Tag Archive for: treatment

What are the best biomarkers and endpoints for future trials?

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.

A glimpse into the world of Prof. Camiel Boon, ophthalmologist

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“The eye is such a beautiful and marvelously small organ, a highly specialized instrument with which we can perceive our environment in all its beauty and complexity.”

Unfortunately, a lot can also go wrong with the eye. As an ophthalmologist, Prof. Dr. Camiel Boon focuses primarily on diseases of the retina, hereditary eye diseases, and microsurgical retinal operations. Camiel Boon is an ophthalmologist and professor of Ophthalmology at Amsterdam UMC and LUMC.

His strong motivation for conducting innovative scientific research stems from daily interactions with patients confronted with serious eye diseases. Prof. Boon says, “There are still too many eye diseases that we cannot treat effectively. That’s what my team and I are striving to change!”

Many patients diagnosed with Usher syndrome in the western part of our country visit ophthalmologist Camiel Boon and his team for biennial check-ups or treatment for eye problems. A treatment to halt the progression of vision loss in Usher syndrome is not yet available. But there are hopeful developments!
It’s time to ask Prof. Boon about his work, his scientific research, and the future innovative treatments for Usher syndrome.

Ophthalmologist Prof. Camiel Boon and Prof. Dr. Arthur Bergen in the laboratory of AmsterdamUMC ©Mark Horn

Hope for the future: pioneering in gene therapy
Prof. Camiel Boon trained as an ophthalmologist and earned his Ph.D. (cum laude, on a dissertation about hereditary retinal disorders, 2009) at Radboudumc in Nijmegen. As an ophthalmologist and now a professor, he conducts research on genetic retinal diseases, such as retinitis pigmentosa (RP), also in the context of Usher syndrome, at Amsterdam University Medical Centers (and part-time at Leiden University Medical Center). He sees patients at Amsterdam UMC, which has been designated as an expert center by the Dutch Federation of Universities and the European Network for Rare Eye Diseases. The gene therapy that Camiel is working on with the laboratory of Prof. Dr. Arthur Bergen (also at Amsterdam UMC) and Dr. Jan Wijnholds (LUMC) could potentially help prevent blindness in the future.

Viral envelopes or non-viral ‘nanoparticles’
Boon states, “At Amsterdam UMC, we are now treating people with a specific type of retinitis pigmentosa (RP) for the first time, which is X-linked and inherited due to a mutation in the RPGR gene. Together with Radboudumc, we are truly pioneering in this area.” Camiel Boon is the lead researcher of this study and the one performing these microsurgical interventions in Amsterdam. “It is a privilege to finally be able to offer potential treatment to the first patients and to carry out these procedures myself. But it is still truly a pioneering time, and we still need to thoroughly investigate whether these techniques are truly effective and safe.”

Gene therapy for hereditary retinal degeneration due to the RPE65 gene is already available and is reimbursed by insurers for some patients with this gene who qualify. Camiel Boon explains, “However, over the past 2 years, it has been found that a significant percentage of patients experience a very unpleasant and concerning complication, namely accelerated thinning of the retina. That is exactly what you don’t want.” Dr. Boon suggests that this may be because the gene therapy causes the newly administered gene to ‘overexpress,’ which is too much for the retina. But it could also be that the viral envelopes used to inject the gene under the retina cause inflammation and damage.

Boon says, “This indicates that much research still needs to be done on the safety and effectiveness of these brand-new techniques. It may be better not to use viral envelopes for this gene therapy. At Amsterdam UMC, we are researching the use of non-viral ‘nanoparticles,’ a type of lipid vesicles as carriers to deliver the genetic treatment to the retina.”

Initiating Sirius for RNA therapy
As the lead researcher at Amsterdam UMC, ophthalmologist Boon was closely involved in initiating the Sirius study for RNA therapy for Usher syndrome type 2A with exon 13 mutations, by the company ProQR. However, it ended in disappointment. Boon says, “I was truly shocked that this company abruptly pulled the plug on this research due to financial setbacks, before the first patients could be treated. We had informed and selected many patients to participate. It was a bitter experience that companies can do this so arbitrarily, and the study seemed to depend on the company’s stock value. This has made me even more critical of the agreements and logistics of such studies and companies, and I hope that colleagues internationally will also do the same. Of course, I hope that the study, now that RNA therapy has been taken over by a new company, will still start. In that case, we will undoubtedly participate again in Amsterdam UMC, under the right conditions and in close collaboration with Radboudumc. We strive to collaborate as much as possible with Amsterdam UMC and Radboudumc on such innovative and challenging studies.”

