HOPE FOR USH1B PATIENTS

CLINICAL TRIAL BY AAVANTGARDE TO COMMENCE

AAVantgarde, an international biotechnology company based in Italy and co-founded by Professor Alberto Auricchio, is dedicated to overcoming the limitations of adeno-associated virus (AAV) vectors in gene therapy. AAVantgarde has developed its own AAV-based large gene delivery platform for retinitis pigmentosa associated with Usher syndrome type 1b (USH1B), utilizing DNA recombination known as dual hybrid AAV.

By the end of March/beginning of April, the first participant will undergo treatment with the dual hybrid AAV designed by AAVantgarde, marking an exciting period ahead.

Usher Syndrome Type 1B (USH1B) is a genetic disorder characterized by congenital deafness, impairment of the vestibular system, and retinitis pigmentosa (RP). It affects approximately 1 in 50.000 people. The condition is caused by mutations in the MYO7A gene, responsible for producing a protein called MYO7A, which plays a crucial role in various cellular processes, including melanosome localization in the retinal pigment epithelium (RPE) and rhodopsin transport in photoreceptor cells.

Motor Protein
MYO7A is an actin-based motor protein responsible for transporting various substances within the cell. These proteins move along thin fibers called microtubules in a manner resembling walking, with two “feet” that alternately bind to the fiber.

Here you can see a short animation of ‘a walking motor protein’:

Motor proteins consist of a head and a tail portion. The head houses the actual motor and consumes energy. The ‘tail side’ contains docking sites where various molecules can be attached. Because MYO7A is a motor protein, the challenge lies in delivering the entire protein healthily to the eye.

Dual Hybrid AAV
Traditional adeno-associated virus (AAV) gene therapy approaches have limitations due to the size of the genes they can deliver. A newer strategy, known as double hybrid AAV gene therapy, aims to address this challenge. In this approach, splice donor and acceptor signals are separately inserted into two AAV vectors, with recombination designed by AAVantgarde. Recombination involves rearranging genetic material to form a single AAV genome that leads to the production of a full-length functional protein.

Watch the presentation on AAVantgarde’s programs here.

Phase 1 and 2 of the Clinical Trial
The first participant is expected to be treated within Q2 2024, with a total of 15 participants to be treated in the study. Safety and effectiveness will be tested at various dosages, with the first results expected to be available by 2025.

In preparation for this clinical trial, a natural history study has been conducted in subjects at Naples, Madrid, and Rotterdam. This study is essential for establishing inclusion criteria and measuring the effectiveness of the treatment.

 

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jCyte stamceltherapie

jCyte Initiates Phase 3 Clinical Trial for RP Cell Therapy

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Biotechnology company jCyte is gearing up to launch a phase 3 clinical trial in the United States for its jCell therapy, following a successful phase 2B trial and with approval from the U.S. Food & Drug Administration (FDA). The company plans to begin enrolling new participants for the next phase of the trial in the second half of 2024.

Cell Therapy
jCells are similar to stem cells that have not yet fully matured into adult photoreceptors. These cells are injected into the vitreous body, the fluid inside the eye, in the middle of the eye. Through an intravitreal injection, it’s possible to achieve an effective dosage for the eye with a low dose, while the medication only minimally enters the rest of the body. jCells are designed to release proteins known as neurotrophic factors to preserve photoreceptors, regardless of the mutated gene causing vision loss. Neurotrophic factors are proteins that can stimulate the regeneration of damaged nerve pathways in experimental models.

New Experimental Treatments
In recent years, an increasing number of genes have been discovered in which hereditary mutations lead to vision impairment. This knowledge has led to new experimental treatments such as RNA therapy, gene therapy, stem cell therapy, and implanted chips connected to the brain. Stem cell therapy is particularly suitable in later stages of the eye disease, when many retinal cells have already died and gene therapy no longer provides relief.

