Sheryl brings a wealth of editorial experience to MJH Life Sciences’ Eye Care Network, having engaged with the readers and the greater ophthalmic community of 

for more than 20 years. As Group Editorial Director, Sheryl’s purview extends across the print and digital network of 

Ophthalmology Times, Ophthalmology Times Europe, Modern Retina 

 Prior to ophthalmology, Sheryl previously covered the fields of audiology and confectionery science/technology/manufacturing.

Sheryl is also passionate about the mission, vision and values of Ophthalmic World Leaders (OWL) and recently completed her term on its Board of Directors. She continues to volunteer as Editor-in-Chief of the organization’s 

Magazine. In 2013, she was honored with the group’s inaugural Rising Star Award.

In addition, she has served as a judge for 

 Health Care Heroes Awards program as well as the Jesse H. Neal National Business Journalism Awards.

Sheryl Stevenson

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Dr David S. Boyer sat down to discuss his presentation, “Inhibition of Connexin-43 for the Treatment of AMD and Diabetic Retinopathy,” at the Angiogenesis, Exudation and Degeneration Meeting, hosted by Bascom Palmer.

Dr Boyer is a partner and ophthalmologist at Retina Vitreous Associates Medical Group in addition to serving as an adjunct clinical professor of ophthalmology at USC.

 Dr Boyer, thank you so much for joining us. At this year's Angiogenesis meeting, you're giving a talk regarding the inhibition of Connexin-43 for a treatment of AMD and diabetic retinopathy. Could you take a few moments and kind of provide an overview of your talk for us?

Sure, thank you again for allowing me to present this. Xi lambda, which is the Connexin-43 locker, closes pathologically open Connexin-43 hemichannels and cell membranes and that inhibits the ATP release into the extracellular space, which activates the NLRP inflammasome process.

With the inflammasomes being activated, you start to get cytokine release inflammation vessels leak, oedema, ischemia, fibrosis, and it's a vicious cycle because this causes further inflammasome release and further ATP release. So if we can block this process, we can reduce the cytokine release and hopefully improve a variety of ocular conditions.

Xiflam, which is a drug, was developed 20 years ago by GSK for migraine; it was abandoned. It had two you know, novel properties. First of all, it inhibited pathologic opening of the Connexin-43 hemichannels, and it also crossed the blood brain retinal barrier. There are over 1000 subjects that were dosed in this study with concentrations ranging from 25, 40 and 80 milligrams, and the dosing was up to three months. In all concentrations, the drug was well-tolerated. So we have robust safety data concerning this drug.

There were a couple of proof-of-concept studies that were interesting. There's a Sprague Dawley rat that is born with diabetes and has a blood sugar level three times the normal range, and these animals actually show micro-aneurysms and macro-aneurysms, and have diabetic retinopathy.

In the group that was treated both the ERG as well as the OCT showed a marked improvement; the micro-aneurysms went away, and the ERG improve. So this is a proof of concept that in diabetes, if we can block Connexin-43 that we will hopefully get an improvement in the retinal vascular system.

Additional treatments have been performed for macular degeneration using a bright light model. And again, the treated group showed a marked improvement of retinal function and also in histopathology when they are treated with Xiflam. We also know that there are a lot of expression of Connexin-43 in the blood vessels in diabetic retinopathy and macular degeneration in human donor retinas.

So we are starting a phase two trial in diabetes: 130 patients, randomized, one-to-one, versus Xiflam versus placebo. We're looking both at the diabetic retinopathy severity as well as diabetic macular oedema. And the final analysis will be at six months, though there'll be an interim data safety monitoring at three months. And this has been run by the Diabetic Retinopathy Clinical Research Network, and we're hoping to start enrolling very quickly.

In addition, we are also looking at geographic atrophy, again, 130 patients being treated with a one-to-one relationship between Xiflam and placebo. And again, we're looking for decrease in growth and the decrease progression of other retinal lesions in a certain specified time points.

So in summary, this treatment may shift us from intravitreal injections to a once-a-day tablet. And since we have good safety data, we may go right ahead into clinical trials to restore normal biologic function of this this regulated inflammasome. And I'm hoping that the trials can start in the second quarter of this year.

 Excellent. We look forward to learning more about those trials. And how do you anticipate these results may help the clinician in day-to-day practice with their patients?

 Well, we're hoping because it's, you know, systemic administration, we're hoping that we also will find that there'll be some renal improvement. Renal function goes very hand-in-hand basically with diabetic retinopathy. As renal function worsens, usually the retinopathy worsens, and some people believe you can even use this worsening as a guide to show that you'll be getting a worsening of the retinopathy.

