Usher syndrome is a rare genetic disorder that leads to both hearing and vision loss due to genetic mutations. Professor Uwe Wolfrum from Mainz University is at the forefront of research into this condition. His work is supported by various foundations and, importantly, by those affected by the disorder.
“In the most severe form of Usher syndrome, children are born deaf,” explains Professor Wolfrum. “They also face balance issues early on, even while sitting or crawling, and eventually, they become blind.” While cochlear implants can help with hearing loss and balance issues can be managed through training, there is currently no treatment for the retinal degeneration that causes vision loss. This situation affects about 8,000 individuals in Germany alone.
Professor Wolfrum has dedicated nearly 30 years to studying Usher syndrome at the Institute of Molecular Physiology at JGU. He emphasizes, “Usher is the most common genetic cause of combined deaf-blindness in humans.” Genetic defects disrupt essential protein molecules in the cells of the inner ear and retina, impacting their function. This particularly affects photoreceptor cells in the eye, leading to a condition called retinitis pigmentosa. Over time, the retina degenerates, resulting in blindness. Research is complicated by the fact that defects in eleven different Usher genes have been identified, each causing various subtypes of the syndrome. Modifier genes can also affect the severity of the disease.
For scientists, Usher syndrome presents a complex challenge. For those affected, it is a progressive condition that they must manage daily. To advance research and offer hope to patients, Professor Wolfrum and his team actively engage with patient organizations and foundations, such as the Foundation Fighting Blindness, USHER2020, the FAUN Foundation, and Pro Retina, which focuses on preventing blindness.
Support for Families
“The most difficult aspect for those affected is the realization that they will likely lose their eyesight and that no cure exists,” says Reinhard Rubow, Vice Chairman of Pro Retina. Often, it is the parents of affected children who need support. Usher syndrome is inherited recessively, meaning both parents must carry the gene, often without showing symptoms themselves. The Pro Retina Foundation helps families with information and support while promoting research into retinal degeneration. They organize lectures, fund professorships, offer scholarships, and support scientific projects like those in Mainz.
Many patients find hope in Professor Wolfrum’s extensive research, which has resulted in over 50 foundational papers on Usher syndrome’s cellular and molecular mechanisms. His team is exploring potential therapies for eye treatment. They are particularly interested in gene therapies that have already been approved for other retinal conditions. “In this process, we use harmless viruses to insert functional gene copies into affected cells,” Wolfrum explains. However, some molecules involved in certain Usher types are too large for the viruses used in other conditions. As a result, the team is also investigating alternative therapies, including different viruses, small molecules, or drugs that can bypass common genetic mutations.
Building Connections with Patients
Direct communication with those affected is “invaluable, especially in studying rare diseases,” according to Wolfrum. This includes interaction through patient organizations, a recent International Symposium on Usher Syndrome at JGU, and the therapy team led by Dr. Kerstin Nagel-Wolfrum. “For some patients, this connection builds the trust necessary to participate in studies,” he adds. Skin biopsies can be obtained from patients to create “living” eye models. In the lab, these cells are transformed into stem cells, leading to the development of retinal organoids, or “retinas in a petri dish.” These organoids mimic the human retina and allow researchers to study defective genes and test potential therapies.
A Long Road Ahead
Wolfrum’s team is also creating animal models for Usher syndrome. Since mice do not exhibit the eye problems associated with Usher, they are collaborating with researchers in Munich and the Czech Republic to use genetically modified pigs, whose eyes are more similar to those of humans. “This unique approach allows us to compare the molecular processes behind Usher in large animal models with those in human organoids,” Wolfrum explains.
Despite these promising developments, the journey to a therapy for Usher syndrome remains long and uncertain. “We conduct preclinical studies on potential therapies based on our basic research findings, followed by clinical trials with patients,” Wolfrum states. A significant challenge is the lack of interest from pharmaceutical companies in researching rare diseases like Usher, as the necessary studies are time-consuming and costly. “Even if a drug is developed, it may benefit only a small number of patients, which is not profitable for companies focused on profit.”
To support this research, patient organizations and foundations like Pro Retina provide crucial financial assistance. “One of our main tasks is fundraising for projects like those led by Professor Wolfrum,” says Rubow. This funding could ultimately help prevent blindness in many individuals. Pro Retina raises money through corporate donations, bequests, government support, membership fees, and private donations from affected families.
Community Fundraising Efforts
An inspiring example of community support comes from a mother of a young boy with Usher syndrome. She organized a fundraising campaign, gathering money from friends, arranging a charity event at her favorite restaurant, and hosting a flea market. Her efforts raised €25,000, which Pro Retina donated to the Mainz researchers in June 2024. Although these contributions are often smaller than those from larger funding bodies, they are vital for supporting ongoing research and raising awareness about this rare disease.
Another shared goal among researchers and organizations is to encourage young scientists to work on rare diseases. Many of them lack personal connections to conditions like Usher, unlike more common diseases like cancer or heart disease. “We need to show that careers in rare disease research are possible,” Wolfrum emphasizes. Pro Retina hosts an annual conference for early-career scientists to share their findings and learn from established researchers like Wolfrum. He actively seeks to inspire students in his university courses.
Future Possibilities
“Basic research into rare diseases provides deep insights into the molecular mechanisms of healthy cells,” Wolfrum explains. “This knowledge helps us understand how diseases develop.” His team is also developing gene-editing techniques to correct cellular defects. “With CRISPR technology, we can precisely cut genes and alter mutations.” While these techniques are not yet ready for patient treatment, Wolfrum believes they could one day help not only Usher syndrome but also many other currently incurable diseases.
Reflecting on his journey, Wolfrum recalls that when he began his Ph.D. in the late 1980s, no Usher genes had been identified. His early research focused on insect sensory systems, where he discovered parallels to human photoreceptor cells. He obtained cow eyes from a slaughterhouse to isolate cells for lab experiments. The genes he later identified encode different proteins, and their interactions within cells have revealed connections between different Usher types. Wolfrum also found that Usher mutations lead to defects in cilia, tiny hair-like structures on cells, characterizing Usher syndrome as a ciliopathy. This field is currently thriving, as cilia are also implicated in various diseases affecting other organs, including the kidneys and brain.
For Wolfrum, fundamental research remains an exciting venture. However, he emphasizes the importance of keeping in mind the patients they serve: “We are not working for other scientists, but for seriously ill people and their families who are desperate for a treatment.”
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