Jean-Francois Korobelnik, MD

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The dexamethasone implant was the first approved drug therapy for retinal vein occlusion. At this time, we had no anti-VEGF [vascular endothelial growth factor] drugs approved, and dexamethasone was the first medical treatment. Before dexamethasone, we only had laser treatment. I would also like to mention the AR-13503 [SR implant], which is an inhibitor of Rho kinase and protein kinase. It is also a sustained-release implant, which is currently being investigated for the treatment of wet AMD [age-related macular degeneration] and DME [diabetic macular edema]. It is the first in ongoing human study of the safety of this implant. We cannot add more information at this time on this drug clinically because it’s still in phase 1. That’s why I would like Dr Korobelnik to say a few words on axitinib intravitreal implant, which is a sustained-release tyrosine kinase inhibitor. We don’t know much about this pathway so far. If we can at least antagonize it sufficiently to reduce the VEGF expression—maybe you can say a few words on this, Dr Korobelnik.

 I think you have said everything, Albert.

It is an anti-VEGF biopolymer conjugate, and an ongoing phase 1 trial, so we only have interim…

 It’s more advanced. Phase 2 for KSI-301 is positive, so they are now recruiting for phase 3. It’s interesting because we know VEGF inhibitor very well. This is a combination of a VEGF inhibitor plus a biopolymer, allowing a slow release of the inhibitor. It is promising. In the trials, they are exploring 1 injection every 24 weeks, so 1 every 6 months. If it works and is safe, that would be interesting, because it is a gel injection, so it should be safe. KSI-301 is a promising long-lasting VEGF inhibitor. I look forward to the phase 3 results.

Then you have to say a few words about inflammation and KSI.

 Of course, it’s the same for all the devices. They may induce intraocular inflammation. Some may be related to debris, to the polymer, or to something that is going to last longer and induce immunogenicity, as we’ve said before. For safety regarding the drug, intraocular safety is something that we have not been using with the 3 old VEGF inhibitors that we have at the moment, so it’s something new. It’s not only intravitreal inflammation, but it’s also retinal inflammation and vasculitis that we have seen with brolucizumab. Now everybody is aware of that risk and is looking carefully at the safety of the retinal surface and in the retina for any new compound.

That is why I am not so euphoric, and a little skeptical, especially when we inject the gel into the eyes. Let’s wait and see for phase 3. This is always the conclusion, if we speak about drugs and drug development.

Videos

Considerations for treating retinal disorders with sustained-release drug delivery implants in an effort to address current treatment challenges in the field.

Sustained-Release Drug Delivery for Retinal Disorders

: Before we conclude, I would like to get some final thoughts from all of you. Let’s start with Dr Korobelnik. Can you say a few words on the future of dry AMD [age-related macular degeneration]?

 We have seen a lot of research activities for new long-duration treatments in wet AMD and in diabetic retinopathy. There is also a lot of research and developments for advanced dry AMD, for geographic atrophy, and there are currently 2 ongoing phase 3 trials from 2 companies that are looking at inhibition of the complement cascade. We should know later in 2021, or in 2022, [whether] those drugs are beneficial to slow down the progression of the disease. If it works, this will be interesting because it’s a completely unmet need [right now]. We’ll see.

 Thank you. So it’s all about inflammation at this time?

 Dr Moosajee, do you have some concluding remarks?

Mariya Moosajee, MBBS, BSc, PhD, FRCOphth:

 I am truly excited by my field. For the first time in our careers, we can now say that there is an approved gene therapy available for patients with inherited retinal disorders, with a wealth of trials to follow up. I would like to see more genes being covered, and that, at the moment, is still a very costly process, so maybe it’s targeting more common pathways. There are gene therapies that are being developed towards a factor called rod-derived cone viability factor, which essentially helps cones to uptake glucose and to convert that into energy and work better. Hopefully that kind of universal treatment will be able to be accessed by more patients with inherited retinal disorders rather than on a gene-based system. It is a promising field and we will learn a lot from the work that is being done in AMD and diabetic retinopathy, in terms of the devices that you’re using and trialing now, and how we can apply that to our field.

