New hope for sufferers of inherited retinal diseases microbiologystudy

Researchers at the University of Oklahoma are advancing the fight against inherited retinal diseases (IRDs) with new genetic research that aims to improve diagnoses and lay the groundwork for future therapies.

For patients with rare forms of inherited retinal diseases, a correct diagnosis is often the only way to preserve eyesight and prevent blindness. Yet, because genetic eye conditions can share overlapping symptoms, clinical evaluations alone are frequently inconclusive.

To close that gap, a team led by Lea D. Bennett, Ph.D., an assistant professor of ophthalmology at the University of Oklahoma College of Medicine, is mapping genetic mutations behind vision loss. A study published in the journal Genes offers fresh insights that could change how IRDs are diagnosed and treated.

“These results clarify and confirm clinical diagnoses, aid in counseling patients on prognosis and family planning and guide treatment options,” Bennett said. “This study not only holds promise for affected individuals but also expands the mutation spectrum to guide understanding of IRDs.”

Inherited retinal diseases are a group of related disorders caused by mutations in genes that affect the light-sensitive layer of tissue in the back of the eye. Worldwide, 1 in 3,000 people suffer from IRDs, which cause progressive vision loss and retinal degeneration. So far, 326 of the roughly 20,000 human genes have been linked to these disorders.

But big questions remain. Some patients with a clinical IRD diagnosis test negative for genetic mutations—a mystery Bennett’s team set out to explore.

To improve diagnostic accuracy and advance the understanding of disease mechanics, Bennett and colleagues at the Dean McGee Eye Institute analyzed the genes of 103 unrelated patients with an IRD. Testing was facilitated by Foundation Fighting Blindness, a Maryland-based charity.

Mutations were found in 70 of the samples, 20 of which were previously unreported genetic variations. Conditions linked to these abnormalities include retinitis pigmentosa, cone-rod dystrophy, macular diseases and third-branch disorders. The most identified gene mutation was in ABCA4. New mutations were confirmed in four genes—ALMS1, GNAT1, RAX2 and RDH5.

Still, while each patient in the study had a clinical IRD diagnosis, 33 of the samples yielded no genetic mutations.

To understand the factors influencing these findings, the researchers evaluated whether each genetically-negative patient was an isolated case within their family and the age of disease onset. Twenty-eight of the 33 reported no family history of a similar eye disease.

Bennett said there are several possibilities that could explain the inconsistencies between the clinical diagnoses and genetic tests. For instance, she said that because certain diseases mimic IRDs, patients with late-onset IRD and negative genetic results may not have disclosed their full medical history.

Another possibility, Bennett said, is that these patients have an IRD associated with a gene or genetic mutation that researchers hadn’t yet discovered, making her findings an important step toward future research.

“There’s so much about hereditary retinal diseases that we don’t know,” Bennett said. “The first step in developing new therapies for IRDs is to map the genetic mutations that trigger them.”

Currently, Luxturna is the only FDA-approved gene therapy for IRDs. Bennett hopes her work can accelerate the search for more treatment options and help pharmaceutical companies identify clinical trial candidates.

Bennett’s work has already made an impact. In 2018 and 2019, she identified a cluster of patients in her clinic with macular degeneration but negative genetic results. What she found was that each patient was taking Elmiron, a medication used to treat interstitial cystitis, a bladder condition that has since been linked to eye issues. When identified early, damage can be prevented by changing medications.

That experience prompted Bennett to deepen her genetic study of IRDs and pursue the current research. At Dean McGee, she’s also coordinating participation in an international Phase 3 trial for retinitis pigmentosa, another genetic disorder that targets the retina.

Bennett said that research from her clinic may eventually help drug companies find the next gene therapy for IRDs. But for now, her work has more immediate impacts.

“I do this for my patients, to give them information, to give them an accurate diagnosis, and to give them hope,” she said. “That’s my entire purpose.”