The good, the bad and the maybe in ocular gene therapies

Ocular gene therapy is not yet ready for prime time, according to David Eichenbaum, MD. Eichenbaum is the director of research at Retina Vitreous Associates of Florida and a volunteer collaborative associate professor at USF Health Morsani College of Medicine in Tampa, Florida. He discussed the status of gene therapy technologies at the Hawaiian Eye and Retina 2024 meeting, held January 13 to 19 in Maui, Hawaii.

“We are still in the infancy of gene therapy. The potential...is very exciting,” Dr Eichenbaum said. Image credit: ©Marharyta – stock.adobe.com

“We are still in the infancy of gene therapy,” he said. “The potential of gene therapy is very exciting.”

In his presentation, Dr Eichenbaum defined gene therapy and described its use in common retinal disease.

The good

In common retinal disease, he explained, the approach is gene augmentation, such as in neovascular and atrophic macular degeneration and diabetic retinopathy the cells inside the eye are altered to become biofactories to produce therapeutic protein.

This is thought to be better than frequent intravitreal injections of therapeutic proteins into the eye routinely as is done for wet macular degeneration and diabetes and recently for atrophic macular degeneration with geographic atrophy.

The potential positives of gene therapy are the possibility for a single treatment, the absence of indwelling devices, and continuous protein production forever, the last of which may also be a drawback.

Dr Eichenbaum described the process of gene augmentation, what makes up a gene therapy, and the process of transduction. He also detailed how the gene therapy becomes an intracellular/intranuclear change to the cell’s DNA and how the treatment theoretically will impact common retinal disease, especially for patients with a high treatment burden, to prevent progression to proliferative retinopathy.

“The prospect of eliminating frequent injections is very exciting,” he said.

The safety of these products is an important issue, including how they are administered, the best vectors, the best capsids, and the best protein products.

“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,” Eichenbaum explained.

One noteworthy success with ocular gene therapy is voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics Inc), developed to treat Leber congenital amaurosis and approved by the FDA in late 2017. In this technology, adeno-associated virus transduces a functional copy of the RPE65 gene into retinal pigment epithelial cells to compensate for the RPE65 mutation. The therapy is injected into the eye through a retinotomy after vitrectomy and separation of the posterior hyaloid.

The bad

A potentially less beneficial aspect of gene therapy is protein production that lasts forever. The change that is made to the cell cannot necessarily be turned off, Eichenbaum explained. This chronicity is associated with 2 major adverse events, the first of which is intraocular inflammation, which occurs to some extent in all gene therapy programs. He reported the need to follow this with extension studies and long-term follow-up.

The second event in some higher-
dose subretinal gene therapy programs is unusual pigmentary changes. Some patients, he pointed out, have lost vision from these in the early-phase investigative programs.

“We need to be able to predict and prevent it if we’re going to bring gene therapy into primetime,” he advised.

The maybe

“The maybe goes back to the patients,” he said. “We may be able to take our patients who are the most highly burdened and reduce their dependence, cost, hassle,…discomfort [and] family’s and caregiver’s time in coming to the retina specialist and receiving ongoing treatment. [This] does benefit patients in a large part if they come in frequently for treatment 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…technology?”

Dr Eichenbaum concluded that while there is established success in the eye with voretigene neparvovec-rzyl, gene therapy remains investigational for common retinal disease with existing therapy.

“This is why we have clinical science and development,” he said. “We are here to figure this out and see where it may fit. Clinical medicine is not one-size-fits-all.”

David Eichenbaum, MD | E: deichenbaum@rvaf.com

Eichenbaum is the director of research at Retina Vitreous Associates of Florida and a volunteer collaborative associate professor at USF Health Morsani College of Medicine in Tampa, Florida. He is a speaker, consultant and investigator for numerous companies and an equity holder/stockholder in Johnson & Johnson Innovative Medicine, Network Eye, ReVive, and USRetina.