Stichting Ushersyndroom supports research on personalized treatments

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RNA Therapy for Ultra-rare mutations

Stichting Ushersyndroom (Dutch Usher Syndrome Foundation) is supporting a new research project led by Prof. Dr. Rob Collin from Radboud University Medical Center (Radboudumc). This project, titled “Personalized Treatment for Retinal Disease Patients with Ultra-Rare Mutations,” focuses on developing innovative and personalized treatments for patients with extremely rare mutations causing inherited retinal diseases.

The urgency of the research
In the Netherlands, an estimated 6,000 people are affected by inherited retinal diseases such as retinitis pigmentosa, Usher syndrome, and Stargardt disease. For many patients, these diseases ultimately lead to severe visual impairments, including night blindness, tunnel vision, and a visual acuity of less than 0.3. Effective treatments for the rarest mutations remain scarce, primarily due to high costs and the small size of the patient groups.

This research focuses on an innovative approach: N-of-1 treatments. These are therapies specifically designed for an individual patient or a small group of patients, using “genetic patches,” also known as antisense oligonucleotides (AONs). These small RNA molecules can correct defects in gene expression, providing new hope for patients with extremely rare genetic mutations.

Research design and collaboration
This one-year pilot project combines advanced laboratory experiments and cell models. Four selected patients with rare mutations will participate in the study. Stem cells derived from their own tissue will be grown into retina-like structures (organoids) to test the effectiveness and safety of AON treatments.

The primary goals of the research include:
1. Developing patient-specific stem cells.
2. Correcting genetic defects using AONs.
3. Testing the safety and effectiveness of future treatments.
4. Establishing a pipeline for future personalized therapies.

The project is being conducted in close collaboration with the Genetics, Ophthalmology, and ENT departments of Radboudumc and is part of the national RD5000 consortium.

Impact of the research
The immediate results of this project will offer hope to four patients. In the long term, this research could significantly impact the development of N-of-1 treatments, potentially benefiting dozens of patients each year. This project lays the groundwork for the broader application of personalized genetic therapies.

Together, we can build a world without limits, without restrictions, without Usher syndrome.

A future full of hope
Thanks to the proceeds from Tim Schroeder’s remarkable cycling tour in America, the Stichting Ushersyndroom can fund this research. Additionally, the National Foundation for the Blind and Visually Impaired (L.S.B.S.), Oogfonds, and Oogcontact Amsterdam are financially contributing to this one-year study.
With this research, we are taking a step closer to a future without limits, without restrictions, without Usher syndrome.

By: Ivonne Bressers
Date: January 7, 2025

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Are rabbit eyes and cell models suitable?

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Assessment of safety and toxicity of genetic patches

Inherited retinal diseases, such as Usher syndrome (deafblindness), are rare conditions that result in a gradual loss of vision. These diseases have a significant impact on the quality of life of patients and their families. While most inherited retinal diseases remain largely untreatable, significant progress has been made in recent years. RNA therapies are being developed that use “genetic patches.” A major focus in the development of such therapies is the high cost associated with safety and toxicity testing of genetic patches.

One requirement that must currently be met before genetic patches can be tested in patients is that their safety—meaning that they are not toxic, harmful, or dangerous—must be demonstrated in two different vertebrate species, one of which must be a primate.

Genetic patch for each mutation
The genetic patch is specifically developed for a particular mutation or group of mutations within a gene. It has already been demonstrated in animal models and in clinical trials that genetic patches developed to mask exon 13 in the USH2A gene are safe. However, these results do not guarantee that the same will hold true for genetic patches designed for other mutations and exons. Consequently, the same tests to confirm the safety of these newly developed genetic patches must be performed. These tests are costly, time-consuming, and involve the use of many animals.

RETOX project
The “RETOX” project (Rabbit Eyes for AON-induced TOXicity evaluation), a collaboration between Radboudumc, Astherna BV, and Stichting Ushersyndroom, aims to investigate whether rabbits can be used as the sole species to rule out potential toxic reactions to genetic patches. Additionally, the project will explore whether these toxicity and safety tests can be conducted in cultured cells in the future.

If the results of the RETOX project demonstrate that rabbits are indeed suitable for determining the toxicity of genetic patches, it would significantly reduce the development costs of these therapies and decrease the number of animals used during the development of genetic patch therapies.

