Orbis Cybersight consultation service that I talked about. To an information pipeline that we’re setting up so that we can deliver care to your patients and select them for gene therapy from afar and help you monitor them after treatment.

And it’s not so impossible. We don’t live in a world filled with money that’s dropping out of holes in the earth and going into the universe. There are rich people everywhere in the world. And there’s international and non governmental agency support all over the world. And if we can use this to underwrite this effort, we can supply the people, geneticists, genetic counselors, the diagnostic technology, ERG, et cetera. And the treatment.

Let’s imagine the plane of Orbis, taking off with a trained retinal surgeon who’s got in his pocket, or in the refrigerator on the plane, 10 vials of gene therapy. And he’s going to fly to a country that has patients who have been preselected via telemedicine and Orbis Cybersight ocular geneticist consults to be eligible for the disease. They’ve had their testing, they’ve had their genetic counseling through an Orbis-trained genetic counselor, let’s say, in their country or by Cybersight. And then this doctor goes and teaches the local doctors how to do the subretinal injection, treats those patients, and then fly away afterwards. This is the future, this is how we can get care into the rest of the world.

Unfortunately, stem cell can’t travel like gene therapy can. That’s going to be another challenge, that’s why it’s going to take longer for stem cell. I tell my patients, single digit years, gene therapy. It’s going to take at least another decade before stem cell is available more widely. It’s going to require local institutional buy in. Many of you are in countries where you’re seeing hundreds of patients a day. How do you do an ocular genetics clinic? It takes dedicated time and again, fundraising is going to be so important.

Our world is changing, it’s raising many opportunities here. We can do this! We can make this happen. Gene therapy is happening right now. Luxturna’s available. It’s been used in many countries. It’s being used here, it shows a lot of promise. And the door is open. I think with time, the FDA and other agencies are going to start to approve gene therapy more rapidly as we see the technology and repeated studies being safe over and over. But we have a ways to go.

It’s important that patients realize that this is still the future, with the exception of Luxturna and all its uncertainties. Patients have to realize when they’re enrolling in a trial, that this is still treatment, this is still research, it’s not yet treatment. And that therapeutic misconception that patients have when they get into a trial that they’re clamoring to do, is, “Oh, I’m going to get treated, I’m going to get treated.” You’re not going to get treated, you’re going to be a research subject. And we have to be honest with our patients. Hopefully it will work, hopefully they will get a benefit, but we don’t know that until we’ve actually completed the study. We have to avoid therapeutic misconception. We have to do appropriate genetic counseling, appropriate diagnosis. That way we can get our patients into trials and these trials can be at your doorstep, as can treatment in the not-to-distant future.

What do I tell my patients? I say I’m not sure. This is what we used to say. Patient would come in and I’d say, I’m not sure what you have. Heart disease, can’t diagnose it, see you later. You’re going to go blind, see you later. Nothing we can do, see you later. I tell my patients there’s going to be a treatment in your lifetime. There will be a treatment in your lifetime. I don’t know when, I can give them single digit years for gene therapy. I don’t know what it’s going to be, I can talk to patients based on their diagnostic studies whether they’re better candidates for gene therapy or stem cell. I don’t know if it’s going to stop progression or but, there will be a greatment in your lifetime. We have to change the narrative. The narrative now has to be you’re going to be cured or you’re going to be treated in your lifetime. Because that is the truth, especially for a young patient. Patients are worried about having kids. I tell them, look, when you have a kid 10 years or 20 years from now when that kid is born, it’s not even a thought, they’re definitely going to be treated. They’re not even going to ever experience the symptoms of the disease that you’ve experienced.

It’s an exciting time. If you have questions, there’s my email.

I’ve already shared the first ones, I shared the link for active trials. That was the clinicaltrials, all one word. Clinicaltrials.gov G-O-V.

What about gene therapy for ocular neoplastic diseases? I am not an expert on those diseases and I would be remiss to be talking. Suffice it to say that somatic cell therapy is very much alive and that is to treat tumors in sito. We have to be careful because we don’t want those treatments to stray from the target. But ocular tumors may be treatable by gene therapy and there is work in that sphere as well.

Another question, may I ask if gene therapy was successful, will it prevent the offspring of the patient to avoid that gene? We create our children via our eggs and our sperm. Treatments that correct a gene defect, whether it be stem cell or gene therapy in the eye are limited to the eye. And therefore the sperm and egg of that individual will still contain the genetic defect and still be able to pass that onto those individuals. The reason you’re asking this question is largely because of the rogue work of the gentleman in China who did CRISPR correction of a disease in germ cells. That was to permanently correct that person’s offspring as well. May have heard about the gene therapy involving the three parent baby from mitochondrial disease where you remove the mother’s mitochondria and put cytoplasm in from a donor while still retaining the mother’s nucleus and the father’s nucleus, a three person baby. That’s been approved for use in some countries, they’re only allowing it on men so it can’t be passed to another generation. But gene therapy to the eye cannot be passed.

