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Gene Therapy Looks Promising for Diabetic Retinopathy

NEW YORK — Gene therapy could provide an effective alternative for controlling severe diabetic retinopathy, researchers say.

The therapy induces cells to make an antivascular endothelial growth factor (VEGF) molecule similar to ranibizumab, said Charles Wykoff, MD, PhD, deputy chair of ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Texas.

“From an efficacy perspective, we’re seeing what you would expect with regular anti-VEGF dosing based on historical trials,” Wykoff told Medscape Medical News. And so far, the treatment appears safe as well, he said.

Here at the American Society of Retina Specialists (ASRS) 2022 Annual Meeting, Wykoff presented preliminary results in the phase 2 ALTITUDE trial of Regenxbio’s RGX-314.

Anti-VEGFs delivered in intravitreal injections can effectively treat very severe nonproliferative diabetic retinopathy in patients without diabetic macular edema. Yet the disease remains the leading cause of blindness among people of working age, Wykoff said.

He cited a recent survey showing that most people with this diagnosis don’t get treatment. “This is largely because of the burdensome necessity for ongoing regular repeated injections,” he said. “Therefore, the development of more durable therapeutics, for example a potentially one-and-done gene therapy, could be a tremendous step forward for diabetic retinopathy management.”

In ALTITUDE, researchers used a specially designed applicator to inject into the suprachoroidal space a vector based on an adenovirus that carries genes encoding for the anti-VEGF fab. The vector is designed not to integrate the genes into the DNA of the host cells but instead implant them alongside that DNA.

To test the treatment’s safety and efficacy, the researchers recruited 15 adults, 25 to 89 years of age, with moderately severe or severe nonproliferative diabetic retinopathy.

These patients had no active diabetic macular edema, and their vision was 20/40 or better. They had not received anti-VEGF injections in the prior 6 months.

The patients’ mean hemoglobin A1c was 8.2, and they were divided among four diagnoses: moderately severe nonproliferative diabetic retinopathy, severe nonproliferative diabetic retinopathy, mild proliferative diabetic retinopathy, and moderate proliferative diabetic retinopathy. Their mean central retinal thickness was 259.2 µm. The patients received a dose of 2.5×1011 genomic copies per eye.

This study did not include a placebo control group. Instead, the researchers followed a cohort of five patients who all had moderately severe nonproliferative diabetic retinopathy. These patients had almost the same mean age and central retinal thickness as those receiving the gene therapy, but a lower hemoglobin A1c: 6.4.

In the eyes that received gene therapy, three developed conjunctival hyperemia and two developed conjunctival hemorrhage, but these were mild and the investigators did not consider them to be related to the drug produced by the injected genes.

One patient developed mild episcleritis 2 weeks after receiving the gene therapy. It resolved with topical corticosteroids. And none of the patients appeared to have intraocular inflammation. This is particularly significant because the patients did not receive any prophylactic steroids, Wykoff said.

“Even though [the mild episcleritis] wasn’t interocular inflammation, I took that extremely seriously. So I think we probably do need prophylactic steroids.”

After 6 months, diabetic retinopathy disease severity improved by at least two steps in seven (47%) of the patients receiving gene therapy, while the disease severity did not improve in any of the patients in the control group.

Best-corrected visual acuity improved by a mean of 0.3 letters in the patients receiving the gene therapy and dropped by 2.0 letters in the control group.

While he found these results to be encouraging, Wykoff said the researchers have not yet analyzed statistical significance, and acknowledged that more patients are needed to get a clear idea of how the treatment is affecting both diabetic retinopathy and diabetic macular edema.

The researchers plan to continue evaluating the patients closely for a year after treatment and then follow them for a longer term. The effects of the treatment could last indefinitely, Wykoff said.

Meanwhile, the researchers are enrolling 40 patients to receive RGX-314 at a higher dose level of 5×1011 genomic copies per eye.

In parallel, the AAVIATE trial is evaluating RGX-314 for neovascular age-related macular degeneration.

Session comoderator Young Hee Yoon, MD, PhD, a professor of ophthalmology at Asan Medical Center in Seoul, Korea, said she would feel more comfortable treating diabetic retinopathy with injections than with gene therapy. “You can start and finish whenever the disease is controlled,” she told Medscape Medical News. “But gene therapy has a permanent effect.”

American Society of Retina Specialists (ASRS) 2022 Annual Meeting: Presented July 15, 2022.

Wykoff reported financial relationships with AbbVie, Adverum, Aerie, Aldeyra, Alimera, Alkahest, Allergan, Allgenesis, Alnylam, Amgen, Annexon, Apellis, Arrowhead, AsclepiX, Bausch + Lomb, Bayer, Bionic Vision Technologies, Boehringer Ingelheim, Chengdu Kanghong Biotech, Cholgene, Clearside, EyePoint, Gemini, Genentech, Graybug, Gyroscope, Ionis, Irenix, Iveric Bio, Janssen, Kato, Kodiak, LMRI, Merck, Nanoscope, Neurotech, NGM, Novartis, OccuRx, Ocular Therapeutix, OliX, ONL, Opthea, Oxurion, Palatin, Perfuse, PolyPhotonics, Ray, RecensMedical, Regeneron, Regenxbio, Roche, SamChunDang Pharm, Stealth, Surrozen, Taiwan Liposome Company, Takeda, Thea, Valo, Visgenx, Vitranu, and Xbrane. Yoon reported no relevant financial relationships. The study was funded by Regenxbio.

Laird Harrison writes about science, health, and culture. His work has appeared in national magazines, in newspapers, on public radio, and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at or follow him on Twitter: @LairdH

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