ProQR announces first results from STELLAR

Summary of Phase 1/2 Interim Analysis of QR-421a for Usher Syndrome Program

A first-in-human clinical trial of QR-421a is ongoing. The Phase 1/2 study, named Stellar, includes adults that experience vision loss due to mutation(s) in exon 13 of the USH2A gene. This Phase 1/2 clinical trial is designed to evaluate the safety and tolerability of QR-421a. Patient benefit will be assessed as well.

Three-months interim findings from Stellar, reported in March 2020, suggested QR-421a given as a single intravitreal injection was safe and well tolerated. QR-421a showed early and encouraging evidence of activity, with 25% of patients showing a benefit across multiple concordant outcome measures and was well tolerated with no serious adverse events. Two of eight participants in the treated groups responded to QR-421a treatment thus far showing benefit in multiple outcome measures.

Across both cohorts thus far, QR-421a was observed to be generally well tolerated with no serious adverse events noted. Based on these early positive findings we will continue the trial as designed at expert centers in North America and select European countries.

Read here the PDF:  Interim Findings of QR-421a Phase 1/2 Clinical Trial for Usher Syndrome and nsRP 

Read press release: ProQR Announces Positive Findings From an Interim Analysis in the Phase 1/2 trial of QR-421a for Usher Syndrome and Provides Business Update

 

A tailor-made genetic patch for very rare mutations

New centre for RNA therapy set up for small patient groups.

Scientists and physicians of the Leiden University Medical Centre (LUMC) and the Radboudumc together started the Dutch Center for RNA Therapeutics (DCRT). This new virtual centre was set up with the objective to develop tailor-made RNA therapy. A therapy meant for patients with rare genetic disorders, such as Usher Syndrome.


Dutch Center for RNA Therapeutics
The DCRT opened its doors for the first time on 29 February 2020, Rare Disease Day. The DCRT is the first centre in Europe to develop RNA therapy for very rare diseases. This is about genetic diseases and mutations that are so rare, that it is less interesting for pharmaceutical companies to invest in developing a treatment. The therapies are targeted on stopping or slowing down progressive genetic eye, brain and muscle diseases by local administration of medication.

RNA therapy for Usher Syndrome
The objective of RNA therapy, also called AON therapy, is to repair the genetic defect at RNA level, so that a smaller but partly functional Usher protein can be made.
For a specific mutation an antisense oligonucleotide can be designed. Antisense-oligonucleotides, abbreviated by ASOs or AONs, can be regarded as a ‘genetic patch’ that covers the area of the mutation and makes it invisible. In this way the cause of Usher Syndrome is removed and, hopefully, the deterioration of the eyesight (and possibly hearing) with this group of patients can be stopped or mitigated.
Erwin van Wijk of the Radboud UMC in Nijmegen, the Netherlands, studies the therapeutic effect of antisense oligonucleotides (AON) for the future treatment for Usher Syndrome.
Jennifer Lentz from New Orleans (LSU School of Medicine, USA) is working on the development of an antisense oligonucleotide (AON) for patients with a specific mutation in the USH1C gene, the c.216G>A mutation.

Non-profit
Over 500 different mutations are known for the USH2A gene and RNA therapy is not possible for all these mutations. RMA therapy will be possible for about one third of the people with mutations in the USH2A gene, but some mutations are extremely rare. The new Dutch Center for RNA Therapeutics (DCRT) wants to develop tailor-made ‘genetic patches’ for this really small group of patients.

‘It is impossible for the industry to make medicines for only a few patients. Therefore it is the duty of the academic hospitals to be there especially for that group’, according to scientist Anniemiek Aartsma-Rus.

The in-house making of a ‘genetic patch’ for one specific mutation has one factor that saves a lot of time. No registration with the European Medicines Agency (EMA) is required.
Together with patients’ associations and subsidies this centre must be developed further in order to make sure that an (affordable) ‘genetic patch’ will be available for all patients with (very) rare mutations in the Usher gene in the future.