Retrospective study on Usher syndrome type 2c due to an abnormal ADGRV1 gene
Recently, we issued a call to participate in the retrospective study for people with Usher syndrome type 2c.
Boon says, “With this study, we aim to map out as large a group of patients with RP in the context of Usher syndrome type 2c due to the ADGRV1 gene mutation from Amsterdam UMC as possible. This is essential to provide a good assessment of the clinical picture, the course, and the prognosis. Additionally, it is important to understand the picture well to select the right candidates for treatment in case of any future treatments. Because you don’t want to take risks if, for example, it’s no longer beneficial because the RP has already progressed too far. We are working to conduct this research with all expertise centers for hereditary retinal diseases from the Dutch RD5000 network. But we also include data from patients from Belgium, Italy, Portugal, and even Australia.
I strongly believe in good collaboration with as many research groups as possible. Within such a network, studies and their impact can be greatly expanded, and thus the results are much more relevant for clinical practice. Therefore, we often collaborate within national and international networks from Amsterdam UMC. For treatment research, we also work closely with Radboudumc. Our lines of research complement each other well. While Radboudumc conducts a lot of research on, for example, RNA therapy, we conduct research on other techniques such as the ‘genetic scissors’ CRISPR/Cas and other new techniques.”

Read here: The very first ADGRV1-zebrafish model has been presented

Confusing Usher syndrome with another syndrome
Usher syndrome is the most common form of deafblindness. Therefore, a DNA diagnosis is crucial because there are other syndromes where hearing and vision are affected. We recently published a study on the PHARC syndrome. Boon says, “In practice, sometimes patients are diagnosed with Usher syndrome when they actually have the PHARC syndrome. We have published an article describing how this distinction from Usher syndrome can best be made. And this is important because it not only affects possible other physical symptoms and their management but also the prognosis and hopefully future treatments.”

Read here the publication.

Cataract surgeries in people with Retinitis Pigmentosa and Usher syndrome
Cataracts at a younger age are common in RP, also in the context of Usher syndrome. Until recently, it was not well known whether this is effective in RP and whether there might be increased risks in the case of cataract surgery in this group. Camiel Boon has wanted to investigate this in a good scientific study for years and recently published a large international study, coordinated from Amsterdam UMC, on the outcomes and risks of cataract surgery in people with RP. Based on the results in 226 patients (295 operated eyes), he found that the procedure often leads to a significant improvement in vision but that the risk of complications is also somewhat higher. Prof. Boon says, “The chances and risks should therefore be clearly discussed in advance with potential candidates for cataract surgery in combination with RP.”

Read here the referentie

Know what you measure: the REPEAT study
A unique study that Prof. Boon proudly talks about is the REPEAT study. Boon says, “It is remarkable that gene therapy is already being tested in people with RP, while we actually still do not know sufficiently how to reliably measure the effect of the treatment. We don’t even know the variation of the same measurement at different times in RP. That is a significant problem because if you don’t know how reliable your measurement is, the interpretation of it is questionable. And then gene therapy studies may fail based on that alone. We have taken a unique initiative: the REPEAT study. PhD candidate Jessica Karuntu is testing how variable and reliable the important measurements for RP are in no less than 50 RP patients (some with Usher syndrome), in various stages of the disease. Think of visual field tests, measurement of visual acuity, but also questionnaires about quality of life. This has never been done before, and the impact of this for research into RP and its treatment (and measurement) is going to be enormous. The pharmaceutical industry has been moderately interested in conducting and supporting this research so far. While the importance of this for their gene therapy studies is significant. I am quite proud that we are achieving this independently of those companies because this has not been done anywhere in the world so far.”

