Usher syndrome type 1F (USH1F) is characterized by deafness, progressive retinal degeneration, and balance issues. Now, using data generated from patients and mice with the genetic mutation for Usher syndrome, the cellular mechanism behind progressive vision loss has been identified. Based on these findings, researchers were able to test a retinoid therapy that improved vision in mice with Usher syndrome. The researchers noted that assessing a similar therapy should be considered in people with Usher syndrome in an effort to slow vision loss.

This work is published in eLife in the paper, “Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome.”

Among Ashkenazi Jews, there is a 2% chance each person is a carrier of the USH1F mutation, accounting for approximately 60% of their Usher syndrome type 1 cases. There are no approved therapies to prevent vision loss or restore vision in people with Usher syndrome.

Prior to this study, only anecdotal data had been reported for USH1F without any detailed data analysis of the worsening eye abnormalities over time. In the early 2000s, researchers initiated an Usher syndrome natural history project and enrolled 13 study participants with USH1F to follow the natural progression of their accompanying blindness over 20 or more years. Based on analysis of vision tests, they found that the USH1F mutation led to 50% of the study participants being legally blind by age 50.

“The identification of a key mutation in the PCDH15 gene nearly two decades ago was a critical breakthrough, facilitating the diagnosis of and carrier screening for a certain form of Usher syndrome, now resulting in the discovery of a potential preventative therapy for vision loss associated with the syndrome,” said Thomas B. Friedman, PhD, chief of the laboratory of molecular genetics at the National Institute on Deafness and Other Communication Disorders (NIDCD).

Zubair M. Ahmed, PhD, professor of otorhinolaryngology—head & neck surgery and ophthalmology at University of Maryland School of Medicine, created an Usher syndrome mouse with the mutation found in 13 of Friedman’s patients. This mutation in the gene PCDH15 (Pcdh15R250X) leads to a shortened version of the protein protocadherin-15.

The mouse Pcdh15R250X variant, the authors noted, “is equivalent to human p.Arg245.” Homozygous Pcdh15R250X mice have visual deficits and aberrant light-dependent translocation of the phototransduction cascade proteins, arrestin, and transducin.

However, the mechanism for how this mutant protocadherin-15 led to blindness was unknown.

Comparing the Usher syndrome mouse model to healthy mice, Ahmed’s team identified two functions of protocadherin-15. First, protocadherin-15 helps light-dark cycle proteins move back and forth between the different compartments of the light-detecting photoreceptors in the eye. Second, protocadherin-15 is also required for recycling molecules essential for functioning eye tissue, known as retinoids. The USH1F mutant mice had reduced levels of retinoids in a certain kind of eye cell.

Next, the researchers gave a retinoid drug to the Usher syndrome mice to see if it improved their vision. Retinoid injections into the Usher syndrome mice increased the electrical activity in the eyes of both younger and adult mice, indicating improved vision function.

“Aside from retinoid replacement, we can also think about developing more permanent therapies to treat or prevent blindness in people with Usher syndrome type 1F that may correct or replace the other functions of protocadherin-15, as well,” said Ahmed.

“The drug we used in mice may provide a first step to improve eye health in people with Usher syndrome type 1F,” said Ahmed. “Unfortunately, these drugs will not permanently cure loss of vision, as the drug does not repair damage or prevent degeneration of the eyes. However, it should improve the function of the tissue that these patients still have.”

Saumil Sethna, PhD, instructor in otorhinolaryngology—head & neck surgery, said, “There are currently FDA-approved relatives of these retinoid drugs that are available and have passed clinical trials for safety, along with 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 launch a clinical trial in patients with Usher syndrome type 1F to see if it can help by preventing continuing vision loss.