The DCRT is made possible by a financial contribution of the Human Genetics department of the LUMC. This non-profit centre will be managed by Dr. Willeke van Roon-Mom and Prof. Annemieke Aartsma-Rus of the Human Genetics department of the LUMC Also neurologists Dr. Erik Niks and Prof. Jan Verschuuren, ophthalmologists Prof. Camiel Boon and Prof. Gré Luyten and hospital pharmacist/clinical pharmacologist Prof. Henk-Jan Guchelaar are involved in this as well. Apart from Dr. Collin, geneticists Prof. Frans Cremers, Dr. Susanne Roosing and Dr. Alex Garanto as well as Dr. Erwin van Wijk as researcher of the ENT department, ophthalmologist Prof. Carel Hoyng and ENT specialist Dr. Ronald Pennings from Nijmegen are involved in the DCRT as well.

STELLAR
ProQR Therapeutics from Leiden has further developed the antisense oligonucleotides (AON), developed by Dr. Erwin van Wijk, into the medicine QR 421a and this is currently tested for effectiveness and safety in a trial called STELLAR. This is a ‘genetic patch’ for exon13, the most frequently occurring mutation in the USH2A gene. The first results will soon be published.
The ‘genetic patch’ must be regarded as a medicine and not as a gene (replacement) therapy. This is because actually no gene is replaced or repaired. The ‘patch’ must be administered repeatedly in order to have a permanent effect on the deterioration of the eyesight.

Development of gene therapy for large USH2C gene

From left to right: Annouk van Nunen, Rick Brouwer, Deborah Heffernan, Erik de Vrieze, Erwin van Wijk, Ronald Pennings, Carol Brill, Renske Schellens, Ivonne Bressers, Sanne Broekman, Jantine van de Watering.

Usher Syndrome patients and researchers of Radboudumc set the tandem in motion again for scientific research into a treatment for Usher Syndrome, this time concerning type 2C. After the successful USH2A Minigenes study, the results of which will be known early in the year 2020 there will be a follow-up. Stichting Ushersyndroom (Dutch Usher Syndrome Foundation) finances, with a contribution from CUREUsher from the UK/Ireland and the Landelijke Stichting voor Blinden en Slechtzienden (LSBS), the new study into Minigenes for USH2C. In order to celebrate this milestone, five researchers of the national Usher Syndrome Expertise Centre of the Radboudumc involved surprised the same number of patients with a ride on the tandem. 

In their white coats head researcher Erwin van Wijk, Erik de Vrieze and ENT specialist Ronald Pennings cycled in a good humour as co-pilots to the agreed place. Only Ivonne Bressers, chairwoman of Stichting Ushersyndroom (Usher Syndrome Foundation) was involved in the plot. Like a string another two half-empty tandems followed with 2 young researchers who are daily engaged in doing research into a treatment for Usher Syndrome, a disorder which slowly makes 400,000 patients around the world both deaf and blind.

With rare diseases like this, the contact between physicians, researchers and patients is crucial. Patients, parents and relatives are the drive force behind the scientific research into a treatment by collecting donations, acquiring resources and close consultation with physicians and researchers. This interaction brings a treatment for progressive deafblindness closer at a faster pace.

“We are unmistakably united as a duo on a tandem; the researcher as co-pilot, the patient as firer.”
Erwin van Wijk, head researcher in the Radboudumc

“The input and knowledge that patients bring up themselves is not only highly inspiring for me and my colleagues, these also put us on new tracks in unravelling Usher Syndrome. We are unmistakably united as a duo on a tandem; the researcher as co-pilot, the patient as firer,” the head researcher of Radboudumc Erwin van Wijk tells us.

Five Usher patients are sitting at a table in a café drinking coffee; some with their backs to the window. Patient Rick Brouwer gets up surprised when Erwin van Wijk appears within his tunnel vision. Rick is one of the people for whom the Minigenes USH2C study gives hope. He has been involved as from the foundation of Stichting Ushersyndroom (Usher Syndrome Foundation) and suffers from Usher Syndrome type 2C himself.
“Today really is an important day! Thanks to the positive results of the Minigenes USH2A study a step is made to USH2C. There soon will be a treatment for all people suffering from Usher!”, Rick calls out deliriously happy.

“For the first time in my life I really have hope that there will be a treatment for all Usher patients all over the world!”
Carol Brill, Usher patient and member of the Board of CUREUsher

Carol Brill of CUREUsher from Ireland is there as well and starts laughing when the researchers seduce them to take a ride on the tandem after having expressed their thanks for their cooperation. Carol: “What a great experience to cycle together through the city! I will come over to live here! For the first time in my life I really have hope that there will be a treatment for all Usher patients all over the world!”