The big picture
Finally, Camiel Boon points out another huge task that he and his group have been working on recently. “We are writing a very large article about all syndromes that can present with RP. A large part of this article is about Usher syndrome. This article is so important because it will help doctors and researchers recognize and distinguish between the different conditions more quickly. And therefore, hopefully start treatment more quickly if available. It will be an article of about 150 pages, more like a book…!”

Exploring new paths with patients
Prof. Boon says, “It is truly a privilege to work as an ophthalmologist in this pioneering time, where we can finally test the first treatments in the laboratory and now even in clinical practice. It is extra motivating to explore these new paths together with patients and patient organizations and to join forces to make as much research as possible into these rare and serious diseases possible.”

During our conversation with Prof. Camiel Boon, Camiel also had a question for us. How can we improve care for patients with Usher syndrome? In Nijmegen, multidisciplinary teams are already working where ophthalmologists and ENT specialists collaborate in the care for people with Usher syndrome. Boon is working to establish this collaboration in Amsterdam UMC together with the ENT department there.

Webinar: Hereditary eye diseases
On April 15, 2024, a free webinar for knowledge sharing was organized by Prof. Camiel Boon (professor of Ophthalmology at Amsterdam UMC), Prof. Dr. Arthur Bergen (professor of Human Genetics of Eye Diseases at Amsterdam UMC), and Dr. Jessica Karuntu (researcher at LUMC). This webinar was organized by the Eye Research Society with the aim of sharing knowledge about hereditary eye diseases such as Retinitis Pigmentosa (RP) and Macular Degeneration and the development of new treatments.

The webinar was conducted in English and was subtitled. You can watch the recording of the webinar here:

 

 

HOPE FOR USH1B PATIENTS

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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.

 

Read also:

Knowledge Portal:

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.

Study into the best approach of USH1B

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Stichting Ushersyndroom (Dutch Usher Syndrome Foundation) announces with pride its financing of a study that will test the best approach for USH1B (gene) therapy by making use of, among others, patient-specific cell models and a large animal model. This may take a (gene) therapy for USH1B to the pre-clinical phase. Dr. Kerstin Nagel-Wolfrum, who works at the Johannes Gutenberg University in Mainz, will lead this project.

Children suffering from Usher Syndrome type 1 (USH1) are born deaf and with a non-functioning organ of balance (the vestibular system). The first signs of loss of eyesight, such as night-blindness and a decreasing field of vision, will present themselves later in the childhood period. USH1 is most often caused by mutations in the MYO7A gene (USH1B). About 14% of all people suffering from Usher Syndrome has type 1B. The MYO7A gene is a very large gene and the Myosin protein is also called a motor protein. Is has a ‘head and a tail’ and therefore it must be replaced or processed as a whole when developing a gene therapy.

New approaches
The large size of the MYO7A gene makes classical gene therapy using an AAV vector impossible. However, new approaches, including double and triple AAV vectors, mini-genes, prime editing, translational read-through and exon skipping, are promising new alternative therapeutic strategies. Please go to the Knowledge portal for further reading.

From skin biopsy to mini-retina
With the help of a skin biopsy from a USH1B patient (fibroblast), Dr Nagel-Wolfrum can further develop these molecular cells into a retinal pigment ephithelium (RPE) and a retinal organoid (RO). The retinal pigment epithelium is found between the retina and the choroid and it clears away the waste products of the rods and cones in the retina. The retinal organoids are also called the mini-retinas.

The possibility to model retinal disorders by means of fibroblasts into mini-retinas created unprecedented opportunities in the research area.

Dr. Kerstin-Nagel-Wolfrum

Gain insights and test therapies
By making use of the ‘mini-retinas’, Dr Kerstin Nagel-Wolfrum will gain more insight into the mechanism that damages the retina and causes loss of eyesight. Apart from this, she wants to subject these retinal organoids (mini-retinas) to various therapies in order to test them for their effectiveness and functionality. Dr Nagel-Wolfrum will also test the mini-genes by conducting an AAV vector-based gene therapy.