Read more about this study on the Health Holland website:
Suitability of rabbits and in vitro models for toxicity assessments | Health~Holland

Stichting Ushersyndroom launches the ‘Usher Crusher Grant’

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We invite international scientists to seize this unique opportunity and submit their most innovative research proposals.

On October 8th, Stichting Ushersyndroom [Dutch Usher syndrome Foundation] officially opens its second international call for researchers: the Usher Crusher Grant. This grant offers scientists worldwide the chance to elevate research on Usher syndrome to new heights. Building on the success of the 2023 ‘Moon Rocket Grant,’ which funded two promising research projects, the Usher Crusher Grant will provide significant support for groundbreaking research.

Valued at €300,000, the Usher Crusher Grant aims to make a substantial contribution to research that aligns with our ultimate moonshot goal: “By 2030, the Netherlands and the world will be aware of Usher syndrome, and its diagnosis, treatment, and care will have become standard practice.”

A powerful boost for groundbreaking scientific research
Stichting Ushersyndroom seeks not only to facilitate scientific breakthroughs but also to actively steer the direction of research. We feel the responsibility to advance scientific studies on all types of Usher syndrome and call on researchers to contribute their expertise within the four key themes of our research agenda:

  • Diagnostics & Prognostics: Our goal is to achieve a genetic diagnosis for everyone with Usher syndrome and improve detection for those without a known DNA diagnosis.
  • Fundamental Research: Understanding the causes of Usher syndrome is crucial for better diagnostics and treatments, and we aim to explore the underlying mechanisms.
  • Biomarkers & Endpoints: Measurable indicators are needed to track clinical progression and assess the effectiveness of treatments in therapeutic studies.
  • Treatment: Our focus is on treatments aimed at slowing or halting disease progression, improving vision, hearing, and balance, and reducing other symptoms such as sleep disturbances.

These themes pave the way for improved diagnosis, care, and treatment for people with Usher syndrome worldwide.

International scientists can submit their proposals now

Winners announced at USH2025
The call for research proposals closes on Rare Disease Day, February 28, 2025. The winner(s) of the Usher Crusher Grant will be announced during the International Symposium on Usher Syndrome (USH2025), taking place on June 19, 20, and 21, 2025, in Nijmegen. This symposium will bring together scientists, clinicians, patients, and their families from around the world to share knowledge, discuss the latest developments in Usher syndrome research, and connect with one another.

With the Usher Crusher Grant, we invite and challenge international scientists to collaborate on building a future where Usher syndrome no longer imposes limits on people’s lives. Together, we can create a world without boundaries, without restrictions, and without Usher syndrome.

 

 

RESEARCH AGENDA
FLYER GRANT
USHER CRUSHER GRANT (PDF)
DOWNLOAD APPLICATION FORM

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‘Moon Rocket Grant’ uit 2023

An important next step in USH2c research

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Erwin van Wijk (Radboudumc) has recently received a substantial grant from the Foundation Fighting Blindness USA to create a large animal model in collaboration with the research groups of Klymiuk (LMU Munich, Germany) and Ellederova & Motlik (PIGMOD Center, Libechov, Czech Republic): a USH2c pig model. This development marks a significant step towards effective treatments for patients with USH2c.

Accelerating therapy development
The grant for developing a USH2c pig model is crucial for accelerating therapy development for USH2c. This model enables the final critical studies, such as tests on the effectiveness, dosage, and toxicity of various therapies for USH2c. Currently, such studies cannot be performed with the available cell and zebrafish models for USH2c. The pig model allows researchers to take these essential last steps before therapies enter the human trial phase.

The pig eye: A valuable model
Although more alternative cell models are becoming available, it is unfortunately still not possible to develop new therapies without the use of animal models. Efforts are being made to reduce the use of animal models as much as possible, in accordance with the 3R principle: Replacement, Reduction, and Refinement. All new therapies are first extensively tested in human cell models and the previously developed USH2c zebrafish model. While these are excellent models for fundamental and translational research, they are not suitable for determining the long-term effects and safety of new treatments.
The pig eye closely resembles the human eye, both in size and morphology, and has already proven its value as a model for Usher syndrome type 1c.

A humanized USH2c model
The proposed model will be a ‘humanized’ USH2c pig model, where parts of the pig USH2C gene are replaced with the human USH2C gene, including the mutations that cause Usher syndrome. This humanized model provides the opportunity to test a wide range of current and future therapeutic strategies.