Promising preliminary investigation
In the year 2016, Stichting Ushersyndroom (Usher Syndrome Foundation) made a financial contribution to the study into the functioning of USH2A Minigenes as a future treatment method. Usher Syndrome is a rare genetic disease in which faults (= mutations) in about ten different genes lead to a progressive form of deafblindness. The large size of the genes in which the most causal mutations are found with most patients makes classic gene therapy impossible. This is because these mutated genes are simply too big to be packed in the available viral vectors that are required for delivering the gene at the correct place in the retina. This is an ultimate challenge for the researchers. A creative solution is needed to still process the gene in a viral vector.

Erwin van Wijk expects to be able to publish the first study results of the USH2A Minigenes study early in the year 2020. Van Wijk will now start a similar study for USH2C, titled ’Pre-clinical development of a minigene augmentation therapy for the future treatment of USH2C-associated retinitis pigmentosa’. Never before a research institute has had the courage to start developing a gene therapy for this huge USH2C gene. Stichting Ushersyndroom (Usher Syndrome Foundation) will subsidise this 4-year study of Erwin van Wijk (and Erik de Vrieze and Ronald Pennings) with € 250,000 with co-financing from CUREUsher and L.S.B.S.

In order to celebrate this milestone, five researchers of the national Usher Syndrome Expertise Centre of the Radboudumc involved surprised the same number of patients with a ride on the tandem. 

The Medical Advisory Council of Stichting Ushersyndroom (Usher Syndrome Foundation) is very positive about this study because of the highly promising preliminary investigation with the USH2A Minigenes, which has demonstrated that it is possible to make minigenes and that these work in the correct/expected way.

According to the members of the Medical Advisory Council, the applicants have the appropriate knowledge, expertise and material at their disposal to carry out the proposed experiments for the USH2C gene (ADGRV1). As far as the members of the Medical Advisory Council know, no study is presently done into USH2C, while this is the third most common form of Usher Syndrome which about 40,000 people around the globe are suffering from.
Cindy Boer (member of the Medical Advisory Council, doctoral candidate internal medicine, faculty of human genomics, ErasmusMC and suffering from Usher Syndrome herself): “In consultation with Erwin van Wijk and Erik de Vrieze the Medical Advisory Council has made an addition to this study proposal. We would like to apply this to humans by making use of human skin cells. In this way we can investigate whether the minigenes behave well in human cells and whether the proteins properly unfold. This may sometimes be different in human models as it is in animal models and therefore it gives a good indication about the functioning of the gene therapy for humans.”
The USH2C Minigenes study is completely in line with the objective of Stichting Ushersyndroom (Usher Syndrome Foundation): “There will be a treatment for Usher Syndrome in 2025!”

The tandems with patients and researchers will continue their journeys; these will be bumpy, but their confidence in the process will drive them and this will bring a treatment for Usher Syndrome closer than ever before. Difficult ways will lead to great destinations. 

The CRUSH study as a preparation for future trials
Earlier this year, Stichting Ushersyndroom (Usher Syndrome Foundation) also financed the CRUSH study of the Radboudumc with co-financing from the Oogfonds and the Dr. Vaillantfonds, a study in which researchers will map out the natural development of Usher Syndrome in great detail. Researchers really intensively follow the Usher Syndrome patients. Expectations are that during a research period of five years more knowledge will have been gained about the development of the deafblindness related to various types of Usher Syndrome.
In case of a positive result of the new study into Minigenes for USH2C the research team will be well prepared for any next phase 1 / 2 clinical trial.

Text: Maartje de Kok
Photo and video: Richard Brusse

Know your gene!

Join the CRUSH database

Usher Syndrome is a rare hereditary disease. In the Netherlands, about 1000 people suffer from Usher Syndrome, but far from everyone has been diagnosed.
Now that the scientific developments are going really fast, the Stichting Ushersyndroom calls on everyone to have their DNA tested and to register with the National Usher Syndrome Expert Centre of Radboudumc in Nijmegen, the Netherlands.

Our dream
The dream of all people who are confronted with Usher Syndrome in their daily lives is that researchers will in time find a treatment to stop the deterioration of eyesight and hearing.
Our dream can come true when all patients with Usher Syndrome know their gene and mutation.
In connection with the new privacy law people suffering from Usher Syndrome are hard to reach and patient files are no longer passed on to other specialists and hospitals.
By taking action yourself and to register yourself in the international CRUSH database of the national Usher Syndrome Expert Centre you contribute to sooner finding a treatment.

