Unlocking the secrets of Usher syndrome

The mistakes are small but carry severe consequences: In Usher syndrome, genetic mutations cause both hearing and vision loss. Cell biologist Professor Uwe Wolfrum from Mainz University is researching the molecular background of this rare genetic disorder - supported by foundations and, not least, by affected individuals themselves.

"In the most severe type of this inherited disease, children are born deaf," explains Professor Uwe Wolfrum. "Furthermore, balance issues appear early on, even when sitting or crawling, and later they become blind." While the hearing loss in Usher syndrome can nowadays be compensated with cochlear implants and balance problems can be alleviated through training, no treatment yet exists for the retinal degeneration underlying the vision loss that accompanies the condition. This represents a heavy burden for the approximately 8,000 people affected in Germany alone.

"The progressive impairment of multiple senses makes the diagnosis a devastating blow, initially robbing all joy from life.

Uwe Wolfrum, Professor, Universität Mainz

As one of the leading researchers in cellular and molecular biology, he investigates sensory cells, their function, and their role in hereditary diseases at the Institute of Molecular Physiology at JGU, having worked on Usher syndrome for nearly three decades. "Usher is the most common genetic cause of combined deaf-blindness in humans," says Wolfrum. "Genetic defects lead to the absence or malfunction of protein molecules in the cells of the inner ear and retina that are essential for the functioning of these organs." This particularly affects the eye's photoreceptor cells, causing retinitis pigmentosa. The retina slowly degenerates, leading to blindness. The fact that defects in eleven different Usher genes have been identified, each leading to various subtypes of the syndrome, makes research particularly challenging. Moreover, so-called modifier genes can further influence the severity of the disease.

For scientists, Usher syndrome represents a highly complex puzzle. For those affected, it is a progressive disability they must cope with both physically and emotionally every day. To advance research and offer hope to patients, Wolfrum and his team maintain active communication with patient organizations and foundations such as the Foundation Fighting Blindness, USHER2020, the FAUN Foundation, and Pro Retina - Foundation for the Prevention of Blindness.

Support for parents of affected children

"The worst part for those affected is the information that they will most likely lose their eyesight - and that there is no cure," states Reinhard Rubow, Vice Chairman of Pro Retina - Foundation for the Prevention of Blindness. In the case of affected children, it is often the parents who need support. Usher syndrome is inherited recessively, meaning it must be passed down from both parents, who are typically symptom-free and often unaware of their genetic predisposition. While a patient association connected to the Pro Retina Foundation provides support and information to affected individuals and their families, the foundation itself promotes research into retinal degeneration. It organizes lectures and discussions with researchers, funds endowed professorships, awards scholarships, and supports scientific projects like those in Mainz.

Many patients find hope in the fact that Professor Uwe Wolfrum and his team have published over 50 foundational papers on the molecular and cellular mechanisms underlying Usher and are exploring potential therapies for the eye. They learn about experimental projects aimed at applying gene therapies to Usher syndrome, which have already been approved as treatments for similar retinal conditions. "In this process, functional gene copies are inserted into affected cells using harmless viruses," explains Wolfrum. "However, some of the molecules involved in certain Usher types are too large for the viruses used in other conditions, so we are also working on alternative therapies - such as different viruses that can carry larger genes, small molecules, or potential drugs that can read through stop mutations." Stop mutations are common genetic changes that prematurely halt the production of a protein, resulting in a non-functional fragment. "By bypassing these stops, we can produce a complete, functional protein and restore the sensory cell's function."

According to Wolfrum, the direct contact with those affected is "invaluable, especially in the study of rare diseases" - whether through patient associations and foundations, the International Symposium on Usher Syndrome held at JGU a few years ago, or the therapy team at JGU, led by Dr. Kerstin Nagel-Wolfrum. "For some patients, this exchange builds the trust needed to participate in studies," says the cell biologist. "We can obtain skin biopsies from patients to create 'living' eye models." In the lab, these cells are transformed into stem cells, which are then used to generate so-called retinal organoids. "These 'retinas in a petri dish' mimic the human retina, possessing all the retinal cell types, forming characteristic cellular layers, and responding to light," Wolfrum explains. "This allows us to study the effects of defective genes on the human retina and better understand them. Moreover, we can test potential therapies on these organoids in a human system."