On to the pre-clinical phase
A large animal model, a USH1B pig, has already been developed and is ready for testing possible therapies. Dr Nagel-Wolfrum will apply the therapy that the pre-study with the retinal organoids (mini-retinas) has shown to be the most effective one when doing research on the pig model. This study is called the pre-clinical phase. If this pre-clinical phase leads to positive results, this can be promising for a possible therapy for patients.

In this project Dr Kerstin Nagel-Wolfrum closely cooperates with:

  • U. Wolfrum (Institute for Molecular Physiology, JGU Mainz, Germany): USH1B pig model
  • S. Gerber (University Medical Centre Mainz, Institute of Human Genetics, Germany): Bioinformatics
  • M. Cheetham (UCL, London, United Kingdom): iPSC-RPE and iPSC-RO generation
  • V. Kalatzis (Institute for Neurosciences of Montpellier, France): iPSC-RPE and iPSC-RO generation
  • J. Gopalakrishnan (Heinrich-Heine University Düsseldorf, Germany): brain organoids

This project will have a duration of 1 year and has been budgeted at
€ 100.000, -. Stichting Ushersyndroom hopes that this study will contribute to the development of one or more effective treatments for people suffering from Usher Syndrome type 1B.

View the PowerPoint presentation about this research by Dr. Kerstin Nagel-Wolfrum

New type of Usher Syndrome discovered: USH IV   

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The team of the Hearing & Genes Expert Centre of Radboudumc lately made a discovery: Usher Syndrome includes four different clinical types. The researchers, with Hedwig Velde as principal author, recently published their study and findings in the leading Human Genetics. With the identification of minor faults (mutations) in the ARSG gene and the description of a new clinical picture, they confirm the discovery of a fourth type of Usher Syndrome. 

This really is an important discovery, which gives more clarity about a number of patients with atypical Usher complaints without a genetic diagnosis. In the meantime, following the identification of ARSG as Usher gene, globally fifteen people have still been diagnosed, now that they all appear to have mutations in the ARSG gene. As it has been demonstrated that these patients have a common pattern of symptoms, this is no longer an atypical picture, but it makes up a new clinical type.       

A patient with an atypical clinical picture
Very rarely a patients visits the outpatients’ clinic showing symptoms that correspond with the clinical picture of Usher Syndrome (loss of hearing combined with retinitis pigmentosa), but which picture deviates from the familiar Usher types. This is called an atypical clinical picture. In some cases no generic cause is found in the Usher genes that are known so far. Consequentially, these patients are unfortunately sent home again without having been diagnosed (and without any clarity). 

Hedwig velde

 Hedwig Velde is researcher and doctoral candidate at the ENT section Hearing & Genes of the Radboudumc. She is studying patients who suffer from loss of hearing but who have not been genetically diagnosed. With her research team she confirmed a new Usher Syndrome type, which is caused by minor faults in the ARSG gene.  

A publication from the year 2018 written by a group of scientists in Israel described the discovery of the ARSG gene with Arylsulfatase G as a protein that might be involved with Usher Syndrome. The researchers from Israel described five persons from three families who all had the same minor fault in the ARSG gene. Such a publication may give other researchers ideas for their studies.  

Studying the DNA of several people within one family sharing the same symptoms is a big help for scientists. Hedwig Velde: “There is a big chance that all patients within the family share the same genetic cause. When outside the family that has been studied another patient is found with the same atypical clinical picture and a minor fault in the same gene, this may confirm the relation between the gene and the clinical picture. Of course, the chance of coming across this patient is really small. Usher Syndrome is very rare.”  

Until the national Expert Centre in the Radboud UMC saw a patient with this atypical clinical picture of Usher Syndrome and Hedwig Velde and other researchers in the Radboud UMC continued the study that was started by the team in Israel in 2018.    

New type now confirmed
With the publication of Hedwig Velde c.s. the researchers confirmed this new type. The researchers found minor faults in the same gene (the ARSG gene), which creates the codes for the Arylsulfatase G protein. This protein is involved in the degradation of another protein and the idea is that malfunctioning of Arylsulfatase G will lead to an adverse accumulation of the protein that normally should be destroyed. With this study the research team also demonstrated that the minor faults in the ARSG gene that have been found really result in a non-functioning protein.  

