Tag Archive for: research

Are rabbit eyes and cell models suitable?

Assessment of safety and toxicity of genetic patches

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

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

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

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

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

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

Stichting Ushersyndroom launches the ‘Usher Crusher Grant’

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

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

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

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

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

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

International scientists can submit their proposals now

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

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

 

 

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

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‘Moon Rocket Grant’ uit 2023

Aavantgarde logo

First patient treated in clinical study for gene therapy for Usher syndrome type 1B

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On September 16, 2024, AAVantgarde Bio, a biotechnology company from Italy, announced that the first patient has been treated in a clinical study investigating the safety and efficacy of a new gene therapy for patients with retinitis pigmentosa as a result of Usher Syndrome type 1B (USH1B). 

This clinical study, named LUCE-1, has been set up to examine how safe and effective the new gene therapy AAVB-081 is in individuals with Usher syndrome type 1B. In this condition, patients lose their hearing and sight due to a hereditary mutation in the MYO7A gene. The study is in phase 1/2, meaning it is still in an early stage and primarily focused on testing safety.

 How does the gene therapy work?
The new treatment, AAVB-081, utilizes a specialized technique designed to deliver larger genes like MYO7A into the eye. This is done by packaging two halves of the gene into viral carriers, known as AAV vectors, which together complete the MYO7A gene inside the cell. The idea is that this therapy restores the production of the Myo7A protein, which may help stabilize the patient’s vision.

Previously successful results achieved
The technology behind this gene therapy was developed by Professor Alberto Auricchio at the TIGEM institute in Naples. As the first-in-human study with this therapy has only just commenced, no data on the results are as yet available. However, scientists have previously studied the therapy in small and large animal models and demonstrated up to 40% improvement in the gene function. As animal eyes have many differences compared to human eyes, comment on the success of the therapy in humans will only be available after the clinical trials. .

First patient
The first patient in the LUCE-1 study has been treated at the University Hospital of Campania in Naples, under the guidance of Professor Francesca Simonelli, an expert in ophthalmology and gene therapy. In the coming period, more patients will be treated, and the results will be evaluated.

This study offers hope for individuals with Usher syndrome type 1B, a group of patients for whom there are currently no treatments available to preserve their vision. The success of this therapy would be a significant step forward in the fight against this progressive disease.

More information

AAVantgarde Bio continues to work closely with researchers to further develop this promising therapy and hopes to assist more patients soon. Stichting Ushersyndroom is regularly updated by AAVantgarde, and we share this valuable information with our supporters through our website, newsletter, and social media. The full results of the study will be announced once the study is completed and the data analysed, although this will take several years.

For further information about the LUCE-1 study:
https://clinicaltrials.gov/study/NCT06591793?term=aavantgarde&rank=2

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Hope for Usher patients  

 Long-term outcomes of cochlear implantation in Usher syndrome

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New insights from research

Recent research by Mirthe Fehrmann and colleagues at Radboudumc has provided significant new insights into the long-term outcomes of cochlear implantation (CI) in people with Usher syndrome. The study focused on the effectiveness of cochlear implants in different subtypes of the syndrome (USH1, USH2, and USH3), with a special emphasis on long-term outcomes. The findings have been published in the renowned journal Ear & Hearing.

Usher syndrome is a hereditary disorder characterized by a combination of hearing loss or deafness and progressive vision loss due to retinitis pigmentosa (RP). As a result, people with Usher syndrome rely heavily on their hearing for communication and orientation. Cochlear implants (CI) offer a solution for many, but until now, there has been a lack of extensive studies examining the long-term effectiveness of CI in the various subtypes of Usher syndrome.

Study design
The study examined 36 patients with Usher syndrome who received cochlear implants at Radboudumc (53 ears). The patients were divided into four groups: early-implanted USH1, late-implanted USH1, USH2, and USH3. Speech recognition with CI was measured at various time points after implantation: at 1 year, 2 years, and 5 years or more.

The study aimed to evaluate the performance of cochlear implants in people with different subtypes of Usher syndrome in both the short and long term. The focus was on improvements in speech recognition and overall satisfaction with the implantation.

Key findings

  • USH1 (early implantation, younger than 7 years): Early-implanted patients (median implantation age = 13 months) achieved excellent results, with 100% speech recognition after an average of 12 years. Early, simultaneous bilateral implantation led to much better speech recognition than sequential implantation.
  • USH1 (late implantation, older than 7 years): In late-implanted patients, CI was primarily used for sound detection, with an average speech recognition of only 12%. However, these patients were satisfied with their ability to perceive environmental sounds and used the implant more as a signaling device.
  • USH2: Patients with USH2 who received a CI generally achieved good results, with an average speech recognition of 85% after 8 years of follow-up. Early implantation and better speech perception with hearing aids before implantation led to better results. Delaying the decision to receive a CI if eligible is therefore not advisable.
  • USH3: Results in USH3 patients were more variable, with an average speech recognition of 71%. The small number of patients in this group and the fact that some had been severely hearing impaired for a long time before receiving a CI explain the variation.

* For more information on the different subtypes of Usher syndrome, read here.

This study demonstrates that cochlear implants are effective in improving hearing in people with Usher syndrome, both in the short and long term. For patients with USH1, early bilateral implantation is strongly recommended for the best results. Late implantation, while providing a signaling function, is not sufficient for effective oral communication.

In USH2 and USH3, early implantation is crucial to slow the progression of hearing loss, especially given the severe visual impairments. For USH2 patients with sufficient speech recognition before implantation, the results are particularly favorable. In USH3, the variability of symptoms creates more uncertainty regarding outcomes, requiring careful counseling. However, it is expected that when implanted early enough, USH3 patients can achieve results comparable to those in USH2.

Practical implications

  • Early implantation is crucial to achieve optimal results.
  • Simultaneous bilateral implantation, ideally between 6 and 12 months of age, is recommended for USH1 patients to maximize speech recognition and hearing performance.
  • USH2 and USH3, good results are achievable, especially when patients have received sufficient auditory stimulation and used hearing aids before implantation. When speech recognition with hearing aids falls below 70% (at 65 dB speech), CI can already be considered.
  • Counseling and education should emphasize the importance of early detection and timely implantation, as well as encouraging the use of hearing aids to keep auditory pathways active.

These findings support a proactive approach to the treatment of Usher syndrome:

  • Screening and early diagnosis are essential to intervene in a timely manner and improve the quality of life for patients.
  • Multidisciplinary collaboration between audiologists, ophthalmologists, geneticists, and rehabilitation specialists can contribute to an integrated care approach.
  • Individual treatment plans should be developed, considering the specific subtype, symptom progression, and the patient’s personal needs.

With timely and appropriate treatment, patients can experience significant improvements in their hearing, leading to better communication and an enhanced quality of life despite the challenges of the syndrome.

Source: Fehrmann, M.L.A., Lanting, C.P., Haer-Wigman, L., et al. (2024). Long-term outcomes of cochlear implantation in Usher syndrome. Journal Name, Volume (Issue), Pages. DOI: 10.1097/AUD.00000000000001544

An important next step in USH2c research

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

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

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

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

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

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

Read also:

 

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What are the best biomarkers and endpoints for future trials?

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

 

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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: https://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:
https://www.ushersyndroom.nl/en/knowledge-portal/research/rna-therapy/

Who cleans up ‘the mess’ from the cones?

LEES ARTIKEL IN NEDERLANDS

New research on the cause of blindness due to Usher syndrome

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

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

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

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

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

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

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

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

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

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

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