Goal and impact of the project
The main goal of this project is to generate a multifunctional humanized pig model for USH2c, in collaboration with the research groups of Nikolai Klymiuk (LMU Munich, Germany) and Jan Motlik & Zdenka Ellederova (PIGMOD Center, Libechov, Czech Republic), who specialize in generating and phenotyping pig models.
Erwin van Wijk’s research group in Nijmegen will design the pig model and produce the necessary components for its creation. In Munich, the pig will actually be created, and in the Czech Republic, a group of pigs will be bred, followed by phenotyping (analysis of vision and hearing function). Finally, various genetic analyses will be conducted in Nijmegen (at the DNA, RNA and protein levels). The project has a duration of three years.

The model is designed to determine the effectiveness of all forms of genetic therapy (RNA therapy, (mini)gene therapy, translational read-through therapy, CRISPR therapy, etc.). This model enables the translation of effective and safe therapeutic treatments from pig to human.

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What are the best biomarkers and endpoints for future trials?

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NEW RESEARCH THANKS TO
THE ‘USHER ACTIE RIJNSBURG’ FRIENDS GROUP

The ‘Usher Action Rijnsbrug’ group of friends present the check to Dr. Suzanne Yzer. From left to right; Marjolein, Liesbeth, Suzanne, Annemarie

Usher syndrome, characterized by sensorineural hearing loss and progressive Retinitis Pigmentosa (RP), presents a significant challenge for the medical community. With the most involved gene, USH2A, treatments for Retinitis Pigmentosa are becoming increasingly promising. The use of correctly chosen endpoints will prevent unnecessary failures of potentially effective treatment studies and accelerate the development of treatments.

Thanks to the years of unwavering enthusiasm and dedication of the ‘Usher Actie Rijnsburg’ group, Stichting Ushersyndroom can financially support an important study into the right biomarkers and endpoints.

Correlation between structure and function
In this study, led by Dr. Suzanne Yzer, ophthalmologist at Radboud University Medical Center in the Netherlands, researchers aim to examine the retinas of patients with Usher syndrome by combining existing ophthalmic examinations with newly developed imaging techniques. The combined information will provide a more detailed correlation between the structure and function of the retina, yielding essential data for a comprehensive analysis. This will enable the identification of the best biomarkers and endpoints for clinical trials for Usher syndrome patients. Biomarkers and endpoints that will aid in treatment trials (clinical trials), ensuring that outcomes and information are indisputable and provide evidence of treatment effectiveness.

“Correctly chosen endpoints help prevent the unnecessary failure of a potentially groundbreaking treatment study.”
Dr. Suzanne Yzer, Ophthalmologist at Radboud University Medical Center

Delay
A poorly designed study or wrongly chosen biomarker or endpoints can lead to years of delay before the therapy becomes available to patients. This is not only a significant disadvantage for the specific treatment but will also deter investors from supporting new studies.

Incorrect endpoints
The failure of a treatment study does not necessarily mean that the investigated therapeutic treatment is ineffective. Studies may fail because of inaccurately chosen inclusion criteria or endpoints. In August 2022, ProQR’s clinical trial was halted for this reason. The endpoints for another clinical trial (for LCA) were not accurately defined, resulting in them not being met. Investors withdrew, leading to insufficient funding to continue the clinical trial for USH2A exon 13.
The clinical trial has since been restarted; Laboratoires Théa (Théa) has taken over the study.

Existing and new imaging tools
With the first clinical trials on the horizon, it is crucial to select the right biomarkers and endpoints. Radboudumc has conducted a large natural history study in a large group of patients with mutations in USH2 genes, the CRUSH study, and the RUSH2a study. Results are expected in the fall of 2024. Since the start of these studies, progress has been made with existing and newly developed imaging tools, such as “Adaptive Optics” and the “High Magnification Module” lens.

Increasing opportunities
The current study focuses on identifying the most reliable biomarkers and endpoints for future therapeutic studies in Usher syndrome type 2. By identifying better endpoints, the chances of demonstrating treatment effectiveness will be increased, helping to advance the development of treatments. This will also make it more attractive to accelerate the implementation of new clinical studies, such as gene replacement therapy for Usher syndrome, including minigenes for USH2A and USH2C, and exon excision therapy.