We’ve covered that.

Can we do more to connect patients in the US with those in Europe and elsewhere in the world? Yes. There’s two ways to connect patients. And connecting is powerful because then we increase our sample size dramatically by doing that. One way is through platforms like Cybersight where you can reach out and we can connect you with individuals who are interested in your disease. Sometimes when a patient comes to me, every patient comes to me, we find out their gene, we do a trial search. As part of their care, we search the world for trials. As part of that search, if there’s no active trial, then we go to literature, or I go to my contacts and say, look, there isn’t something right now, I know a patient. I know a doctor who’s interested in your disease. And we let them know that so that they have some hope.

At the same time, we can start to form communities of patients and those communities can sometimes help affect change. There’s a book by Ricky Lewis called, blocking on the name, “The Gene Fix” I think it’s called. About how powerful patients can be and families can be in spurring along therapy. Look at “Lorenzo’s Oil” as a good example. But definitely getting in contact, the ocular genetic community is small, we know each other, we want to get patients together to help move therapy along.

I talked about the gene therapy for mitochondrial disease. How can healthcare professionals who are interested in this treatment be trained in it? I talked a little bit about that as a function of Orbis in the future, when the technology becomes more generalizable. The Spark Theraputic’s Luxturna, if you’re a designated treatment center the surgeons have to attend the specific treatment training course to learn how to do that. I think that eventually there’s going to be, the technology’s going to become widespread, it will be like doing anything else in any procedure where a lot of people are able to do it. You’re not going to need special training and that’s just a matter of time.

There is not much to report with regards to corneal disease gene therapy. The trials are just starting. Really isn’t something that we can say right now in any way, shape, or form but it’s very promising. One of the things that has slowed down kind of paradoxically, in gene therapy in the cornea, has been corneal transplant. We got really good treatment for those diseases even though some reoccur in the graft, many don’t. Or photorefractive therapy. When you have a good treatment, and you’re balancing the resources that you want to put into a good treatment versus a disease that has no treatment, people are more attracted to the no treatment category. But there is an increase of interest in the corneal dystrophies. And glaucoma is another possibility for a topical treatment, but we have a lot to learn about glaucoma.

We talked about LHON. May I ask about the failure of gene therapy due to the carriers? Not sure I understand that question. If you want to clarify that question I’d be happy to try and take that on.

Gene delivery on suprachoroidal, which was better? The question, I’m going to read it outloud because it asked a lot of things. Is subretinal or suprachoroidal better for the AAV or nanoparticles? There are many different strategies for gene therapy. There is a suprachoroidal injector that’s been developed and is going to be undergoing for choroidal anemia. Each has its own risk, each has its own complications. Each has its own benefits. Depends on the disease and where the pathology of the disease is.

Take, for example, Batten’s disease. In Batten’s disease the entire retinal thickness is infected. The ganglion cell layers are affected and the photoreceptors are affected. Doing a suprachoroidal injection isn’t going to work, it’s not going to get where you need it. That’s why intravitreal therapy is being tried to get a virus that will go throughout the retina. There’s not a right answer to that question. Each treatment, each gene, each mutation is going to determine the answer that’s best for each disease.

Yes, that’s correct. Using RNA in viruses is another way, as I said. Small interfering RNA is one of the ways we’re treating diseases.

And in retinoblastoma, is the one area I don’t cover. Maybe we’ll have to set up a retinoblastoma lecture in gene therapy. I’ll invite our retinoblastoma doctor, Dr. Vikas Khetan from India who’s joining us in the new year. Maybe we’ll set up a webinar on that topic individually.

Do the fellowship program accept international fellows without USMLE? Yes, we do. The fellowship program is labeled a research fellowship. But you have full clinical care, you see all the patients, diagnose the patients. And therefore, since you’re not prescribing and since you’re not directly giving independent advice to patients, you can come and do the full clinical fellowship under a research label and USMLE is not required.

Let me take one more question here. I think I covered them all, and we’re right on time.

Thank you very much. Again, my email was on the screen. Feel free to ask questions by email. Thank you to Lawrence Sica who’s a fantatasic technician that makes these happen. Thank you to all of Orbis for all the work you do around the world. Remember Cybersight is out there and waiting for your ocular genetics consults. We’d love to take them, we’re happy to start that service and help you any way that we can. Find the resources, make your diagnoses, get treatment to patients, whatever it is, use Orbis Cybersight. Thanks all very much, have a nice day.

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December 3, 2021

Last Updated: October 31, 2022

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