Hawaiian Eye and Retina 2024: Sizing up the impact of gene therapy in ophthalmology

David A. Eichenbaum, MD, discusses the promising aspects of gene augmentation for treating common retinal diseases, addresses concerns about perpetual protein production, and considers the potential positive impact on patients by reducing treatment burdens in his talk at Hawaiian Eye and Retina 2024. He recently spoke with Ophthalmology Times Group Editorial Director Sheryl Stevenson.

Video Transcript

Editor's note - This transcript has been edited for clarity.

Sheryl Stevenson: We are joined today by Dr. David Eichenbaum, who is among the faculty at this year's Hawaiian Eye and Retina meeting. Welcome to you, Dr. Eichenbaum. Always a pleasure.

David A. Eichenbaum, MD: Pleasure to be here. Thank you for inviting me to chat with you, Sheryl.

Stevenson: Sure. I'm really curious about the title of your talk, one of your talks that you're presenting, regarding 'Gene Therapy: The Good, the Bad and the Maybe.' Tell us about that.

Eichenbaum: Yes! That was a fun title to come up with. And this is because we're still in the infancy of gene therapy. What's super exciting is the potential of gene therapy. What's a little bit confusing is what is gene therapy and what are we doing. Well, the talk is meant to demystify a lot of that and define what gene therapy is; specifically, what we're doing in common retinal disease, as well as to give sort of a 30,000-foot view of the more advanced gene therapy programs that we have ongoing with completed enrollment in early phases and ongoing enrollment in later phases.

So the good, the bad, and the maybe. The first part of the presentation talks about what we're doing. In common retinal disease, we're typically doing gene augmentation. What we're doing for macular degeneration of the neovascular type and the atrophic type as well as for diabetic retinopathy is we're altering the cells inside the eye to basically become biofactories to produce therapeutic proteins—which theoretically is better than us putting therapeutic proteins into the eye routinely with frequent injections into the intravitreal location like we've typically done for the last 20 years for wet macular degeneration and diabetes, and only recently for atrophic macular degeneration with geographic atrophy.

So the talk describes the process of gene augmentation, what makes up a gene therapy, the process of transduction, how the gene therapy becomes an intracellular and intranuclear change to the cell's DNA. And then we talk about how that theoretically will impact common retinal disease, and especially help patients who have a high burden of treatment. And we do know there is a subset of patients with wet macular degeneration who require a lot of shots as a subset of patients with diabetic retinopathy who need ongoing treatment if you're going to treat them with biologics to prevent them from progressing to proliferative retinopathy.

And we know that with our current complement modulating therapies to achieve any anatomic benefit, you need a lot of shots. So the concept with gene therapy is if we can make the eye make therapeutic proteins, then perhaps we can spare these patients most of their shots. And that's very exciting.

Of course, we have to wrap our head around the safety of these products, the way that we administer them, the best vectors, the best capsids, the best protein products. It's very nuanced and much more complex than even developing a biologic. But there is a lot of hope that gene therapy will successfully affect our most highly burdened patients and give them good outcomes with a reduction in the number of treatments that they need.

Stevenson: So that sounds like the good. How about the bad?

Eichenbaum: So the bad...what's the double-edged sword of gene therapy? Well, the most interesting and potentially less beneficial part is that there is protein production forever. You cannot necessarily turn off the change that you make in the cell. So part of the good is that we're producing proteins forever. But the other side of the coin is that we're producing proteins forever.

And we do know that there are two major adverse events that we need to figure out for gene therapy to be successful. The first is intraocular inflammation, which we see to some extent in all gene therapy programs. Some programs have more significant inflammation than others. But it's something we need to follow on for quite a while with extension studies and long-term follow up because the gene product is produced, as I was saying, forever.

And the other, in some higher-dose subretinal gene therapy programs, is we see unusual pigmentary changes and some patients have lost vision from these in the early phase investigative programs and we need to be able to wrap our head around that, predict it, and prevent it if we're going to bring gene therapy into the primetime. So with all the potential good there is potential bad that we need to learn more about before we can say that gene therapy is ready to go.

Stevenson: All right, and then what about the maybe?

Eichenbaum: The maybe goes back to the patients. We may be able to take our patients who are the most highly burdened and reduce their dependence, their cost, their hassle, their discomfort, their family's time, their caregiver's time in coming to the retina specialists, coming to me, and receiving ongoing treatment—which does benefit patients in a large part if they come in frequently for high burden disease, but we'd love to be able to provide that benefit without the high burden and that's the maybe. Can we do this...can we affect the patients positively with this novel new technology.