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Using data generated from patients and mice with a genetic mutation for Usher syndrome, researchers from the University of Maryland School of Medicine (UMSOM), National Eye Institute (NEI ) from the National Institutes of Health and the National Institute on Deafness and Other Communication Disorders (NIDCD), documented the natural history of visual impairment in patients and identified the cellular mechanism underlying progressive vision loss.

Based on these results, published on November 9, 2021, in the journal eLife, the team was able to test a retinoid therapy that improves vision in mice with Usher syndrome. The researchers said evaluating a similar therapy should now be considered in people with Usher syndrome to see if this therapy might slow vision loss.

Usher syndrome type 1F (USH1F) causes deafness, progressive vision loss, and balance problems. Among Ashkenazi Jews, there is a 2% chance that each person carries the Usher syndrome type 1F mutation, which accounts for about 60% of their Usher syndrome type 1 cases. There are no approved treatments to prevent vision loss or restore vision in people with Usher syndrome.

“The drug we used in mice may be a first step to improving eye health in people with Usher syndrome type 1F,” said Zubair M. Ahmed, PhD., Professor of otolaryngology — Cervicofacial surgery and ophthalmology at UMSOM. “Unfortunately, these drugs will not permanently cure vision loss because the drug does not repair the damage or prevent eye degeneration. However, it should improve the function of the tissues that these patients still have.”

Study first author Saumil Sethna, PhD, Instructor in Otorhinolaryngology – Head and Neck Surgery, said, “There are currently FDA-approved relatives of these retinoid drugs that are available and have passed safety clinical trials, as well as others that are in phase II clinical trials to treat other types of vision loss disorders.”

The team hopes to partner with one of the companies testing these drugs to initiate a clinical trial in patients with Usher syndrome type 1F to see if it can help prevent ongoing vision loss.

“The identification of a key mutation in the PCDH15 Nearly two decades ago, the gene was a critical breakthrough, aiding in the diagnosis and screening of carriers of some form of Usher syndrome, now leading to the discovery of a potential preventative treatment for the loss of syndrome-associated vision,” said Thomas B. Friedman, Ph.D., head of the Molecular Genetics Laboratory at NIDCD “This work illustrates the value of basic science research in the development of new diagnostics and therapeutics.”

Prior to this study, only anecdotal data had been reported for Usher syndrome type 1F without any detailed analysis of the data on the worsening of ocular abnormalities over time. In the early 2000s, co-authors of this study, including Dr. Friedman of the NIDCD, started a Natural History of Usher Syndrome Project and recruited 13 study participants with Usher Syndrome 1F to follow the natural progression of their blindness over 20 years or more. Dr. Ahmed was a postdoctoral fellow in Dr. Friedman’s lab at the time. Wadih Zein, MD, an NEI ophthalmologist specializing in hereditary retinal degenerations, was the principal investigator of the natural history study and summarized the patient results collected over the years. Based on analysis of vision tests, Dr. Zein found that the Usher syndrome type 1F mutation led to 50% of study participants being legally blind by age 50.

Separately, Dr. Ahmed created a mouse with Usher syndrome found in 13 of Dr. Friedman’s patients. This gene mutation PCDH15 leads to a shortened version of the protein protocadherin-15. However, the mechanism of how this mutant protocadherin-15 led to blindness was unknown. To unravel this, Dr. Zein’s teams of Dr. Friedman and Dr. Ahmed decided to collaborate and compare the eye characteristics of humans and mice with this genetic condition that they had independently collected over the years.

By comparing the mouse model of Usher syndrome to healthy mice, Dr. Ahmed’s team identified two functions of protocadherin-15. First, protocadherin-15 helps light-dark cycle proteins move between different compartments of light-sensing photoreceptors in the eye. Second, protocadherin-15 is also needed to recycle molecules that are essential for eye tissue function, called retinoids. Usher syndrome type 1F mutant mice had reduced levels of retinoids in a certain type of eye cell.

Next, the researchers gave mice with Usher syndrome a retinoid drug to see if it improved their vision. Injections of retinoids in mice with Usher syndrome increased electrical activity in the eyes of young and adult mice, indicating improved visual function.

“Besides replacing retinoids, we may also think about developing more permanent therapies to treat or prevent blindness in people with Usher syndrome type 1F that could also correct or replace other functions of protocadherin-15” , said Dr. Ahmed.

E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and John Z. and Akiko K. Bowers Professor Emeritus and Dean, University of Maryland School of Medicine, said: “People born deaf, like people with Usher Syndrome, rely on their other senses to communicate with and understand the world. Subsequent vision loss can pose significant challenges and can be isolating. This work here is building fundamental discoveries that could one day improve the lives of people with rare genetic conditions like Usher syndrome.”