Positive Phase 2B Results
In a phase 2B clinical trial with 85 patients for jCells, 39 percent of patients received the high dose of the treatment and showed an improvement in visual acuity of 10 letters (two lines on an eye chart) or more. In the lower dosage cohort, 16 percent showed an improvement of 10 or more letters. Significant improvements were also observed in treated eyes in contrast sensitivity, visual fields, and mobility-related visual function (as captured in the VFQ-48 questionnaire). These questionnaires provide an important indication alongside visual functions of whether there is also improvement in daily life mobility.

jCyte is a biotechnology company dedicated to preserving and restoring vision in patients with retinitis pigmentosa (RP) and other degenerative retinal conditions. For more information, visit www.jcyte.com.

More information available at our Knowledge Portal:

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. 

Resumption of the clinical trial for RNA therapy for USH2a has been terminated

UPDATE September 27, 2023

In mid-August, we reported that ProQR Therapeutics, which had previously been forced to halt its two promising clinical trials, had found a new partner in Laboratoires Théa (Théa) to continue development. Unfortunately, this collaboration has been terminated prematurely.

One of the conditions for finalizing the agreement was that several key ophthalmic employees of ProQR would enter into employment with Théa. Regrettably, some employees have decided not to proceed with this, making it impossible to meet this closing condition. As a result, Théa has terminated the agreement.

The immediate consequence is that the clinical trial testing RNA therapy for individuals with Usher syndrome 2A will not be resumed at this time.

The full press release can be read here.

 

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ProQR has announced an agreement with Laboratoires Théa to acquire Ultevursen  programs.

In August 2022 ProQR decided to focus exclusively on the development of the Axiomer® RNA editing technology platform. ProQR Therapeutics was forced to stop promising clinical trials unless they found a new strategic partner to continue.
Read about this: http://www.ushersyndroom.nl/klinische-trials-celeste-en-serius-worden-noodgedwongen-stopgezet/

The new partner
Laboratoires Théa (Théa)
has signed an agreement with ProQR to continue the further development of the IRD Sepofurses and Ulteverses programs. Théa is European pharmaceutical company specialized in the research, development, and commercialization of eye care products. This family-owned is based in Clermont-Ferrand, France.

Within Théa, a fully dedicated team specializing in inherited retinal disorders and a new organization are currently being set up to manage these projects. More information on the next steps for these programs will be available in the coming weeks from Théa.

About Ultevursen
Ultevursen (formerly QR-421a) is a first-in-class investigational RNA therapy designed to address the underlying cause of vision loss in Usher syndrome type 2a and non-syndromic retinitis pigmentosa due to mutations in exon 13 of the USH2A gene. QR-421a is designed to restore functional usherin protein by using an exon skipping approach with the aim to stop or reverse vision loss in patients. Ultevursen is intended to be administered through intravitreal injections in the eye and has been granted orphan drug designation in the US and the European Union and received fast-track and rare pediatric disease designations from the FDA.

The transaction is expected to close in the third quarter of 2023.

For further information or enquiries about the announcement today, please email: patientinfo@proqr.com.

The press release from ProQR can be found via this link.

Read more about RNA therapy on our Knowledge Portal:
http://www.ushersyndroom.nl/en/knowledge-portal/research/rna-therapy/

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!

DONATE

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’.

 

READ PAPER

Read also:
How are things going with the ‘minigenes USH2c’ study?

Development of gene therapy for large USH2C gene

Two sides to the story

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When your world turns dark

Joyce de Ruiter was sixteen years old when her parents had to tell her that she’d been diagnosed with Usher syndrome: an inherited dis- order which deteriorates hearing and especially vision during life, often resulting in people becoming deaf and blind. “Finally, the puzzle pieces of hearing loss and night blindness had been named, but at the same time your whole future outlook wavers.” Joyce tells us about the impact this diagnosis had on her life and how it gradually turned into something she now draws strength and courage from.