Start setting up your own patient file!

Ask your therapists for your medical data, such as audiograms, eyesight measurements, visual field tests, genetic and other results, and keep these at home in a file.

As soon as a study is started, you will be asked to participate. Then it will be convenient to already have your own patient file at hand. Specialists can see whether you meet the criteria of any study based on your own file. You can now register for the CRUSH database, so your contact data will be known already.

Do you want to know how you can ask for a DNA test? Please go to the knowledge portal for further reading.

Into daily life with an artificial organ of balance

The introduction of the artificial organ of balance has come one step nearer closer again, thanks to a subsidy of over € 700,000 from ZonMw, Health Holland and the Heinsius Houbolt Foundation. With this financial impulse scientists of the Maastricht UMC+ will implant an artificial version of this minuscule organ into eight patients suffering from serious imbalance problems. This is the first time that the daily life with an artificial organ of balance will be simulated in a test environment. The objective is to sooner make the treatment available to patients.

Micro-CT-scan of the human inner ear; yellow: individual nerves; blue: bone and membrane structures (Copyright: Maastricht UMC+)

The organ of balance is located deeply in the so-called petrous bone, behind the ear (one on each side). Here it makes sure that we experience a stable world. People with whom the organ stops functioning on both sides, experience a feeling of disorientation, dizziness and/or discomfort. They continuously lose their balance and this strongly restricts their daily functioning. As much as 75% of the patients is unfit for work. So far, treatment by surgery or medication has been impossible. The artificial organ of balance is meant to change this.

Balance and hearing implant
Another important scientific development is the introduction of the vestibulo-cochlear implant (VCI), a balance and hearing implant in one.
USH type1– there are three different clinical types – includes both congenital deafness and failure of the organ of balance. A part of the people suffering from USH type 3 is confronted with failure of balance in later childhood or at a later age. 
The artificial organ of hearing and balance, the VCI, can improve the lives of these patients.  

Daily use
The artificial organ of balance is a small implant which takes over the work of the ‘real’ organ. First of all, it registers the movements that people make. These signals are then passed on to the brains to determine the orientation and to keep the balance. Since the development of the first prototype in 2012, the physicians of the Maastricht UMC+ and the university hospital of Geneva have given an artificial organ to thirteen patients. At this moment, the implants are only used in test settings. “Now is the time to bring things closer to the patients and to study the daily use”, according to ENT specialist Dr Raymond van de Berg and his colleague Marc van Hoof.

Available in a few years
The artificial organ of balance, called a Vestibular Implant (VI)) is implanted into the ear by surgery. This VI can be inserted beside an already present cochlear implant. The VI can be available to all patients in the Netherlands in about 5 years.

Quality of life
With this subsidy, an artificial model of the organ of balance can be implanted into eight patients with failure of the organ of balance on both sides. For this patients are hospitalised in a rehabilitation setting in which the daily use, the functioning and the safety of the implant are analysed. Additionally, an overview is made of the personal requirements and needs of the patients. Also, it is investigated whether the amount and quality of information sent from the implant to the brains can be further expanded and improved. Van de Berg: ‘Of course, the eventual objective is to literally and figuratively offer the patients more balance and so give them back their quality of life and enable them to better function in society.’ At a rough estimate, Europe counts 500,000 patients suffering from imbalance problems. The introduction of the artificial organ of balance could help hundreds of patients in the Netherlands.

Participation in user committee
A female patient suffering from Usher Syndrome is a member of the user committee of the VertiGO! study. She assists in the further development of the VI and the VCI. This patient does not have the VI/VCI herself.

The study is titled ‘VertiGO!’ and the research is co-funded by Health Holland, the Hoormij Foundation, ‘De negende van’ Foundation, the Usher Syndrome Foundation and external partners, including the University of Geneva, manufacturer MED-EL, the Heinsius Houbolt Foundation, the Apeldoorns Duizeligheidscentrum, LUMC and the Radboud UMC.

Source: Maastricht UMC+

Study of the natural Development for USH1B started

18% of the 400,000 patients suffering from Usher Syndrome around the world has mutations in the USH1 gene. Due to the mutations (changes) in the USH1B gene the myosin protein is not or hardly produced. Due to a shortage of the myosin protein the cochlea in the ear of the unborn child is not properly built up during pregnancy. Consequently, children suffering from USH1B are born deaf and have balance problems. The first signs of reduced eyesight will show during childhood. This starts with night-blindness to be followed by an ever narrowing field of vision. Children born with USH1B are given cochlear implants on two sides in their early childhood, which make them hear well and enable them to properly develop speech and language, if necessary supported by sign language.

