An international team led by researchers at Case Western Reserve’s School of Medicine has designed a targeted therapy that shows early promise in treating a genetic disorder that damages both hearing and vision over time.

Usher syndrome—the most common cause of inherited dual sensory deficit—is classified into three separate types based largely upon the timing of the onset of symptoms and their ultimate progression. For their project, Case Western Reserve faculty Kumar N. Alagramam and Yoshikazu Imanishi led scientists in developing a small molecule to mitigate the effects of a gene mutation involved in Type 3 Usher syndrome (USH3). No treatment is currently available to stop or slow the progression of vision or hearing loss in USH3.

The team tested the approach in mouse models, and found that it attenuated hearing loss and ultimately prevented deafness. Their findings appeared earlier this year in Nature Chemical Biology.

“One of the most exciting implications of this research is the potential for real-world translation, as the key to increasing the odds of success for any treatment is the ability to apply it before symptoms appear,” said Alagramam, associate professor and director of research for the otolaryngology department at the School of Medicine. Patients with Type 3 Usher Syndrome “are born with the ability to hear and acquire speech and language, with the majority of cases being diagnosed by the age of 10 years. Genetic testing can be used to identify at-risk … patients before the onset of hearing loss, and the small molecule treatment … could, in theory, be started preemptively.”

The finding of this targeted therapy in a mouse model holds much promise for the thousands of patients diagnosed with USH3, as well as their families.

In addition to Alagramam and Imanishi, assistant professor of pharmacology, the team included chemists from BioFocus (U.K.) who optimized the original “hit” small molecule identified at the School of Medicine, and Case Western Reserve researchers who characterized the biochemical properties of the molecules.

The team utilized a novel research strategy involving a cell-based high-throughput screening of small molecules capable of stabilizing the mutant gene responsible for USH3, Clarin-1-N48K (CLRN1N48K), a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure activity relationships, resulting in the identification of the compound BF844.

To test the efficacy of BF844, the School of Medicine scientists developed and studied a mouse model that mimicked the progressive hearing loss of USH3.

“Notably, these research findings could have broader implications beyond USH3 and hearing loss. Because the human [form of the] mutation causes both hearing and vision loss, this small molecule targeted therapy could, in principle, prevent both sensory deficiencies in USH3 patients.” Imanishi said. “Moreover, many monogenic disorders are caused by point mutations which destabilize the protein products. Our drug discovery strategy, in theory, will be applicable to identify drugs stabilizing these mutant proteins.”

While the research was made possible through a combination of federal and philanthropic support, one of the key organizations involved was the Usher III Initiative, a foundation that Cindy Elden and her father, Richard Elden, launched in 2007.

A major advocate within the USH community, Cindy Elden was correctly diagnosed with USH3 in her 30s after being misdiagnosed with USH2 for most of her life.

Alongside her father, who has long been dedicated to finding a treatment for his daughter, Elden co-founded the Usher III Initiative as a progressive research consortium that aims to identify the cause of, and develop a cure for, USH3. They are working closely with the School of Medicine with the goal of advancing their findings into an eventual treatment for USH3.

“We were very proud to support the School of Medicine on this groundbreaking research. Their discovery of the pathogenic mechanism associated with hearing and vision loss in CLRN1N48K USH3 patients was an exciting first step, followed by their development of the novel small molecule, which has been shown to stop mice with USH3 from losing their hearing. Combined, these scientific strides open the door for future USH3 treatment, and give me and the USH3 community tremendous hope,” said Elden.

This work was supported by the Usher III Initiative (YI, KNA, and BioFocus group); Hope for Vision (YI); the Prince Family Foundation (YI), Case Western Reserve University (YI), the National Institutes of Health Grants R01-DC010816 (KNA.), R01-EY020826 (YI) and R24 EY021126 (KP); and the Arnold and Mabel Beckman Foundation (KP).