The clinical picture of the type does not fit in with the already known Usher types I, II and III. Apart from a later starting age of both the loss of hearing and the retinitis pigmentosa, the ophthalmic defects are more centrally located. This means that the vision problems with these patients rather occur in the central part of the field of vision as opposed to the other Usher types, which usually show problems in the outer part of the field of vision (the periphery). As the clinical picture is consistent with all USH IV patients, researchers of the Radboud UMC are of the opinion that this is not atypical Usher, but a new clinical type: Usher Syndrome type 4.   

Hedwig: “By publishing these findings, we as researchers hope to start up a discussion in the scientific world. Various studies may together lead to the confirmation that the findings are correct or, in some cases, rebut these findings. In case of USH IV it is the accumulation of evidence in several publications that enables us to confirm that this clinical type really is a new Usher type.”    

By now, globally several patients have been diagnosed for this Usher Syndrome type and for minor faults in the same ARSG gene. Previously, these patients used to be categorised in the group ‘diagnosis unknown with atypical Usher symptoms’.    

The course of Usher Syndrome type IV
Both the loss of hearing and the complaints related to retinitis pigmentosa start at a later age with people suffering from USH IV. Patients started to develop complaints concerning hardness of hearing between the ages of 20 and 40 and the retinitis pigmentosa between the ages of 40 and 60. Based on the audiograms of USH IV patients, the research team has been able to calculate that the loss of hearing starts about the age of 17.  

The course and the progressiveness are not necessarily milder than with the other Usher types. “We still have little insight into the course of USH IV, because only fifteen patients have been described and we therefore have to base our findings on this small group.” 

Genetic tests or not?
With this discovery the researchers of the Radboudumc have managed to fit in yet another piece of the ‘Usher puzzle’.” Thanks to this, a part of the patients with an unknown diagnosis will eventually be given clarity and this is really important to this group of patients.  

Unfortunately, there still are people for whom the Usher-related symptoms cannot be confirmed by a diagnosis. This makes genetic tests so important!    

The physicians indicate that, of course, the choice is still to be made by the patient. One patient attaches a lot of value to a confirmation by means of genetic tests, while another does not.  
Hedwig: “There are various reasons to have genetic tests done or not. An advantage of a genetic diagnosis is that with this the development of a disorder can better be predicted and that this may help the patient to adapt to the situation. Imagine that you are hard of hearing at a young age and that there is a small chance of becoming visually impaired. However, if you know that you will be visually impaired, then you had better concentrate on the kind of care that will help you both early and later in life. For instance, in this case learning sign language will not be a long-term solution for your loss of hearing, but good hearing aids may make a substantial contribution.”  

Genetic tests will also help the scientific world to get further. For example, as scientific research allows for comparing the DNA of various patients, new genetic causes can be discovered. Besides, this offers a possibility for meticulously mapping out the relation between a minor fault in a gene and the corresponding complaints.
Hedwig: “Because of this, future patients can be better informed about their diagnoses. On the other hand, it is also important for any future genetic treatments to know the exact underlying deviations in the DNA.”    

Usher Syndrome: 4 types and 11 genes involved
In 2022, type IV and the ARSG gene will be added to the list of Usher types and genes involved in the development of Usher Syndrome. So at this moment, Usher Syndrome distinguishes 4 types with 11 different genes involved. [Ed.: This evidence is not entirely conclusive for USH1J (CIB2) yet]
For all these genes scientific evidence has been provided that minor faults (mutations) in these genes will result in Usher Syndrome.    

The Knowledge Portal of the Usher Syndrome Foundation provides a complete overview of the genes with the names of the ‘protein involved’.     

Here you can read the publication of the article by Hedwig Velde c.s. in Human Genetics.  

 

Moon-Rocket Grant

Usher Syndrome Foundation Grant Call:
The Moon-Rocket Grant

The use of the word ‘Ushers’ for people with Usher syndrome is meant with a wink and refers to the meaning of the English word ‘Ushers’. People with Usher syndrome are the messengers of an important story or message.

The ‘Ushers’ tell what they need, what kind of help they need, what they find important and how they experience their life with Usher syndrome.