Joyce and her brother were hearing impaired from birth and started to experience initial symptoms of night blindness around puberty, which was strange, as it didn’t run in the family. A diagnosis was lacking until her then 18-year-old brother’s vision deteriorated even further and an ophthalmologist diagnosed Usher syndrome. Joyce was diagnosed with the same disorder when she was just sixteen years old, radically changing her life and future plans. “I wanted to study, work, get married, and have a family. Would that still be possible? When I discovered the study Visual Marketing the fire started burning again, even though the name of the study didn’t sound very useful when you have a visual handicap. But I always kept making choices that made me happy and I’m convinced this enables me to do the things I want to do – despite all the limitations.”

Rushing life no longer
Joyce has worked in HR, Communications, and Events. “I crossed my own limits for too long, because I felt like I had to cram a whole life into half. After my third burnout at age 30, I was declared incapacitated, also because my vision kept deteriorating. It was another one of those moments: what can I still do, what do I want? My eyes and ears didn’t work so well anymore, but there was nothing wrong with my brain.”

INVESTING IN A POSSIBLE TREATMENT IS CHEAPER THAN LIVING WITH THE LIMITATIONS

She decides to tell her personal story in the newspaper, on radio, and on TV as an ambassador for the Dutch Usher Syndrome Foundation, in order to underline the importance of scientific research and development of treatments. This is how the speaking profession came on her path and she has been working hard on her business for 6 years, with success: “As an independent entrepreneur, I now speak at conferences and events about change and agility. Usher constantly confronts you with problems and changes that you have to learn to deal with. I link my personal story to insights in psychology about how to develop an agile mindset. With that, I try to be of value to other people. I think that is the most meaningful thing you can do in a human life.”

Tunnel vision, literally
Joyce is now 38. Her hearing loss is 70 decibels, but with advanced hearing aids she can still function reasonably well. Her vision is greatly reduced, though. “Last year I still had 18 degrees of vision, which is less than a toilet roll I can see through. My orientation on the street is becoming more and more difficult, I haven’t been able to ride a bicycle for years and I feel unsafe in crowded environments; all because of my reduced vision. This is why scientific research is so important. Investing in a possible treatment is ultimately cheaper than living with the limitations. It would be fantastic if a treatment can be found that stops the deterioration and that children do not have to experience any hearingor sight restrictions at all. Of course, we hope that all patients with Ushers syndrome will recover.

That is why the volunteers of the Usher Syndrome Foundation are putting their heart and soul into continuing to make research into a treatment such as that at the Radboud university medical center possible.”

 

 

Bringing light to the dark

From discovering the gene to, hopefully, developing a therapy which will give patients a positive outlook. Erwin Van Wijk has been involved with Usher syndrome research from start to finish, which is quite unique in this field of work as it shows how rapidly developments are following up on each other. “In the most severe form of Usher, children are born deaf and slowly start to lose their vision before puberty. We developed a genetic patch that may be able to limit the damage to vision, our data and the results of the trials look positive.”

 “The hearing problems in Usher are not easy to treat because the underlying cause already arose during development in utero”, says Erwin. “With my research group, I have focused mainly on the visual problems. These arise during life, so there are more opportunities to do something about them at an early stage. The goal of the research was therefore to slow down or even prevent the deterioration of vision. First of all, we need to know which and how genetic defects lead to problems. Mutations in the USH2A gene are the most common, so we took that gene as the primary starting point for developing a therapy.”

Restoring the function of light-sensitive cells
Usher syndrome arises from a genetic mutation which causes the loss or malfunctioning of the corresponding protein usherin. Slowly but surely, the light-sensitive cells in the eye progressively die as a result, and people become vision impaired or at a later stage even completely blind.

The question is: How can this disease process be stopped? Erwin: “Replacing the mutated gene was technically almost impossible because the USH2A gene is extremely large. Instead, we taped the region of the gene with the mutation with a genetic patch. As a result, a slightly shorter protein is produced, lacking the mutation. When carefully selecting the region to skip, the resulting ‘shortened protein’ could work almost as well as the original protein. In principle, this would then solve the problem. In cells we saw that the genetic patch indeed masked the region of the hereditary error. Next, we had to demonstrate that the shortened protein is also functional in the eye.”