A hopeful but long journey

The JGU researchers are also working on animal models for Usher syndrome. Since mice do not develop the malfunctions in the eye characteristic for Usher, Wolfrum's team collaborates with researchers in Munich and the Czech Republic on genetically modified pigs as their eyes are more similar to the human eye than that of mice. "What makes this approach unique is that we directly compare the molecular processes behind Usher in large animal models with those in human organoids," Wolfrum emphasizes.

While these are promising developments, the road to a therapy for Usher syndrome remains long and difficult to predict. "Based on the findings of our basic research, we conduct preclinical studies on potential therapies using our disease models, to be followed by clinical trials with patients," says Wolfrum. A major challenge is the low interest from pharmaceutical and medical technology companies in researching rare diseases like Usher. "Basic research and the necessary preclinical and clinical studies are time-consuming and expensive - and even if they lead to a drug, it will benefit only a small number of patients. This is not profitable for a profit-oriented company."

Therefore, patient organizations and foundations like the Pro Retina Foundation provide financial support for this research. "One of our key tasks is fundraising for research projects like those led by Professor Wolfrum," says Reinhard Rubow. "These efforts may one day help prevent people from going blind." The Pro Retina Foundation finances its work through a combination of corporate donations, bequests, government funding, membership fees, and, not least, private donations, often from affected individuals and their families.

Fundraising among friends

The mother of a young boy with Usher syndrome got particularly creative in organizing a fundraising campaign, Rubow recalls. "She collected money from friends, convinced her favorite restaurant to hold a charity event, and even organized a flea market." The money she raised ultimately contributed to a EUR 25,000 donation which the Pro Retina Foundation handed over to the Mainz researchers in June 2024. Although such donations from foundations and patient organizations are often smaller than third-party funding Wolfrum secures from organizations like the German Research Foundation (DFG), they are a very valuable supplement for funding the costly cell biology projects. These donations can fill funding gaps, enabling current experiments to continue without lengthy application processes. Additionally, they help raise public awareness of this rare disease.

Another shared goal is to inspire young researchers to work on rare diseases. Most of them don't have personal experience with Usher patients and are thus less intrinsically motivated for working in this field. It's different in the case of cancer or cardiovascular diseases, where many have a family member or friend affected. "Therefore, we need to demonstrate that scientific careers can be built around the study of rare diseases," Wolfrum emphasizes. The Pro Retina Foundation, for example, hosts an annual conference for early-career scientists to present their latest findings and "draw inspiration from luminaries like Uwe Wolfrum," says Reinhard Rubow. Wolfrum himself seeks to spark enthusiasm for research on rare diseases among students and young scientists in his courses at the university.

"Basic research into rare diseases provides a deep insight into the molecular mechanisms of healthy cells," says Wolfrum. "This knowledge then helps us understand why diseases occur." His team is also developing gene-editing techniques to fix cellular defects. "With CRISPR technology, also known as gene scissors, genes can be precisely cut, mutations can be removed and altered." Such technologies are not yet ready for patient treatment. "However, it is foreseeable that one day they could help treat not only Usher syndrome but many other currently incurable diseases."

From insect antennae to human retinal defects

When Wolfrum was working on his PhD in the late 1980s/early 1990s, no Usher gene had yet been identified. His doctoral thesis focused on the sensory systems of insects. "In doing so, I discovered parallels between insect sensory cells and human photoreceptor cells - which led me to Usher syndrome." Early in his research, he obtained cow eyes from a slaughterhouse to isolate cells and molecules for lab experiments. "The Usher genes that were then gradually identified encode quite different proteins," explains Wolfrum. The discovery that these Usher proteins interact with each other within cells and form networks provided a molecular connection between different Usher types. Additionally, Wolfrum found that Usher mutations cause defects in cilia, the hair-like projections on the cell surface, and characterized Usher syndrome as a ciliopathy. "Today, the study of ciliopathies is booming, as they also play a role in diseases of many other organs, like the kidneys and the brain."

Developing new hypotheses, exploring even speculative ideas, and venturing into scientific uncharted territory - that's what makes fundamental research fascinating for Wolfrum to this day. But what's most important to him is to convey to young researchers who they are really working for. "And that's not other scientists, but seriously ill people and their families, who are longing for nothing more than a treatment."