Currently, there is no treatment available for 400.000 ‘Ushers’ in the world. What is needed for the ‘Ushers’ is more knowledge and research into the Usher Syndrome. That is why Stichting Ushersyndroom [Dutch Usher Syndrome Foundation] awards the Moon-Rocked Grant: € 100,000 for research into Usher Syndrome.

The Moon-Rocket Grant
The goal of the Moon-Rocket Grant of the Usher Syndrome Foundation is to realize our formulated moonshot: “a cure for Usher in 2025!”.

The Moon-Rocket Grant is intended to financially support research into Usher Syndrome (any form or subtype).
All research proposals submitted must fit into one of the four core values ​​the Usher Syndrome Foundation has defined by:

  • Treatment
  • Understanding
  • Diagnostics
  • Impact

The Moon-Rocket Grant will award a maximum of €100,000 per research. If there are several eligible projects, more projects can be funded. A maximum of € 200,000 is available for financing.

For more information click on the buttons below.

MOON-ROCKET GRANT FLYER GRANT CALL APPLICATION FORM

Do you have any questions or would you like to receive the application form in Word version? Mail to research@ushersyndroom.nl

Minigenes USH2A: General status

By Erwin van Wijk, lead researcher Radboudumc

Errors in the code of the USH2A gene explain the development of Usher syndrome in about 50% of all patients.
In addition to Usher syndrome, these errors can also lead to non-syndromic Retinitis Pigmentosa; loss of sight but without the hearing problems.
The USH2A gene contains the code for the protein usherin. After translation, the mistakes in the genetic code of USH2A also end up in the usherin protein, with the result that this protein loses its function and people lose their sight (and hearing). Giving patients a new copy of the USH2A gene that does not contain these errors could be an obvious solution. This is the principle of gene therapy.

However, for USH2A this is not as easy as it sounds.

New copies of genes are delivered with inactivated viruses, into which the genes are packaged. These viruses can be seen as small trucks. However, the loading platforms of the viruses are small. So small, in fact, that the USH2A gene simply doesn’t fit. Developing a classical gene therapy for USH2A is therefore extremely difficult from a technical point of view.

As an alternative, we have the “genetic patch” methodology, also known as exon skipping. The first patch tested is performed on patients tested in clinical trials.

Good news, but only for a limited target audience. QR-421a works for people with errors in a specific part of the USH2A gene: exon 13. This method can be extended to other USH2A genes and even to other Usher genes, but always remains only applicable for a limited number of patients.

Is there no alternative?

A few years ago we started with a new idea: can we not artificially shrink the USH2A gene, so that it fits in the loading platform of a virus and can therefore be delivered to the place where it is needed and can be used by all people with USH2A-related retinitis pigmentosa?

The main advantage is that, if effective, this method may be of value to all patients with USH2A-related retinal problems. The project “Minigenes USH2A” was born and made possible in part by a contribution from the Dutch Usher Syndrome Foundation (Stichting Ushersyndroom).

Four shortened USH2A genes were made and inserted into the retina of the USH2A zebrafish model. The shortened usherin proteins made from these minigenes in the zebrafish eye ended up in the right place in the light-sensitive cells of the retina, rods and cones. Functional tests by measuring electroretinograms (= ERG) indicate that these mini-usherin proteins are indeed (partially) functional. We have patented these results. How well they work remains to be investigated, but it is a promising starting point for further developing this method.

In the meantime, we are also looking into cultured cells to see where these mini-proteins go and whether they do not accumulate in a place where we would not want this. Fish, of course, are not people. It is therefore important to translate these results into models that are closer to humans.

We are currently trying to establish a partnership with a company that can help us take these important next steps.

Read also:

Swim at night and take a nap during the day

Zebrafishes suffering from USH2A have a disturbed sleep rhythm

Are patients suffering from Usher Syndrome so tired because of the huge efforts made in connection with their poor hearing and eyesight or is something else going on? Researchers in the Radboudumc try to find an answers to this question. There are indications that perhaps there is more going on, a genetic cause. The people of the Radboudumc have been busy trying to unravel Usher Syndrome for decades already. This summer, the research into ‘The recognition of sleeping problems with patients with the USH2A gene’ will start. Stichting Ushersyndroom (Dutch Usher Syndrome Foundation) will finance a large part of this study.