For patients suffering from USH1B there is little information available about the natural development of the eyesight. After the start of the RUSH2a and the CRUSH studies in the Radboud UMC in Nijmegen, the Netherlands, a study into the natural development of USH1B was started in the Oogziekenhuis Rotterdam, the Netherlands. The first patients have already been included, but more participants are required. In this study researchers want to follow 15 – 20 participants with 3 eye tests in 2 years.

Read the call of the Oogziekenhuis Rotterdam below.

Usher type 1B: call for participation in the natural development study.

A study into the natural development with patients suffering from the Usher Syndrome type 1B was started in the Oogziekenhuis Rotterdam, the Netherlands. This type of Usher is characterised by serious deadness and balance problems from birth, followed by a development of retinitis pigmentosa (RP) during childhood. The Usher Syndrome type 1B is much more uncommon than, for instance, Usher Syndrome type 2A. Therefore less is known about the seriousness and the progression of this type of retinitis pigmentosa. Usher type 1B is caused by changes (mutations) in the MYO7A gene. This gene determines the code for the myosin protein. The function of myosin is, among others, to take care of transport in the retina cells. Professor Alberto Auricchio of the TIGEM institute in Naples, Italy, has studied gene therapy as a treatment of RP caused by MYO7A mutations for many years. He has received a major grant from the European Union to continue his research (www.ushther.eu)).

A part of this large project is the natural development study, in which not Only the University of Naples but the Oogziekenhuis Rotterdam and an institute in Madrid participate as well. The information gained from this study will eventually be very important to be able to compare the effect of gene therapy with ‘doing nothing’.

This study includes 3 extensive eye tests in the Oogziekenhuis Rotterdam: there is a baseline measurement which will be repeated after 1 en 2 years. It is important to mention that no treatment will be tested in this part of the study.

We would like to come in contact with patients who want additional information about the study and who may want to participate. It is important that you carry MYO7A mutations. Another restriction is that children younger than 8 years cannot participate. If you want additional information about this study, you are heartily invited to contract Dr Ingeborgh van den Born of Ms Annemiek Krijnen (tel.: 0031-(0)10 -4023449, e-mail roi@oogziekenhuis.nl.

Do you suffer from Usher Syndrome type 2? Register for the CRUSH study in Nijmegen, the Netherlands. Participants are needed for this study as well! Read more about the CRUSH study and how to register

The RUSH2a and the CRUSH studies

CRUSH has been aligned to RUSH2a
Also thanks to the Medical Advisory Council of the Usher Syndrome Foundation, the content of the CRUSH study has been aligned to RUSH2A. This means that the research questions and the study measurements are largely similar, allowing the results of the CRUSH study to be compared with those of the RUSH2a study. This comparison is of scientific value.
The set-up of the CRUSH study leaves the expertise centre in Radboud UMC some space to make adjustments in the research protocol. In the international RUSH2a study this is highly restricted, as this study is to be conducted in all countries in exactly the same way.
Examples of differences are: the CRUSH study is somewhat more focused on the quality of life (questionnaires). The CRUSH does not apply a smelling test, but the RUSH2a study does. The CRUSH tests for balance, which the RUSH2A does not. The RUSH2A applies genetically stricter inclusion criteria. Some patients are not eligible for RUSH2A whereas they are for CRUSH and vice versa.

A large group of patients
Internationally, both syndromic and non-syndromic Usher patients are eligible for the RUSH2a study. Patient will not participate in both studies.
Patients with non-syndromic retinitis pigmentosa are not eligible for the CRUSH study.
Only patients with a mutation in the 2a gene will participate in the RUSH2a studies. The CRUSH study can include patients with mutations in various gene types. Both studies are equally important from a scientific point of view. One study does not have more advantages or risks than the other.
20 patients can participate in the RUSH2a study and for the CRUSH study 50 patients will be selected and asked to participate. The RUSH2a will be coordinated from the Ophthalmology department department, whereas the ENT department coordinates the CRUSH study.