This will ultimately benefit all patients with Usher syndrome. The goal is to achieve successful treatment and administer the drug or therapeutic treatment in the earlier stages of the disease, thus preventing severe loss of photoreceptors. The findings will be published in scientific journals and will contribute to the advancement of gene-specific therapies for retinal diseases.

Thanks to the Usher Action Rijnsburg and the co-financing from the Vaillantfonds and the Aanmoedigingsfonds van de Koninklijke Facultatieve the Stichtig Ushersyndroom can financially support this research.This project is budgeted at € 226.000,- and will last for three years.

Friends group of Liesbeth
‘Usher Actie Rijnsburg’ is a friends group that takes action for their friend Liesbeth and other people with Usher syndrome. They organize various activities and an annual event to raise as much money as possible.

Patient and researcher: a dynamic duo once again cycling together

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BUT NOW ON A RACING TANDEM WITH GEARS

In a remarkable collaboration between patients with Usher syndrome and researchers from Radboudumc, a crucial next step is made possible in the research towards a treatment for Usher syndrome type 2C (USH2C).

In 2020, researchers and patients embarked on a joint journey in the research on USH2C. The research, funded by Stichting Ushersyndroom (Dutch Usher Syndrome Foundation) with co-financing from L.S.B.S. and CUREUsher, has faced some setbacks, including delays due to the COVID-19 pandemic. Although the research has experienced some delays, the initial results appear to be very promising. Researchers and patients are striving to accelerate this crucial and innovative research. Patients worldwide are uniting to raise funds for the Usher Syndrome Foundation so that a follow-up to this study can be made possible.

Bike ride
In their sporty attire, researcher Merel Stemerdink, cheerfully acting as a co-pilot along with patient (and treasurer of Stichting Ushersyndroom Rick Brouwer as the stoker, cycled to the Railway Museum during the Usher Awareness Day last summer. They cycled over 75 kilometers from Arnhem to Utrecht. Smoothly, focused, and at a fast pace! Merel regularly races in her free time, and Rick is a trained triathlete.

In rare diseases such as Usher syndrome, the contact between doctors, researchers, and patients is crucial. Patients, parents, and loved ones drive scientific research towards a treatment by collecting donations and closely consulting with doctors and researchers. By working together, a treatment for progressive deaf-blindness comes into view more quickly.

Accelerating as a duo on the tandem
Patients with Usher syndrome and researchers from Radboudumc are once again putting the tandem into motion for scientific research towards a treatment for Usher syndrome type 2C. Currently, various treatment strategies, including the USH2C minigenes, are being tested in a USH2C zebrafish model developed specifically for the research. The initial results, which are expected to be announced by the end of 2024, are very promising. Therefore, efforts are being made to raise funds to continue this research beyond 2025.

Promising research
USH2C is caused by mutations in the ADGRV1 gene, and these errors in the gene lead to a progressive form of deaf-blindness. One of the promising treatment strategies for inherited blindness is ‘gene augmentation,’ where a healthy copy of the involved gene is delivered to the eye using a viral vector. What makes the development of this therapy challenging is that the ADGRV1 gene is incredibly large: so large that it cannot be packaged into the viral vector. Therefore, artificially shortened versions of the ADGRV1 gene have been created – the ADGRV1 (USH2C) minigenes. These minigenes fit into a viral vector, and currently, it is being investigated using the USH2C zebrafish model whether these mini-genes are actually able to take over the function of the defective ADGRV1 gene.

Another treatment strategy, called ‘exon skipping,’ allows specific exons (the specific regions of the ADGRV1 gene where mutations are located) to be skipped. In theory, this can restore the normal function of the gene. Although this is currently targeted at a smaller group of patients, the initial results in zebrafish provide hope for a more personalized approach to treatment.

Watch here the presentation ‘USH2C Research’ by Merel Stemerdink. With subtitles in Dutch and English.

Researchers and patients
A group of Americans contacted Rick Brouwer via the private Facebook group Usher 2C and called the researchers at Radboudumc. Soon, a symbiosis developed between the patients from the USA and the researchers at Radboudumc. Strong involvement between researchers and patients increases motivation and inspiration to further advance and accelerate current research.

Follow-up Study
Although the analyses and outcomes have yet to be published, the initial results are very promising. A follow-up study to also test the strategies on human organoids is being designed and will be submitted for advice to the Scientific Advisory Board of Stichting Ushersydroom later this year.