Researchers have used the zebrafish model since several years. In the laboratory of the Radboudumc both healthy zebrafishes and fishes suffering from Usher Syndrome are swimming about. Researchers noticed that the sleeping pattern shown by the fishes with a mutated USH2A gene differs from that of their healthy congeners. Actually, they sleep more often during the day and less often at night. According to Erwin, project leader of the zebrafish lab and engaged in research into Usher Syndrome for years already, the sleeping fishes are quite remarkable. It is day, there is sufficient light in the aquarium and the eyesight of the fishes is still good enough to be able to properly see light and dark. Still, they regularly fall asleep during the day.

Sleep-wake rhythm
The sleep-wake rhythm is strongly controlled by light. The retina sends signals to the pineal gland in the brains to make the sleeping hormone melatonin when the light intensity decreases. It is known that a decreasing light perception can disturb this system. However, RP patients regularly mention sleeping problems and fatigue in an early stage already, independent of the seriousness of their visual impairment.

Fatigue
Usher Syndrome is also called ‘fragmentary observation’: both hearing and seeing are done in small fragments that subsequently have to be made into a whole. This is hard work for the brain. Therefore it is not surprising that many people suffering from Usher Syndrome are tired quickly and have a higher chance of getting overstimulated and loosing energy. The energy-absorbing process of continuously compensating the one sense with the other leads to fatigue.

Sleep enables the body to recover, such as replenish energy sources, adjust muscles and other cells and reduce stress. While sleeping, we also process all we have seen, heard and done during the day. The brains are stimulated all day and have to process all this information.

Quality of sleep
The quality of sleep depends on the deep sleep, the so-called REM sleep. This makes the body recover. A good night’s rest means quickly falling asleep and sleeping all night through. In case of insufficient REM sleep, you do not feel refreshed well when you have to get up. Non-optimal REM sleep over a longer period will lead to chronic fatigue with a risk of other physical complaints.

Not tired at all
At the end of the day, when it begins to grow dark and the lights are switched off in the zebrafish lab, the last round is made in the lab. Many fishes have become less active already and are hanging around in the water without moving. They also do not react when Erwin van Wijk is walking along the aquariums.

When visiting the zebrafish lab in the evenings, he tries to make as little noise as possible and the lights are dimmed. When he switches off the lights to close the lab and leaves the lab, some groups of zebrafishes stay awake and active. The zebrafishes with mutations in the USH2A gene are not going to sleep, they are not yet tired at all.

Expression in the pineal gland
The most frequently mutated RP genes (USH2A and EYS) are both highly expressed in the pineal gland of various animal models. Researchers show that the proteins of these genes involved are not only present in large quantities in the eyes and ears, but in the pineal gland as well. This may mean that the proteins concerned also play an important role in the pineal gland and in the regulation of the day and night rhythm.

Zebrafishes with mutations in the USH2A gene show a deviating sleep-wake rhythm, while these test animals hardly show any retina degeneration.
Based on these findings researchers suspect that the sleeping problems of these groups of patients are the cause of the disorder and not just the consequence of a reduced visual function.

Comprehend
A treatment for sleep-related complaints with people who have mutations in the USH2A and EYS genes, may substantially improve their quality of life. In this project clinical and fundamental research are combined in order to comprehend these problems. The common results of these two research lines may give some tools to improve the care of patients suffering from RP and Usher Syndrome together with ophthalmologists and sleep experts.

Various research institutes are involved in this project: the Radboudumc under the leadership of Erwin van Wijk, Slaap/Waakcentrum SEIN, Hospital Gelderse Vallei, Radboud University and the Donders Institute.

This four-year study will start this summer and the costs are estimated to be € 285.000,=.  Stichting Ushersyndroom (Dutch Usher Syndrome Foundation) makes a contribution of € 125.000 with co-financing by the Dutch Dr. Vaillantfonds. Other funds that have contributed are: LSBS, ANVVB, Support Fund UitZicht (Beheer ’t Schild), the Gelderse Blindenstichting, FNWI/IWWR.