Zebrafish as part of the solution
Erwin stumbled upon an unexpected animal to establish whether the genetic patch could preserve visual function. “Zebrafish happen to have an USH2A gene and protein that’s very similar to those of humans. If a mutation is introduced into this gene, the visual function of the zebrafish is also significantly reduced. They are an excellent model for studying USH2A-related visual dysfunction and for determining the effect of a therapeutic intervention. Indeed, visual function of USH2A mutant zebrafish treated with the genetic patch was highly improved.”

INITIAL RESULTS FROM A CLINICAL STUDY IN PATIENTS ARE HIGHLY PROMISING

 After this, the first careful steps towards the translation of the results into a use in humans could be taken. First tests in Usher patients with a mutation in the specific region of the USH2A gene showed promising outcomes, resulting in the design of a large multicenter follow-up study in which the results of the initial clinical trial will hopefully be corroborated in a large cohort of patients. If results hold up, a request for market introduction can be submitted to the American FDA and the European EMA.”

Source: PULSE Magazine #1 2022

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.”

——————————–

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

Does this mutation cause blindness? It does, doesn’t, does!

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Janine Reurink ends long lasted controversy with major implications for healthcare


Initially there was no doubt a specific mutation in the USH2A gene caused the eye disease retinitis pigmentosa. Spanish research undermined that clarity and left patients in limbo. Until new research by PhD candidate Janine Reurink made it abundantly clear that the cause is indeed to be found in that USH2A gene. A textbook example of science in action.

We know of ten different genes that can cause Usher syndrome if they contain a mutation. Mutations in these genes eventually lead to deafness and blindness in patients with Usher syndrome. Mutations in Usher genes sometimes ‘generate’ other disorders as well. For example, a specific mutation in the Usher2A gene (USH2A) causes the eye disease retinitis pigmentosa (RP) when inherited from both father and mother. This mutation causes one spot in the USH2A protein to change the amino acid cysteine to phenylalanine, another amino acid. All this was genetically and clinically fine-tuned at the end of the last century. If you had such a specific double mutation in the USH2A gene, you didn’t have Usher syndrome but RP and the clinical problems were limited to blindness.

Smoldering controversy
Then suddenly a publication appeared about a Spanish family with RP. It wrote that researchers had found two individuals with exactly those specific USH2A mutations. But without any vision problem, which after all is an essential characteristic of RP! Erwin van Wijk, who has been researching Usher syndrome at the Radboudumc for over more than ten years: “That caused rather a lot of commotion among researchers and patients, because it meant this specific mutation could not be the cause of RP! Everyone who had previously received this diagnosis had apparently been misdiagnosed. So the real cause had to be found somewhere else in the genes.”
The publication causes many clinical genetics centers around the world to stop diagnosing RP on the basis of this USH2A mutation and all these patients should actually be re-screened. This also applies to Nijmegen. In the meantime, doubts continued. Was the screening in this Spanish family complete and reliable enough? – the results were never confirmed in any other study. Requests from different research groups to check the DNA of those families were not granted. Thus, a smoldering controversy about the value of the Spanish research ensued..

No alternatives mutations found
In recent years, Van Wijk and colleagues developed a promising therapy for a number of mutations in Usher genes. This therapy is based on a technique in which a piece of the RNA is ‘taped off’ (exon skipping). This prevents the mutation from being read and creates a protein that once again functions properly. These therapeutic ‘genetic patches’ can also be used for the specific USH2A mutation, but based on the Spanish family research the causal link with the eye disease is being questioned. As long as it’s unclear whether or not this mutation causes RP, no health insurance company will ever reimburse such a therapy. So a conclusive answer is needed. That proof was exactly what Janine Reurink set out to provide as part of her doctoral research.
Reurink: “First of all, we looked at several patients with the USH2A mutation to see if another explanation could be found for the disorder. To do this, we mapped their entire genome and examined it on all sides. The result? We did not find any alternative genetic explanation. Based on our research, the USH2A mutation remains the only possible explanation.”

