An important next step in USH2c research

 

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:

 

‘Our Carin’ in Times Square

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On May 16th, it was Global Accessibility Awareness Day. Microsoft paid extensive attention to this by organizing an event at the Rijksmuseum in Amsterdam where they launched and explained their accessibility technology. At the same time, a major campaign also started in New York’s Times Square where Carin de Bruin was featured on the large billboards for two weeks!

With the help of CoPilot, Microsoft’s AI tool, descriptive information about the various artworks is created so that people with visual impairments can also get an idea of the artwork.

As an expert by experience with a visual impairment, ‘our’ Carin was invited to test the AI-generated descriptions and provide feedback to improve them. Additionally, she appeared in the Dutch and American promo videos (filmed at the Rijksmuseum), and the so-called ‘shorts’ (short videos) in which she also appears are shown life-size on the Microsoft building in New York Times Square!

Every artistic interpretation deserves to be part of the conversation.
Quote; “Art is more than something to be admired by the eye. It’s a powerful statement. A personal resistance. An emotional connection to the world around us. But for some, like Carin de Bruin who has Usher syndrome, a rare inherited disease that causes both hearing loss and blindness, art is often not accessible. She regularly relies on friends and guided tours to access art museums. “Sometimes it feels like I’m excluded,” says Carin. “My low vision impacts a lot of aspects of life like education, employment, and social activities, but also my experience of cultural things.”

Read more about the collaboration between Microsoft and the Rijksmuseum here. You can also hear an example of an audio description: ‘Self-portrait’ by Vincent van Gogh.

 

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:

 

 

The Lifelong Vision Project

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CONSORTIUM RECEIVES 22 MILLION EUROS

In an ambitious attempt to combat blindness, a consortium of leading researchers led by Prof. Caroline Klaver from Radboudumc has launched the mission “Lifelong Vision.” With an award of 22 million euros from the NWO Gravity program of the Ministry of Education, Culture and Science (VWS), this project aims to develop revolutionary treatments for blindness.

Blindness ranks among the top 15 most disabling conditions and affects both young and old. The project focuses on Inherited Retinal Disease (IRD), including Retinitis Pigmentosa and Usher Syndrome. In the Lifelong Vision project, scientists in the fields of molecular biology, regenerative medicine, epidemiology, and artificial intelligence will join forces to find patient-centered solutions for blindness.

Knowledge, innovation, and answers to questions.
So, what exactly will the Lifelong Vision project bring? It won’t deliver direct mutation- or gene-specific treatments for individual retinal diseases like Usher Syndrome, but it will provide answers to overarching questions:

Can we revive lost vision and photoreceptors (regeneration)? Can we use AI and 3D bio-printing to print and implant new cells? Can we efficiently and effectively correct hereditary errors? Can we deliver genetic therapies to the retina more efficiently? These are long-term projects with a high risk of disappointing outcomes.

For the development of personalized therapies (for example, for USH2A, 2C, and 1F), subsidies from Stichting Ushersyndroom, Uitzicht, ZonMW, Foundation Fighting Blindness, and other funds are still essential. The Lifelong Vision project will serve as an umbrella under which these specific projects will be linked. Knowledge from Lifelong Vision will be used to make treatments for Usher Syndrome more effective, specific, and safer. The involved researchers in the consortium could never have gained this very specific knowledge and insights without this special subsidy of 22 million.

Gene-editing: precision in gene repair
A crucial part of the Lifelong Vision project is the development of genetic therapies. Researchers will focus on accurately repairing errors in genes, rather than replacing entire genes. This precision approach could be a promising step forward in treating vision problems caused by genetic abnormalities.

Artificial Intelligence: customized treatments
To ensure that the right patients receive the right treatment at the right time, artificial intelligence (AI) will also be developed. These AI systems will help identify suitable candidates for the therapies developed in this project.

Protection of eye cells and cell therapy: inspired by zebrafish
Additionally, researchers are looking into how to protect cells in the eye. Extensive research has already been done on why a cell in the eye with a genetic defect dies. This provides clues on how to keep cells alive, for example, with a special cocktail of proteins that help the cells. Unlike humans, zebrafish have the ability to regenerate dead cells in their retina. This process is also known as regeneration. By carefully studying and better understanding this process in zebrafish, scientists hope to gain new insights that will help to activate the regeneration process in humans (regenerative therapy). Erwin van Wijk, a researcher at Radboudumc, is involved in this research, with zebrafish models for Usher Syndrome being central.

Advanced bio-printing: a new retina
Another innovative development within Lifelong Vision is the use of advanced bio-printing technology to produce a new retina. By layering cells on top of each other, researchers aim to create a retina that is compatible with the human eye and can integrate with the choroid.

“With investments like these, we ensure that we remain at the forefront of the scientific world in the Netherlands. This brings important new insights and innovations that we all benefit from. I am proud that we have such scientific talent in our own country. That is not self-evident. Really something to cherish.”
Robbert Dijkgraaf (Minister of Education, Culture and Science)

The Lifelong Vision Consortium
Eight research institutions are participating in the Lifelong Vision project. The project is led by Caroline Klaver of Radboudumc. Other principal investigators include Rob Collin and Ronald Roepman from Radboudumc, Camiel Boon and Arthur Bergen from Amsterdam UMC, and Clarisa Sánchez from the UvA.

About Gravity
The Gravity program encourages excellent research in the Netherlands. The program is intended for scientific consortia conducting innovative and influential research within their field. The goal is to stimulate research programs to achieve breakthroughs of international significance.

Source:
Radboudumc
Amsterdam UMC
Oogvereniging

Patient and researcher: a dynamic duo once again cycling together

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BUT NOW ON A RACING TANDEM WITH GEARS

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

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

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

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

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

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

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

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

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

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

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

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

Jack from the USA is also cycling along!

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

Also read:

 

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:

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jCyte stamceltherapie

jCyte Initiates Phase 3 Clinical Trial for RP Cell Therapy

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

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

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

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

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

More information available at our Knowledge Portal:

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

Foundation supports innovative research into retinal diseases

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

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

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

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

Picture made by Charlotte Andriessen.

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

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

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

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

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

UPDATE September 27, 2023

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

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

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

The full press release can be read here.

 

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

In August 2022 ProQR decided to focus exclusively on the development of the Axiomer® RNA editing technology platform. ProQR Therapeutics was forced to stop promising clinical trials unless they found a new strategic partner to continue.
Read about this: 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/