Onderzoekers en patiënten met Ushersyndroom overhandigen een cheuq ter warde van €285.000 voor het slaaponderzoek. Ze staan voor de kast met aquaria met zebravissen.

In the zebrafish lab Radboudumc. From left to right: Erik de Vrieze, Thijs Bouwman, Niels Bouwman, Ivonne Bressers. Jessie Hendricks, Devran Braam, Erwin van Wijk and Juriaan Metz.

Stichting Ushersyndroom [Dutch Usher Syndrome Foundation] Awards Grant to Usher III Initiative to Support Patient Database

A global Usher III patient (USH3) database for future clinical trials

This year, the North-American foundation Usher III Initiative has taken preliminary steps towards collecting the information necessary to establish the first comprehensive global USH3 patient database. This resource will be critical to the design of future clinical trials and will significantly advance knowledge of the disease and its impact on patients. Dr Ronald Pennings from the Radboudumc is one of several physicians and experts around the world collaborating with the Initiative in this effort. 

Cindy Elden and her father Richard, co-founders of the Usher III Initiative

Usher III Initiative
Usher III Initiative is a US based non-profit organization dedicated to developing a treatment for Usher Syndrome type 3 a rare genetic disorder characterized by progressive loss of both hearing and vision. It is estimated that over 400.000 people around the world suffer from Usher Syndrome, of which type 1 and 2 are the most common types. Only 2 percent of the patient population suffers from USH3, which is most prevalent among Finnish and Ashkenazi Jewish populations. 

Preliminary clinical trial design
The Initiative has developed BF844, a new therapeutic candidate for the treatment of USH3.
The Initiative is completing pre-clinical toxicity studies to demonstrate that BF844 can be safely administered in humans in compliance with US Food and Drug Administration (FDA) regulations. They expect that clinical trials will commence in 2022. These studies are supported by a $1M grant the Initiative recently received from the Foundation Fighting Blindness.

Consortium
Together with the Usher III Initiative and a global consortium of physicians, Dr Ronald Pennings will participate in the establishment of the USH III Patient Database. “Aggregating comprehensive genetic and  clinical data on USH3 patients is necessary to determine inclusion and eligibility criteria as well as the most effective design for clinical trials.”, commented Cindy Elden, President and Co-Founder of the Initiative and an USH3 patient.

Collaboration
Stichting Ushersyndroom [Dutch Usher Syndrome Foundation] has committed to making a $ 10,000 contribution to support this effort. This grant aligns with the mission of the Stichting Ushersyndroom, to find treatments for all types of Usher syndrome.  

“Usher Syndrome is a serious disorder, which has a deep impact on the lives of patients and their social environments.  We want to stop this disorder from the bottom of our hearts”, commented Ivonne Bressers, chairwoman and co-founder of the Stichting Ushersyndroom and USH2 patient. “We are happy to be able to participate in an international study for USH3-patients.”

Cindy Elden: “On behalf of the Usher III initiative, but also personally, I find it very inspiring to meet other people with Usher syndrome who would like to be active in the search for a treatment for all of us!”

The consortium will not be collecting any information that identifies specific patients, so the database cannot be used to recruit participants for clinical trials. Patients interested in participating in future clinical trials are encouraged to register with My Retina Tracker and the Ush Trust. Once trial investigators and sites have been identified, treating physicians may also recommend individual patients to the appropriate officials. Pursuant to global patient privacy protections, the Usher III Initiative cannot receive confidential patient data. If patients, family or friends want to connect with the Usher III Initiative for more information, they are invited to email info@usheriii.org or connect on Facebook.
Dutch patients can contact Stichting Ushersyndroom for more information on Usher syndrome and contact with fellow sufferers.
For medical advice on Usher syndrome, information on (preclinical) developments of therapeutic approaches to treat Usher syndrome or additional (genetic) diagnostics, they can reach out to the expertise center of the Radboudumc via ushersyndroom@radboudumc.nl. 

Related links:
www.usheriii.org
www.radboudumc.nl/expertisecentrum/ushersyndroom
www.ushersyndrome.nl
www.ushersyndrome.nl/knowledgeportal