What about the database?
The CRUSH database is a database specifically set up for patients suffering from Usher Syndrome. Here not only the contact data and genetic results are saved, but those of the field of vision and hearing tests as well. The CRUSH database provides an overview of all patients suffering from Usher Syndrome in a uniform database and this may simplify selection processes for participation in a study and/or trial.
The CRUSH database is managed by the Usher Syndrome Expertise Centre in the Hearing & Genes department of Radboud UMC.
An Usher Syndrome patient who has been registered for the RD5000 database will not automatically been registered for the CRUSH database and vice versa. The ENT specialists and the ophthalmologists in Radboud UMC work closely together, thus ensuring exchange of knowledge within this Academic Centre. You can register for the CRUSH database by sending an e-mail to ushersyndroom@radboudumc.nl

Natural development for USH 1B
A study into the natural development with patients suffering from the Usher Syndrome type 1B was started in the Oogziekenhuis Rotterdam, the Netherlands. The information gained from this study will eventually be very important to be able to compare the effect of gene therapy.

CRUSH study and database for unraveling Usher Syndrome

Usher Syndrome
Usher Syndrome is a rare hereditary disease. Children suffering from Usher Syndrome are born deaf or hard of hearing and they will also develop a visual impairment from their teenage years. This starts with night-blindness and an ever narrowing field of vision, like looking through a straw. Usher Syndrome eventually leads to deafblindness. Sometimes imbalance problems are also involved. The diagnosis has a great impact on the perspective. There is no treatment yet, but there are promising developments worldwide.

Developments in scientific research
Join the CRUSH databaseAt this moment, an increasing number of centres around the world are busy developing a treatment for the various types of Usher Syndrome (Usher 1b, 1c, 2a, 2d and 3) aimed at inhibiting or stopping the deterioration of vision and hearing. The Radboudumc particularly puts the emphasis on this kind of research on Usher Syndrome type 2a, the most common type of Usher Syndrome that is caused by mutations in the USH2A gene. This gene contains the code for the usherin protein, which plays an important role in the eye and the ear. One of the (gene) therapeutic studies that is conducted is the exon-skipping method. Here one of the coding exons (informative parts of the gene) is removed from the gene and ‘covered’ by a so-called ‘genetic patch’. This results in a shorter but possibly also more functional usherin protein in the retina, by which the deterioration of the eyesight will be stopped or slowed down. Recently, the pharmaceutical company ProQR announced that it will start the first phase 1/2 trials for mutations in the exon 13 at the end of the year 2018. . See ‘ProQR will be start with first trials Ushersyndrome 2a’
In order to be able to test the effectiveness of this type of medicine in clinical trials, it is important to have a clear picture of the natural development of the disease.
However, the exon-skipping method is not suitable for all types of Usher Syndrome and it will take a lot more research to find solutions for all Usher patients. Still, the first important breakthroughs in research are made now!

Ronald Pennings, ENT specialist at Radboudumc Nijmegen (the Netherlands):
“The eventual goal of the Expertise Centre for Usher Syndrome is to be globally leading in the development of (gene) therapy for Usher Syndrome.”

Usher Syndrome Expertise Centre
Dr. Ronald Pennings is recently received the prestigious title ‘Principal Clinician’. With this he wants to set up a trial centre for medicinal treatment of patients with hereditary loss of hearing, including Usher Syndrome, within Radboudumc. Prof. Carel Hoyng is as ophthalmologist of the Radboudumc also directly involved in the care for and research into Usher Syndrome. Additionally, he leads the trial centre of the Ophthalmology department, which is studying retina degeneration by means of testing new medicines. Hoyng and Pennings together lead the Expertise Centre for Usher Syndrome. “The eventual goal of the Expertise Centre for Usher Syndrome is to be globally leading in the development of (gene) therapy for Usher Syndrome. Not only the developments in the laboratory of Erwin van Wijk, but also detailed examination of the natural development of Usher Syndrome with as many people as possible will enable us to obtain this position”, according to Ronald Pennings.