Cindy Boer (member of the Scientific Advisory Board and PostDoc Osteoarthritis, genetics, microbiomics & omics at ErasmusUMC and diagnosed with Usher syndrome herself): “In an earlier advice, we proposed an addition to the research. We want a translation to be made to humans using human skin cells. This allows you to investigate whether the minigenes behave well in human cells and whether the proteins fold correctly. This can sometimes be different from animal models and therefore provides a good indication of whether gene therapy will work in humans.”

Future Plans
The research team is also looking towards the future with a postdoc project proposal scheduled for 2025. While the treatment strategies are currently being evaluated in the zebrafish model, the future project will translate these findings to humans. The project will focus on evaluating the treatment strategies in human cells and retinal organoids. The success of these approaches could lead to expansion to other forms of retinal degeneration, and possibly further refinement of ongoing research into new treatments for Retinitis Pigmentosa caused by mutations in the USH2A and USH2C genes.

Jack from the USA is also cycling along!

Taking action together to accelerate research
This time, a racing tandem with both a patient and a researcher on board. Patients from Sweden are now also involved, and a global crowdfunding campaign has been launched. With great confidence in the process propelling them forward and bringing a treatment for Usher syndrome closer than ever before. The funds collected are managed by Stichting Ushersyndroom and are earmarked for further USH2C research. The involvement of patients, both locally and globally, is propelling research into USH2C to new heights. These global efforts to raise donations are conducted through the FundMe platform: ‘Fund a Cure for Usher Syndrome 2C’.

Also read:

 

Ontwikkeling van een ‘netvlies-op-een-chip’ platform

Foundation supports innovative research into retinal diseases

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Development of a ‘retina-on-a-chip’ platform 

An important new study has been launched to offer hope to people suffering from hereditary eye diseases such as retinitis pigmentosa, Usher syndrome, macular degeneration, and Stargardt disease. Led by Dr. Jan Wijnholds of the Leiden University Medical Center (LUMC), researchers are working on a special chip on which they can mimic a piece of human retina. The project is named the “Human retina-on-a-chip platform” and aims to develop an advanced platform for studying the retina and testing candidate drugs.

What is a ‘retina-on-a-chip’? 
The current research involves ‘retinas-on-a-chip’, miniature culture dishes in which human retinal tissue is grown. This allows scientists to study the retina in the laboratory and test potential treatments. However, these chips have limitations, including a lack of stability of the cultured retinas.  

Ontwikkeling van een ‘netvlies-op-een-chip’ platform

Picture made by Charlotte Andriessen.

Why is this research important? 
In hereditary retinal diseases, cells in the retina die, eventually leading to blindness. Although there are promising treatments and gene therapies, there is a need for an improved platform to test them. Dr. Jan Wijnholds and his team are focusing on optimizing the existing ‘retina-on-a-chip’ concept.  

How will Dr. Jan Wijnholds approach this? 
Dr. Wijnholds will make a crucial improvement by adding retinal pigment epithelium to the ‘retinas-on-a-chip’. This pigment layer, similar to what is naturally present in the human eye, enhances the stability of the cultured retinas. However, adding functional pigment layer is a technological challenge due to the microscale at which it occurs.  

What are the potential benefits? 
The improved ‘retina-on-a-chip’ platform will enable researchers to more accurately mimic the human retina in the laboratory. This opens the door to a better understanding of healthy and diseased retinal cells, as well as testing new treatments. Dr. Wijnholds will also look for biomarkers, measurable indicators that indicate whether retinal cell death is occurring and how severe it is. These biomarkers can help doctors predict disease progression and measure the effectiveness of treatments.  

 What does this mean for the future? 
Although this is fundamental research, it could lead to faster development of treatments for people with retinal diseases. The Usher Syndrome Foundation supports this two-year project with a financial contribution of €100,000, expressing its confidence in the value of this groundbreaking research. The ultimate goal is to offer hope to patients with hereditary retinal disorders by enabling more effective treatments. 

Who cleans up ‘the mess’ from the cones?

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New research on the cause of blindness due to Usher syndrome

A research team led by Dr. Ronald Roepman (www.roepmanlab.com) is conducting research at Radboudumc, Netherlands, to investigate the underlying cause of vision loss in Usher syndrome. In this study, titled “Harnessing Autophagy to Combat Macular Degeneration,” they aim to gain more clarity on the death of cone cells in the retina. In a healthy eye, waste products in the retina are “cleaned up,” but in retinal diseases like Usher syndrome, this process is insufficient. The cones ultimately die because waste accumulates in harmful quantities within these cells. Thanks to the efforts of the participants in ‘Nederland wandelt voor Usher’ (Event Walks for Usher), Stichting Ushersyndroom (the Dutch Usher Syndrome Foundation) can finance a significant portion of this important research.