Crystal clear evidence
In Nijmegen, much Usher research is done in zebrafish. This time it was also used for additional research, looking for as much evidence as possible. Reurink: “With the CRISPR/Cas9 system, a molecular scissors with which pieces of DNA can be very precisely cut away and replaced, we made a zebrafish with exactly the same mutation as in humans. Analysis of retinal cells in the eye of these fish showed that the corresponding proteins are then no longer or hardly produced. Normal production is really very thoroughly disturbed by the mutation. What’s more: as a result, other essential proteins for vision no longer end up in the right places. We also made an ERG, a kind of brain film for the eye. It demonstrated with crystal clarity that vision is really affected in zebrafish with this mutation. In short, extensive genetic bio-molecular and functional research clearly shows that the USH2A mutation is indeed the underlying cause of this form of retinitis pigmentosa. In terms of a detective novel, we now really have tracked down the culprit.”

Impact on healthcare
The research by Reurink and colleagues has been published in NPJ Genomic Medicine. For people with RP with a USH2A mutation, it’s clear now that this is the real causative, pathogenic mutation. Further search for a (non-existent) cause is no longer necessary. Meanwhile, the clinical genetics laboratories at Radboudumc have adjusted their diagnostics accordingly. Something that many more laboratories worldwide are likely to do in the near future. Moreover, patients are now eligible for therapy as soon one is available. A nice example of PhD research with impact on healthcare.

Radboudumc
Promotion Janine Reurink – USH2A-associated disease. Genetics, pathogenesis and treatment

Thursday April 6, 2023 at 12.30 pm

Two groundbreaking projects awarded

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‘Moon Rocket Grant’ awarded to two groundbreaking projects

At this moment, there is no treatment yet for Usher Syndrome, a disorder that globally 400.000 people suffer from. In order to find a treatment that can stop, slow down or even reverse the process of becoming both deaf and blind, more knowledge and research into Usher Syndrome are needed.

Therefore Stichting Ushersyndroom (The Dutch Usher Syndrome Foundation) presents the ‘Moon Rocket Grant’: € 200.000, – for research into Usher Syndrome with a maximum of € 100.000, – for each study.

The Moon Rocket Grant
Stichting Ushersyndroom has launched the Moon Rocket Grant: a large pot of money for pioneering research into (a treatment for) Usher Syndrome. The objective of the Moon Rocket Grant from the Stichting Ushersyndroom is to effectuate a moonshot formulated by us: ‘A treatment for Usher Syndrome in 2025!’ This moonshot includes all types and subtypes of Usher Syndrome.

The study proposals must fit in with one of the four core values of the ‘Moon Rocket Grant’: Treatment, Knowledge, Diagnostics and Impact.
Every study (fundamental, translational or clinical) must lead to a treatment option, more knowledge and understanding, better diagnostics and an increase of the impact for every type of Usher Syndrome.

The Medical Advisory Council extensively tested and assessed all submitted study proposals. After this first assessment there was a second round: an on-line presentation with a short interview, after which the final selection for the award was made.

The Moon Rocket Grant goes to …..

Stichting Ushersyndroom announces with pleasure that two projects are eligible for the Moon-Rocket Grant 2022.

Prof Mariya Moosajee (UCL Institute of Ophthalmology, London, UK), will receive € 100.000, – for the project:

Prof Mariya Moosajee

“Large Gene Augmentation with non-viral episomal vectors for Usher syndrome”

Use of non-viral plasmid vectors for Usher Syndrome
It is well-known that the AAV (adeno-viral virus) vector is used for gene therapy, but this vector has a limit to the size of the gene. Most Usher genes are way too large for being packed into an AAV vector. When applying gene therapy to the retina of patients using the AAV vector, sometimes thinning of the retina (also called atrophy) can develop. Therefore alternative ‘packaging’ vectors are to be found for future gene therapies for Usher Syndrome.