 Thank you. Dr Peto, some words from your side?

 I completely agree that we live in an exciting era of diagnostics and treatment. Something we’ve learned from the pandemic is that patients adapt very well to the new environment. We are now seeing patients over the age of 90 who will happily have a virtual consultation with us. We are seeing people who are using home monitoring devices, and we’re also seeing patients who happily come to virtual clinics where they spend very little time, get images quickly, and then only come back to a busy clinic if they need injections or treatment. We need to learn from these developments, we need to cherish them and go on with providing the best service because this helps us to strategize and restratify our clinics and get everyone to the right clinical pathway.

 Do you think this digital world will reduce the quality? Five years ago we all spoke about multimodal imaging, high-quality images, and combining images from different modalities, just to be more secure and do more sophisticated diagnostics. Now everything is digital. We do images with devices at home, which don’t have the quality as compared with devices in a big hospital, and you can’t combine different images. Do you think the quality will go down a little bit?

 What we need to do is to make sure that the quality of those images that we get supplied with go up. When they started the anti-VEGF [vascular endothelial growth factor] injections, we didn’t have SD OCTs [spectral domain optical coherence tomography], we had time domain OCTs. As soon as more people used them, more people needed to have an OCT, and more people needed more details—suddenly the price dropped, and a lot of new functions appeared. I’m hoping that the home monitoring devices will undergo the same type of development. We must remember that, in a lot of patients, we only need to decide if they need to come in or not, and if they need an injection or not. So we might not need every single time and every bit of imaging that we usually do at diagnosis. If we’re clever about it and we get good images, then we might be able to change the dynamic of a clinic to those who are higher risk.

 We must differentiate between initial visit baseline to make the diagnosis, then we need multimodality and follow-up. For follow-up, OCT probably does it all. So home monitoring with OCT can be promising. We don’t need multimodality on each visit.

 I think that’s why we call it monitoring, because, for diagnostics, you need to get the diagnosis right. They can have all sorts of other diseases that mimic AMD, and old patients with diabetes can have a lot of other diseases as well. We need to establish a secure diagnosis, especially if we don’t see them regularly in the clinic.

 Thanks to all of you and to our viewing audience. We hope you found this 

 discussion to be rich and informative. Thank you very much.

Key takeaways from a discussion on the management of age-related macular degeneration, diabetic macular edema, and inherited retinal disease and insight regarding what to look forward to as the field advances.

Optimizing Care For Patients With Retinal Disorders

 As a concluding remark: We have all been affected by the COVID-19 pandemic, and our retinal practices have changed dramatically. What will last from this experience and from the changes in our practices?

 My cohort of patients were deemed nonurgent in the pandemic. So a lot of the practitioners were told to cancel appointments to allow for capacity for AMD [age-related macular degeneration] and the serious diabetic patients. However, I quickly converted to virtual consultations. Especially in genetics, what we call teleogenetics, is extremely accessible through virtual platforms. Virtual consultations are something that we will continue to do going forward. From an inherited eye disease point of view, we can limit the amount of follow-ups that we give patients and maybe try to reduce that referral to a specialist center, but have joint care with local district general hospitals so patients aren’t traveling so much. Maybe we can introduce home monitoring and use digital technologies moving forward. We can also instigate more diagnostic hubs in local areas, where patients can get their autofluorescence and OCT [optical coherence tomography], then we, as clinicians, can remotely monitor those patients following up with more virtual consultations.

The impact of the COVID-19 pandemic on the management of patients with retinal disorders and considerations for how new practices may be adopted into future practice.

Managing Retinal Disorders: Lessons Learned From COVID-19

Dr Moosajee, can you talk more in depth about gene therapy in retinal disease? I would also like you to address virus and nonvirus approaches; vectors and nonvectors.