Crucial discovery
Hereditary blindness is a profound condition that seriously affects the lives of many patients. Researchers have been searching for effective treatments for some time, but the question of why waste products in the retina are not cleared in hereditary retinal diseases has remained unknown until now. Dr. Ronald Roepman, who collaborates in this promising project with Dr. Erik de Vrieze and Dr. Erwin van Wyk, recently made a crucial discovery that may provide an answer to this question. This could be a significant step toward a solution. Dr. Ronald Roepman says, “If you understand why the cones don’t clean up the waste, then you might be able to help them clean it up, perhaps with medication.”

Autophagy
The research focuses on understanding the mechanism of ‘autophagy’ in cone cells. Autophagy is a biological process in which certain components of a cell, such as damaged proteins or foreign particles, are broken down. Recent research data suggest that dysregulation of this process is a significant cause of cone cell death, leading to progressive vision loss in hereditary retinal disorders.

Death due to self-waste
An Usher gene contains instructions for producing a protein that keeps the light-sensitive cells in the retina – the rods and cones – healthy. Errors in this gene can lead to the protein’s malfunction and disrupt the processes. Cones produce substantial amounts of waste products, which are normally cleared through the autophagy process. If the Usher proteins are absent or not functioning properly, the cones cannot dispose of their waste products and essentially drown in their own ‘mess.’ The researchers aim to determine how the genetic defect is responsible for the malfunctioning autophagy.

Zebrafish and retinal organoids
The research team uses zebrafish as a model organism in the laboratory due to the striking similarities between their eyes and those of humans. They will compare healthy cone cells with cone cells displaying disrupted autophagy using zebrafish. Additionally, the research team will use retinal organoids, small retinas grown in the laboratory using cells from both Usher syndrome patients and people with healthy eyes. These organoids provide a valuable platform to study the autophagy mechanism in healthy and diseased cells.

Hope for finding a safe and effective treatment
Once the autophagy mechanism is understood, the research team will search for substances that can stimulate the autophagy process, thereby reducing or preventing cone cell death. With the help of a database containing thousands of substances known to stimulate or inhibit proteins, they hope to find a safe and effective treatment.

Also, for other hereditary retinal diseases
This promising research will not only contribute to detailed knowledge about autophagy and cone cell death but also offer possibilities for further treatment development. If the results of this research prove successful, this project could slow down vision deterioration and have a significant impact on the quality of life for Usher syndrome patients. Dr. Roepman says, “It could offer a solution not only for Usher syndrome but also for patients with Retinitis Pigmentosa (RP), Macular Degeneration (MD), and all other forms of hereditary retinal diseases.”

The current project has a duration of three years. Stichting Ushersyndroom plays a significant role in the research by financing a large portion of the required budget. We are not the sole financiers of this research. Thanks to the L.S.B.S. (National Foundation for the Blind and Visually Impaired) and the donors of the Oogfonds (Dutch Eye Foundation), they are co-funders for this project, providing a valuable financial contribution to make this promising research possible.

The voucher was presented during the festive day at the Railway Museum in Utrecht on Global Usher Awareness Day 2023.

You can support us through a donation. With your contribution, the Stichting Ushersyndroom can finance scientific research. Research aimed at finding a treatment for Usher syndrome, so that becoming deaf and blind can be halted!

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Every donation is valuable and brings us closer to solutions for Usher syndrome.

The very first adgrv1-zebrafish model has been presented!

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Recently, an article was published in the journal Cells about the scientific research on USH2C. Merel Stemerdink and her colleagues at the Radboudumc have developed a zebrafish model with a gene defect in adgrv1 (the gene associated with USH2C). This is the very first animal model for ADGRV1-associated retinal dysfunction, and therefore a crucial step to enable further research on therapy development for ADGRV1-related RP.

Merel Stemerdink (right) has developed the mini gene products and shows them to Ivonne Bressers (Stichting Ushersyndroom). Ivonne (left) looks at the PCR strip in her hand.