Prof Mariya Moosajee has in cooperation with Dr Richard Harbottle (DKFZ German Cancer Research Centre, Heidelberg) developed a DNA plasmid (USH2A-S/MAR-vector) which can hold the full-length USH2A-DNA.
The DNA plasmid has been tested in a zebrafish model as well as in patient cells taken from a skin biopsy.

Prof Mariya Moosajee will use the ‘Moon-Rocket Grant’ to test the system of DNA plasmid in an already existing rabbit model for USH2A.
If the application of this alternative gene replacement strategy turns out to be successful, this will have a great impact for all inherited retinal diseases. After this study, it may be possible to start a phase 1 clinical trial for patients and it also may offer solutions for other large Usher genes. Gene therapy making use of DNA plasmid may have additional advantages; application (several times) with a limited immune response. Prof Mariya Moosajee hopes this approach will be safer and can avoid some of the complications that are seen in the current viral gene therapy. This project will at least take 2 years and has been budgeted at over € 200.000. Moorfields Eye Charity and Cure Usher will also be contributing to this project. With the contribution of the ‘Moon Rocket Grant’ from the Stichting Ushersyndroom the budget has been covered and the study can start.

The second project to be financed by the Moon Rocket Grant is the study of Monte Westerfield (Neuroscience, university of Oregon) and Erwin van Wijk (Radboud University Medical Center, Nijmegen, the Netherlands) entitled:

Prof. Monte Westerfield and Dr. Jennifer Phillips

“Exon-skipping as a future treatment for USH1F associated retinal disease” 

In this collaborative study Monte Westerfield of the University of Oregon and Erwin van Wijk of the Radboud UMC will develop and evaluate a treatment for Usher syndrome type 1F-related retinal disease based on the exon skipping methodology.

About 20.000 people worldwide lose their eyesight as a consequence of PCDH15 mutations. This condition is named USH1F.
The PCDH15 gene codes for the protocadherin 15 protein (PCDH15 protein) and is essential for normal eyesight and hearing. The PCDH15 protein contains multiple predicted extracellular cadherin (EC) domains. Many USH1F patients have mutations in the region encoding the EC domains number 6 (EC6) and 7 (EC7), resulting in a non-functional or even absent PCDH15 protein.

The ultimate goal of the researchers is to develop a treatment that halts the progression of PCDH15-associated visual dysfunction. For this, they will adopt the principle of “exon skipping” and develop a “genetic patch” that will instruct the light-sensitive cells inside the eye to skip the region of the PCDH15 gene that codes for the EC6 and EC7 domains. In this way a somewhat shorter but hopefully still functional PCDH15 protein is produced, specifically lacking the EC6 and EC7 domains.

A pilot study exploring the therapeutic potential of “exon skipping” for USH1F was conducted some years ago. In this study the researchers targeted another domain in the protein, but this did not result in a restored function of the PCDH15 protein. With the knowledge gained in the past few years the researchers can now better predict whether or not the remaining protein after exon skipping will be functional. Based on these improved prediction tools they now opt for “skipping” the region encoding EC domains 6 and 7.
In previous studies of both Monte Westerfield and Erwin van Wijk it was shown that zebrafish are suitable animal models for this study. To obtain functional proof for the proposed concept of skipping the EC6-EC7 encoding region of PCDH15, the researchers aim to remove this part of the PCDH15 gene from the zebrafish genome and analyze whether these ‘treated’ zebrafish will have a better eyesight than the untreated mutant zebrafish with USH1F mutations.

This research project was budgeted at € 100.000, – for a period of 24 months.

The objective of Stichting Ushersyndroom is to finance scientific research that is to lead to a treatment that will show down, stop of even reverse the deterioration of hearing and eyesight. Apart from this, the foundation also (financially) supports the improvement of the quality of life, the growth of knowledge and information about Usher Syndrome and to enhance the contact between fellow-sufferers.

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