So I think that it's, it's important to realize that, you know, our patients really have a hard time coming in, we can use this drug a little earlier in the cycle. They don't have to come in as often hopefully for evaluations, they don't have to receive the injection—which in many cases, you know, is well-tolerated and patients drive home. But in other cases, they have a day or day and a half that they're not feeling well that the eye is irritated, even with appropriate precautions after the injections are given. So I'm hoping that we start to see that we can start to have pills that will be able to help us and of course in addition when patients escape they will have the intravitreal injections, but hopefully they can be minimized.

 This transcript has been lightly edited for clarity.

Videos

Dr David S. Boyer describes how blocking Connexin-43 may improve the retinal vascular system function in patients with diabetes, potentially creating a future of oral medication for treatment of diabetic retinopathy and AMD.

Blocking Connexin-43 may improve diabetic retinopathy, AMD

Dr Sean Ianchulev discusses the novel robot-assisted ab interno gonio-intervention and what it means for ophthalmologists offering surgical solutions for glaucoma. This new surgical technique offers precision down to the micron level, which is more precise than a surgeon can achieve by themselves.

Dr Ianchulev is the Chief Executive Officer of Eyenovia as well as a professor of ophthalmology at New York Eye and Ear Infirmary of Mount Sinai.

This new surgical technique offers precision down to the micron level, which is more precise than a surgeon can achieve by themselves.

Gonio-intervention robot-assisted glaucoma surgical procedure offers high precision

On February 11, 2022, Dr SriniVas R. Sadda presented a talk, “Choriocapillaris and Atrophy Associated with Neovascular AMD,” at the Angiogenesis, Exudation and Degeneration meeting, hosted by Bascom Palmer.

Dr Sadda is a professor of ophthalmology at the Doheny Eye Institute at UCLA.

 Dr Sadda, thank you so much for joining us. At this year's Angiogenesis meeting, you will be giving a presentation regarding choriocapillaris and atrophy associated with neovascular AMD. Could you give us a little bit more highlights of your talk?

I spoke on the relationship between the choriocapillaris and atrophy associated with wet AMD. And one of the great things in the last few years is that OCT angiography has allowed us to actually study the choriocapillaris. And we've learned a lot about the relationship between the choriocapillaris and a number of different diseases.

And my area of interest in particular has been in the topic of choriocapillaris and AMD. And we've learned, for example, that the choriocapillaris worsens as the AMD disease progress goes along. And in fact, the status of the choriocapillaris may actually predict the rate of progression of atrophy in the life.

We also observe that, for example, in patients with wet AMD, the choriocapillaris tends to be poor in the areas that develop neovascularisation. And maybe neovascularisation is developing as a compensatory response to that poorer choriocapillaris. Whereas in eyes with atrophy, the choriocapillaris is diffusely abnormal throughout the macula. And maybe that's why those eyes go on to develop atrophy, because they don't have even a good enough choriocapillaris to develop neovascularisation.

One of the things that we've also observed is that patients who have type one neovascularisation—or neovascularisation below the RPE—that such patients seem to be protected against the development of atrophy. In fact, sometimes we think about this as maybe being some type of a cure for atrophy.

And we wondered whether or not the choriocapillaris—or whether or not the development of a circulation like the choriocapillaris—may be a reason why these neovascular lesions may actually be protecting against the development of atrophy.

So most recently, we've studied the small vessel circulation that develops at the surface of these neovascular lesions, these type one lesions in particular. And what we observed was that lesions that seem to be less associated with atrophy, they tend to develop a better or more extensive small vessel circulation. Sometimes we call that the neo-choriocapillaris—whether that's the right term or not remains to be determined.

But the point is that this small vessel circulation that these membranes may be developing may be an important reason or mechanism as to why they can actually rescue the retina against atrophy.

And so if that's the case, and again, these are small studies still, and we'd like to see them replicated by other investigators as well. But if that proves to be correct, then it might be that in our future, our goal—with regards to treatments of wet AMD—may have to also consider what are we doing to the choriocapillaris, or this new small vessel circulation arising on the surface of these neovascular lesions in order to get the best long-term outcomes for our patients.

And what might be a next step in this research?

So really, the next step is replicating our findings. I'm a big believer that to really be confident in a result, you want that to be replicated by different cohorts, different studies, but also by different investigator teams. So I think that's important. I'd love to see that.

And I think the next important step for us personally in my lab is really thinking about, well, what happens to this in context of different treatments? Because I sort of suggested that this may have some implications for us and how we treat patients, and if that's the case, we need to understand the impact of, for example, different treatment strategies on the development of this neo-choriocapillaris circulation.

This transcript has been lightly edited for clarity.