CRUSH study and a CRUSH database
The CRUSH study will map out and analyse the natural development of the progressive disease Usher Syndrome with 50 patients for a period of five years.
The protocol of this study is in line with the first international natural development study, the RUSH2A study of Prof. Duncan in California, with makes exchange of data possible.
Apart from the CRUSH study, an (international) accessible CRUSH database will be set up in the Radboudumc as well for properly recording the results of the examinations.
The CRUSH database is a collection of various clinical data, including audiograms, field of vision examinations and DNA results. In this way the prognosis can be better recorded and a possible explanation for the large individual differences in loss of hearing and eyesight between patients, even of the same family, can be found. This CRUSH database will be accessible for other centres, so they can store their data in the database as well.
Most patients are already known in the national RD5000 database, but this database only contains personal data and the diagnosis. The Radboudumc works together with the physicians and researchers working with the RD5000 database. The CRUSH database, in which the clinical data of patients are stored as well, is intended for all people who have been diagnosed with Usher Syndrome. Researchers of the CRUSH study will select patients from the CRUSH database who meet the criteria and then invite them to participate in the CRUSH study. You can register for the CRUSH database by sending an e-mail to ushersyndroom@radboudumc.nl

Stichting Ushersyndroom, Ronald Pennings (ENT specialist) and Carel Hoyng (ophthalmologist) of the Radboudumc advise all patients suffering from Usher Syndrome to compose their own files, making sure that the data will quickly be known when registering for the CRUSH database. See ‘Start setting up your own patient file!’

‘CRUSH USH’
Annouk van Nunen, secretary of Stichting Ushersyndroom and patient herself is happy with the start of the CRUSH study and the CRUSH database. “At this moment there are many families within which several children are affected by Usher Syndrome. However, even between brothers and sisters there are major individual differences in the level of deterioration of eyesight or hearing. If it is known which external factors may influence the deterioration of eyesight and hearing, patients can timely anticipate and make a contribution to slowing down the deterioration themselves. Everyone participating in the CRUSH database makes a contribution to finding the solution. As soon as the CRUSH study has been started, the focus will be shifted towards the acquisition of more funding, so as to make it possible to follow more patients suffering from other types of Usher Syndrome in detail in the future in a study. All patients (young and old, type 1, 2 or 3) play crucial roles in the eventual unraveling of Usher Syndrome.”

In short, the CRUSH study and the CRUSH database are in the interest of all people diagnosed with Usher Syndrome. This is the only way to unravel the disease more quickly and to substantially shorten future trials in the Netherlands or elsewhere in the world.
The full financing of the CRUSH study is guaranteed by Stichting Ushersyndroom for a period of five years, also thanks to the donors and the co-financing of the Dutch Dr. Vaillantfonds and Oogfonds. #CRUSH4all

Read Press Release ‘Patient and physician jointly take the first step towards treatment of deafblindness’

Patient and physician jointly take the first step towards treatment of deafblindness

Stichting Ushersyndroom finances CRUSH study

The expertise centre for Usher Syndrome in Radboudumc in Nijmegen (the Netherlands) will start a natural development study into Usher Syndrome. This is a very important step in the research into a treatment of Usher Syndrome, because this study may substantially shorten the running time for trials. Ophthalmologists and ENT specialists will together conduct this CRUSH study. Stichting Ushersyndroom will finance this five-year study with over €257,000,–, made possible by the donations and the co-financing of the Dutch Dr. Vaillantfonds and the Oogfonds.

The CRUSH study (Characterizing Rate of progression USHersyndrome) is a cooperation between the Usher Syndrome Foundation, ophthalmologists, ENT specialists and the researchers of the Radboudumc. This study will map out and analyse the natural development of the progressive disease Usher Syndrome with 50 patients for a period of five years. Children suffering from Usher Syndrome are born deaf or hard of hearing and from their teenage years their eyesight will deteriorate as well. This starts with night-blindness and an ever narrowing field of vision, which is like looking through a straw. Usher Syndrome is the most common type of deafblindness.
By starting now to properly register of the natural development researchers can determine how many people are required, what studies are to be conducted when and how long a trial must take in order to be able to unambiguously and exactly register the effect of a treatment compared with the natural development.

CRUSH study as a track-record for other eye diseases
By starting natural development studies with 50 patients suffering from Usher Syndrome a track-record is built up which can be extended in the future. By mapping out the deterioration of vision and hearing, the basis is laid for the future evaluation of the effectiveness of clinical trials related to Usher Syndrome. These experiences are not only important to patients suffering from Usher Syndrome, but to patients with other hereditary eye disorders as well. This study can be an example of how the running time can best be shortened to make sure that studies into effectiveness can be started in time.

A. van Nunen, secretary of Stichting Ushersyndroom and patient herself:

“The CRUSH study can help ophthalmologists and ENT specialists to inform patients better about the prognosis and the development of the deterioration of their eyesight and hearing, thus enabling people suffering from Usher Syndrome to better arrange their lives.”

