Gyrate atrophy is a rare, autosomal recessively inherited genetic disease that leads to progressive vision loss. Found in less than one in 100,000 people worldwide, the disease is caused by mutations in the ornithine aminotransferase (OAT) gene, resulting in deficiency in ornithine aminotransferase — an enzyme important for metabolism of ornithine, a nonprotein amino acid that derives from arginine, a protein amino acid. This deficiency explains the accumulation of ornithine in bodily fluids, with levels approximately 10 times higher than normal. Ophthalmologic features include childhood myopia, poor adaptation to the dark and retinal degeneration. Older patients develop cataracts in their second decade and progressive loss of vision.

Currently, the only documented treatment for gyrate atrophy is a diet limited in arginine — which is present in all natural protein including meat, nuts and seeds. The diet results in reduction of ornithine to near normal levels and slows or prevents progression of retinal degeneration. However, the diet is not easy to follow, says David Valle, M.D., a professor of genetics, pediatrics and ophthalmology at the Johns Hopkins University School of Medicine who has devoted much of his career to researching the disease. Gene therapy replacement or correction of the defective OAT gene would be a more effective treatment for the disease.

To help make a gene therapy a reality, Valle has collaborated with retina specialist Mandeep Singh, M.D., Ph.D. and pediatric ophthalmologist Jefferson Doyle, M.D., Ph.D., M.H.S., co-directors of Wilmer Eye Institute, Johns Hopkins Medicine’s Genetic Eye Disease Center. The trio is working trying to find ways to diagnose gyrate atrophy earlier — ideally during infancy — and develop a gene therapy treatment.

The group is conducting clinical and lab research in parallel, taking a two-pronged approach that Singh says is rare in genetic research. Doyle’s lab is working on potential gene therapies, while at the same time, Singh and Valle are leading the Gyrate Atrophy Ocular and Systemic Study (GYROS), a global natural history study to determine the best design for the clinical gene therapy trial once the medicine is ready.

If both components go well, an effective gene therapy medicine — and the trial to test it — could be ready within five years.

“What’s happening at Hopkins is we’re developing these two things from the get-go because if you do them sequentially, it just takes too long and our patients risk losing vision day by day,” says Singh, the Andreas C. Dracopoulos Professor of Ophthalmology at Wilmer.

Having both Singh’s knowledge of retinal degeneration and Doyle’s expertise in pediatric myopia involved in gyrate atrophy research is encouraging to Valle, the Henry J. Knott Professor at Johns Hopkins Medicine.

“I think we’re going to learn some very interesting things about how the defect in ornithine metabolism produces the clinical features of gyrate atrophy,” he says.

GYROS Study

GYROS, which is open to enrollment, will follow 45 people with gyrate atrophy from 12 sites around the world for four years to establish a solid foundation of data that can guide development and assessment of effective gene therapies for preserving vision in people with gyrate atrophy.

Throughout the study, a range of imaging and visual function assessments will be carried out to better understand the progression of gyrate atrophy and its impact on the retina. GYROS will support researchers, determine outcome measures and select participants for clinical trials of emerging treatments.

Collecting this data will help researchers identify patients to enroll based on disease stage and decide which measurements to track in the clinical trial to evaluate how well the medicines work as treatments. “This combination is our best bet to ensure a clinical trial with a successful outcome,” Singh says.

GYROS is financially supported by the Foundation Fighting Blindness, the U.S. Food and Drug Administration and Conquering Gyrate Atrophy.

Pioneering Treatment Paths

While Singh and Valle have worked on making the clinical trial happen, they teamed up with Doyle, the Andreas C. Dracopoulos and Daniel Finkelstein, M.D., Rising Professor of Ophthalmology, who has focused on the lab work to develop potential gene therapies for the disease.

Doyle says this research is a natural fit for his lab because many people who are diagnosed with gyrate atrophy present with very high myopia as children.

“We have a strong interest in studying genetic disorders that have a very high preponderance for severe myopia to try to better understand what drives pathological eye growth,” he says.

The goal for Doyle’s lab is to have therapeutic options for Singh and Valle to consider within four years. Two years in, they have developed one gene therapy that appears to fully correct the key biochemical defects in gyrate atrophy mice that are believed to be the drivers of the retinal degeneration.

Now, having been able to normalize the biochemical defects, Doyle’s lab is looking into whether the therapy can also correct the retinal degeneration in mice.

A Patient’s Perspective and a Family’s Foundation

Keya Acharya, a 26-year-old psychotherapist and social worker in New York City, was diagnosed with gyrate atrophy at age 16. Her optometrist discovered dark spots on her retina during a routine eye exam, which were confirmed to be gyrate atrophy.

Acharya says her central vision is strong and she can do most daily activities without worry, but she has lost some of her peripheral vision. At night, she uses a cane because of her compromised sight. Due to the rarity of the disease and the lack of available information about it, what comes next is uncertain.

“It feels up in the air,” she says. “It’s unknown how fast my vision could decline.”

Acharya, who is one of Singh’s patients, says she is excited to know that he and his peers are working to find a treatment for the disease.

“I’m cautiously optimistic,” she says. “I’m curious to see what will happen and where the research will go from here.”

Acharya’s parents, Karabi and Malay, founded Conquering Gyrate Atrophy in 2019 to build awareness of the disease, raise money for research and connect researchers.

“If we don’t start even saying ‘gyrate atrophy,’ no one will pay attention,” says Karabi Acharya.

The group’s efforts have facilitated collaboration among researchers at various institutions, including on a scientific symposium at Johns Hopkins in February 2020. The event brought together more than 20 retinal specialists from various areas of the globe including the United Kingdom, the Netherlands, Australia and the United States. The symposium helped kick-start significant research and collaboration on gyrate atrophy. Such collaborative efforts are seen as crucial to accelerate progress toward a treatment for this rare disease.

“Anyone who even was thinking about this disease was in that room,” Karabi Acharya says. “And I have to say, it was really incredible.”

Funding from Conquering Gyrate Atrophy has enabled Doyle to hire a graduate student to focus on lab work for the gyrate atrophy research.

Doyle, Singh and Valle say they are grateful for the Acharya family’s efforts to help find a way to treat the condition at a genetic level and stop it early, thereby preventing people from losing vision in the first place.

“We just think what this family is doing to help us develop a treatment is incredible,” Singh says. “Because of them, we can now hopefully find a way to cure our patients.”