At Angiogenesis, Dr SriniVas R. Sadda discusses how choriocapillaris may predict the rate of progression of atrophy.

Exploring the link between choriocapillaris, atrophy and neovascular AMD

At the Angiogenesis, Exudation and Degeneration meeting, Dr Nadia K. Waheed presented her talk entitled, “CFI Supplementing Gene Therapy in GA Clinical Trial Update.” She discussed the Phase I/II study for the AAV-based viral vector, GT005, from Gyroscope Therapeutics.

Dr Waheed, thank you so much for joining us at this year's Angiogenesis meeting, and we look forward to learning more about your presentation. Could you tell us more about your talk regarding CFI supplementing gene therapy in geographic atrophy?

Absolutely. Sheryl, thank you so much for having me and just really enjoying the talks at Angiogenesis this year. I presented on a complement factor I supplementation in patients with geographic atrophy using a gene therapy approach. So these are some of the preliminary results from the focus study.

And the focus study is a Phase 1/2 study using Gyroscope Therapeutics GT005, which is an AV2-based viral vector that is injected subretinally in the subretinal space, and produces complement factor I. Now complement factor I, as you know, is a natural factor produced, and it's one of the only inhibitory enzymes within the complement system. So the goal of complement factor I is actually to slow down the over-activation of the complement and to push back the hyperactivity of the complement system that takes place.

So in this study, it consists of two parts. It's a first inhuman Phase 1/2a study, and there's a dose escalation phase with GT005 using three different doses, and then there's a dose expansion phase using the standard transvitreal subretinal surgical approach.

Now additionally, in part 2 of the study, we use a different surgical approach and the surgical approach uses the orbit subretinal delivery system, which is a specific specialized system that delivers gene therapy into the subretinal space, truly into the subretinal space, without doing a transvitreal surgery and thereby avoiding the risks of the of the tranvitreal surgery.

So the results that I presented were primarily of the transvitreal surgery with a little bit on the ongoing subretinal delivery system or subretinal delivery system surgeries as well, are mostly just the safety data from there. And, you know, what we saw was that subretinal gene therapy with GT005 appear to be a well-tolerated.

Additionally, you know, one of the things that's unique about this study is that it has a very robust sampling and biomarker measurement profile. So we do something in the vitreous space and look for a complement factor I levels before and after administration of the gene therapy. And what we saw was that there was a significant sustained increase in complement factor I levels that persisted out to a year and for some patients, we have two-year data, and we see that there's still elevation of these complement factor I levels at the two-year time point.

Additionally, what was really interesting, you know, if complement factory I actually does what it's supposed to do, which is it down regulates the complement system, then you would expect to see some of the byproducts of the complement system, as well as the byproducts of the amplification loop of the complement system to go down, right? And so what we did see was that, you know, that the byproducts of inhibiting with CFI, you know, the byproducts of C3 breakdown products actually did go down in our patients, they went down in a very significant and sustained way, and continued to be reduced all the way to the to the one-year sampling time point. And in the small number of patients that we have followed out two years, we also saw that BA, which is a measure of the amplification loop of the complement system, was also downregulated. So a significant sustained reduction in BA levels at a level at which we expect it to be if we were truly inhibiting the complement system in a clinically meaningful way.

And then additionally, you know, if it is inhibited, then you would expect chronic inflammation to go down. And as a result of chronic inflammation going down, you would expect C3, which is input into the complement system to go down as well. What was really interesting—and I do think this is the first time that it's ever been seen—is that not only do the downstream products go down, but the entry product, which is C3, also was reduced in these patients when we looked at them at the one-year time point. And this seems to correlate with a reduction in chronic inflammation in these patients.

So really, really interesting results from my perspective, just looking at, you know, the biomarker data from here and of course, the study is ongoing. It's looking also at geographic atrophy lesion size. And additionally there are two Phase 2 studies, the HORIZON and EXPLORE studies, that are ongoing using, you know, the same GT005 gene therapy product with CFI supplementation that are currently enrolling and hopefully will give us a better answer in terms of the clinical endpoints for these patients. 

Excellent, very interesting results. Dr Waheed, thank you so much for your valued insights.

Thank you so much, Sheryl. Thank you for having me.

Dr Nadia K. Waheed reviews the latest updates on the FOCUS trial, evaluating AAV-based viral vector GT005 for the treatment of geographic atrophy.

Author | Sheryl Stevenson

Articles

Gonio-intervention robot-assisted glaucoma surgical procedure offers high precision

Exploring the link between choriocapillaris, atrophy and neovascular AMD

Updates on FOCUS trial: CFI supplementing gene therapy in GA

Blocking Connexin-43 may improve diabetic retinopathy, AMD