Usher patients hope that this study will also provide an explanation of the individual differences within families and to find and answer to the question which external factors have influence on the development of the disease. For this reason a CRUSH database will be set up apart from the CRUSH study. Annouk van Nunen: ‘Knowledge about the natural development for each mutation improves the early diagnosis and guidance of young parents and the care for people suffering from Usher Syndrome. The CRUSH study can help ophthalmologists and ENT specialists to inform patients better about the prognosis and the development of the deterioration of their eyesight and hearing, thus enabling people suffering from Usher Syndrome to better arrange their lives.’
Do you want to know more about the CRUSH study and the CRUSH database? Read ‘CRUSH study and database for unraveling Usher Syndrome’

Stichting Ushersyndroom finances restart of ‘minigenes’

Usher Syndrome is a rare hereditary disorder. The children suffering from this disorder are born deaf or hard of hearing and apart from night-blindness they also experience a progressive loss of eyesight. Eventually, people suffering from Usher Syndrome become both deaf and blind. Usher Syndrome is the most common type of hereditary deaf-blindness. There is no treatment yet that can stop the deterioration of both hearing and eyesight, but there is hope.

Large gene
Although more than half of all people suffering from Usher Syndrome have mutations in the USH2A gene, this gene is not a target in the current studies into the development of gene replacement therapy. This is because of the size of the protein coding sequence of the USH2A gene (>15,000 bases!). A DNA fragment of such a length does simply not fit into the currently used gene therapeutic vectors (harmless viruses used for packaging genetic material and delivering this at its destination).

Minigenes: the solution for the problem?
In the ‘minigenes’ project, the USH2A gene is artificially made smaller by taking specific parts of the gene and sticking these together (= minigene). This makes it possible to insert these minigenes into the current vectors for use in genetic therapy.
In this project the therapeutic effect of shortened USH2A protein variants will be tested in the zebrafish model. If this is successful, this project may lead to a pre-clinical treatment method for USH2A-related retina degeneration, with which the deterioration of the eyesight could be stopped (within 5 to 10 years). This will have a tremendously positive impact on the quality of life of individual patients. The treatment can be applied to all people suffering from Usher Syndrome.

Stichting Ushersyndroom wants to finance scientific research that offers hope to all people suffering from Usher Syndrome and give a positive impulse to the ‘minigene’ research with an amount of €35,000. The remaining amount was supplemented by ENT Radboudumc. This is guaranteed and so ensures completion of the first phase of this study.

“Minigenes study;
hope for all people
suffering from Usher Syndrome”

Time-consuming and specific
In the Radboudumc, researchers are also conducting other studies that may offer solutions for smaller groups of people with specific mutations in the USH2A gene. However, this study, which tests the therapeutic potential of exon skipping, is a very time-consuming study as a specific treatment is to be developed for each mutated exon. All the more because over 500 different mutations have been identified in the USH2A and these are spread over the entire gene. Even when the developments in the ‘exon skipping’ study show positive progress, this method still does not offer a solution for a significant part of the people with a mutation in the USH2A gene, because the build-up of the gene and protein are not suitable for this.
Recently, a joint venture was entered into with a pharmaceutical company for further development of this exon skipping method into a possible first trial in a few years.
SWODB also made a donation for financing a part of the ‘exon skipping’ study

Start-up Usher Syndrome database
In view of all developments concerning the research into Usher Syndrome it is really necessary to start the ‘Usher Database’ project. First of all, the Usher database is an essential collection of personal data, genetic data and extensive clinical data obtained by conducting a broad set of eyesight and hearing studies. The results of the most recent studies help to make an overview of the natural deterioration of eyesight and hearing of all people suffering from Usher Syndrome. These data will form the basis for future trials during which gene-therapeutic interventions can be tested and compared with this natural deterioration. Secondly, by studying these data an explanation can be found for the huge variation that is found in the clinical picture (even within families sharing the same genetic background).

Therefore the Usher database goes much beyond the national RD5000 database, in which at this moment only genetic and personal data of patients with hereditary retina degeneration are stored.
Usher Syndrome Foundation will concentrate on acquiring funds for the start-up of this project. Without this study and the Usher database the trials of gene-replacement therapies, which may be developed in a couple of years, cannot start either.