 Absolutely. The gene therapy field for hereditary retinal disorders is vast. There are hundreds of trials underway for this, and now the most common vector system that we use is the adeno-associated virus [AAV]. There are gene therapy trials for achromatopsia: 

 is the main genetic cause there. Choroideremia has reached phase 3 and we’re waiting to hear the results of that. These adeno-associated viral vectors have a size limit of the gene that it can accommodate. It can accommodate genes that are essentially less than 4000 bases in size. The smaller genes are fine, but you start to get in trouble with genes that are bigger than that, that are also common causes of these retinal degenerations. For example, 

, which is the most common cause for Usher syndrome type 2, but also one of the most common causes of nonsyndromic retinitis pigmentosa, and that gene is something in the region of 18,000 bases in size. How do we then package these genes to deliver it back into the retina so that we can potentially apply this to more people? There are now a lot of studies going into developing dual AAV vectors whereby we split the gene into components and put them into individual AAV vectors with a linker so that, when it’s translated, you end up forming the complete cDNA [complementary DNA] that can be translated into a protein.

They are now in the development of these nonviral gene therapy vectors. One is a DNA plasmid that has a component called a scaffold matrix attachment region; it essentially will allow any sized gene to be carried, even portions of chromosomes, but this can easily accommodate the 

 gene. These viral vectors are still in preclinical development and have gotten into nonhuman primates as well. However, they are showing relatively long expression—up to a year in mouse studies—and good expression of the protein in the retinas following subretinal injection. There are pros and cons to these new types of vectors. The con is that it doesn’t have the infective capability of a virus. We may need to start to use some of the devices that you talked about, like the microneedles or micro-electroporation systems that you’re developing for AMD [age-related macular degeneration], etc, to help these vectors enter into photoreceptors. The pros are that it can carry a gene of any size. They don’t have any viral components, so you’re going to reduce your chance of an immune response. They don’t integrate into the genome, so you reduce your chances of incisional mutagenesis. These specific components, like these S/MARs [scaffold/matrix attachment regions], which are naturally found within our own chromatin that help it to bind, prevent these vectors from being silenced and allow them to replicate extra chromosomally. These are coming into the future that may be the next generation of gene delivery vehicles as we go forward.

Thank you. This was very interesting. The nonviral vectors have a better safety profile and larger cargo capacity, and they have the potential for repeated administration. Sooner or later, if we can overcome the major drawbacks, maybe nonviral vectors will be available, at least for retinal diseases. Do you have experience with the first retinal gene therapy, the Luxturna from Spark Therapeutics? 

 Yes. This is the adeno-associated viral vector that has now been approved by the FDA and the European Medicines Agency. It is approved by our NHS [National Health Service] and is available to patients, and there are sites all over the world offering this. So far, we have seen positive results. This viral vector was approved on the multi-luminance mobility maze test, where we classically see the patient at baseline. Then a year after treatment, where they’re able to navigate through the maze at 1 lux level successfully in a short period of time. In the UK [United Kingdom], my experience with pediatric patients and adults who have now had this, we are seeing a stability, if not improvement, in the children with their visual acuity and their vision in dim light, and also in improving navigational vision for older patients. The hope is that if we can also potentially deliver these genes through intravitreal, we might reach more parts of the retina because, at the moment, we’re just going for the area where we apply the bleb, and there are still islands of retina in the periphery that would be beneficial if we could treat these with the gene therapy. There is still a lot of work to do and a lot of progress to be made in general in trying to optimize the results of these gene therapies.

Dr Mariya Moosajee comments on the next generation of gene therapy for inherited retinal disease and highlights various systems under investigation.

Author | Jean-Francois Korobelnik, MD

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Optimizing Care For Patients With Retinal Disorders

Managing Retinal Disorders: Lessons Learned From COVID-19

Future Gene Therapy for Inherited Retinal Disease

Sustained-Release Drug Delivery for Retinal Disorders