Using these fish as an animal model, Merel will also start testing the effectiveness of the ADGRV1-minigene therapy in the coming year.

The official title of the paper is ‘Generation and Characterization of a Zebrafish Model for ADGRV1-Associated Retinal Dysfunction Using CRISPR/Cas9 Genome Editing Technology’ and it has been published in a Special Issue of Cells titled ‘CRISPR-Based Genome Editing in Translational Research’.

 

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Sleep problems Usher patient appears to be a hallmark feature of the disease

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Vision impairment is not the driver of fatigue and sleep problems

It was always thought that fatigue and sleep problems in patients with Usher syndrome are the result of increased efforts to compensate for their dual sensory impairment: limited vision combined with hearing loss. Researchers from Radboudumc show in Ophthalmology Science that this idea is incomplete. Besides severe problems with hearing and vision, sleep problems also seem to be a hallmark feature of the disease.

Patients with Usher syndrome experience major problems with vision and hearing. They are born profound deaf or hearing impaired and around puberty they also start to slowly lose their eyesight. These are the central features of the disease. The large individual differences in disease severity and progression are closely related to the underlying genetic defect and the type of Usher syndrome. “Besides hearing and vision loss, patients occasionally also encounter some other problems, like balance deficits, but these have been recognized as part of the disease,” says researcher Erwin van Wijk. “In addition, sleep problems and excessive fatigue are also regularly reported in the consulting room. The fatigue has always been regarded as a result of the dual sensory impairment that patients have to deal with. It’s generally assumed that the sleep problems often reported by patients are the result of their impaired light perception. After all, individuals with poor light perception gradually lose visual day and night rhythms, having a significant impact on their sleep quality.”

Poor sleep
Researchers at Radboudumc are in close contact with patients, mainly via the Dutch Ushersyndrome Foundation. “At one point we noticed that very many patients complained about sleep problems and fatigue”, says Van Wijk. “That intrigued us. Was perhaps something else going on than we always anticipated? Under supervision of Erik de Vrieze, Juriaan Metz, Rob Collin and myself, PhD student Jessie Hendricks started a survey to further investigate this. Fifty-six Usher syndrome type 2A (USH2A) patients and 120 healthy controls were subjected to a set of five validated questionnaires to assess sleep quality, sleep disorders, fatigue, daytime sleepiness and chronotype.” The results indicated that USH2A patients indeed experienced a strongly reduced sleep quality and that they were more often sleepy and tired during the day as compared to controls. But most strikingly, their sleep problems were not related to the severity of their visual impairment. Van Wijk: “These findings perfectly matched the reports of several parents of young USH2A patients, but that were never given a proper follow-up.”

Hallmark feature of Usher syndrome
At a first glance, it may seem only a gradual difference, but the finding is much more significant. Van Wijk: “Actually, it means that the ubiquitously reported sleep problems by USH2A patients are not primarily due to impaired light perception, but that these problems already exist in patients who still have a near normal eyesight. Sleep problems should therefore probably be considered as an additional hallmark feature of Usher syndrome, and not as a consequence of poor or deteriorating eyesight.” Of course, this conclusion based on questionnaires, needs further substantiation. This can be done, for example, through research in an existing zebrafish model for Usher syndrome. Zebrafish also have a distinct sleep pattern. Is it also disturbed? And is there evidence in the brain that Usher syndrome-associated proteins are somehow involved in regulating sleep? These research questions are currently being followed-up.

Improvement in quality of life
Van Wijk points out another aspect of the research. If sleep problems indeed turn out to be part of the disease, there might be a possibility to treat these problems. “Currently, sleep problems are not included in the daily care for Usher syndrome patients, because it is not yet being recognized as a hallmark feature of the disorder. As a result, the visit to a sleep clinic is often not reimbursed by health insurance companies. This hopefully changes based on the study published in Ophthalmology Science and the follow-up studies that are currently being conducted. Treatment of sleep problems will be a major step forward in improving the quality of life of Usher syndrome patients.”

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Paper in Ophthalmology Science: Evaluation of sleep quality and fatigue in patients with Usher syndrome type 2a – Jessie M. Hendricks, MSc, Juriaan R. Metz, Hedwig M. Velde, Jack Weeda, Franca Hartgers, Suzanne Yzer, Carel B. Hoyng, Ronald J.E. Pennings, Rob W.J. Collin, H. Myrthe Boss, Erik de Vrieze, Erwin van Wijk