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.

Zebrafishes hope for the future?

If you suffer from the Usher Syndrome, your eyesight increasingly deteriorates.
This cannot be prevented yet, but perhaps this will be possible in the future. Last February, a campaign was started for the development of a possible treatment for people suffering from Usher type 2a.

For many years, I was in the belief that there was no treatment for the disorder that I and my daughter suffer from. I am hard of hearing, I have a small field of vision and I know that eventually I will become completely blind. I also know that my daughter will go through exactly the same process. Then I heard at a meeting that there might be some hope after all. This happened to Maartje de Kok, campaign leader of The campaign team collects money for the development of a genetic treatment method for people suffering from Usher Syndrome. This method may stop the deterioration of the eyesight. Here the team closely works together with the MUS Foundation, a foundation that supports people suffering from Usher Syndrome and their families.

Stop deterioration
Maartje and others draw hope from the Zebrafish project, a gene-therapeutic study into the development of a treatment for people suffering from Usher type 2a (Usher 2a). ‘There is no treatment at all for Usher 2a yet’, Erwin van Wijk explains. He is project leader of the Zebrafish project and researcher at the Radboud UMC. ‘Therefore we as yet specifically focus on this type of Usher. (HIER HOUDT HET ARTIKEL OP DE WEBSITE OP) Usher Syndrome is caused by mutations in genes. A gene contains the genetic code for the production of one or more proteins. In case of Usher this involves proteins that are crucial for the functioning of the eyes and the ears. We know by now that faults (also called “mutations”) causing Usher Syndrome can be found in ten different genes.
With this research we try to achieve that, despite this deviation in the genes, a protein is still produced that remains functioning sufficiently. In this way we hope to be able to stop the deterioration of the eyesight.’

In order to accomplish this, another method is used than the ‘classic’ gene replacement therapy that researchers in the United States use for Usher type 1b. ‘The therapy for Usher 1b does not work for Usher2a’, Erwin says. ‘This is because the gene to be replaced in case of Usher 2a is so large, that this is technically impossible. We try to solve this problem by applying an alternative approach, the so-called exon-skipping method. Here the “fault” in the gene is masked (“skipped”) so the body does not include this producing a new protein. The protein of such a repaired gene is not completely perfect. It is a bit shorter and therefore it does probably not function for 100%. However, we hope that it will function sufficiently to stop the deterioration of the eyesight. We want to test the effect of this method on zebrafishes. This is because the eyesight of zebrafishes deteriorates when the Usher 2a gene has a deviation, just like with humans. This contrary to mice, for example.’

‘The story of the Zebrafish project came to me as a bombshell’, Maartje remembers. ‘For three weeks, I was just busy asking myself whether I would dare to devote myself to making this research possible. After these three weeks I though that I just had to have the courage to do so. Even if this were not for me any more, then perhaps for my daughter.’

Fight against yourself
The Usher Syndrome has a great impact on the life of Maartje. ‘I have two physical impairments that negatively strengthen each other. This is not only highly inconvenient, it also costs a lot of energy. I also have four children. I impose limits on them in the house, but at the same time I want to be a fine mother.’ Therefore Maartje is constantly fighting against herself.
When she was told that daughter Jente also suffers from Usher, she saw her life pass before here eyes. ‘Problems with choosing a study, give up sports, no more riding a bike. She will also have to go through all those painful moments and I can only guide her if I can keep dealing with this in a proper way.’ This is hard, because sometimes being deafblind is frightening, Maartje knows. ‘I have experienced a moment that I did not hear and did not see anything. I had the flue and I felt the deafblindness come over me. I was terrified.’
‘At the same time, I can better let go of the disorder since I had this experience’, Maartje continues. ‘For I am still here. I run, I write blogs, I participate in the organisation of a large campaign. Even if I can see nothing in the future, then I am still here and there are lots of possibilities.’ Nowadays, she cuts up every day in pieces. ‘My family is my mindfulness training. I always focus on one thing. When I am walking the children to the bus, then this is what I am doing. I must not dream away or take my mobile phone while I walk.’

Maartje is a member of the campaign team that will make the Usher Syndrome widely known in the coming period. ‘We particularly want to make people aware, share knowledge and collect money with happenings’, according to Maartje. The MUS Foundation will organise a national Usher day on 12 September. This day is both for people suffering from the Usher Syndrome and for parents, guides and professionals. There will be lectures as well as workshops, personal accounts and music.

The team members will also participate in Co-cycling, a pleasure ride organised by interns on 20 June. ‘Here we will certainly attract attention with our tandems and buddies’, she thinks. ‘Our image is playful, frivolous, creative and certainly not miserable. We just hope we may keep our eyesight.’

In good spirits
How big is the change that the deterioration of the eyesight can be stopped indeed? Erwin emphasises that there is still a long way to go. ‘The first experiments are very promising, but we are careful. The last thing we want is to arouse false hopes in people.’ There are still a lot of questions. ‘Does it really work for humans? Is it safe, are there no side effects?’ A lot of money is needed to find answer to these types of questions.

Maartje: ‘110.000 euros for starting up the study and 90.000 euros for setting up the database. This database is necessary for being able to explain individual differences. Just to be perfectly clear, we collect money for all people suffering from Usher Syndrome. In fact, this study may also offer perspectives for other types of Usher.’
Maartje is in good spirits that the money required will be collected. ‘Also thanks to the partners a lot can be done. We already organise events ourselves and we also want to mobilise people. Perhaps this research will be too late for our generation, but then just let’s do it for the next generation.’

What is Usher Syndrome?
Usher Syndrome is a hereditary disorder that can visit both men and women. This syndrome was in 1935 called after the Scottish ophthalmologist Charles Usher, who did extensive research into this syndrome.
People suffering from Usher Syndrome are hard or hearing or deaf on both sides from birth.
Besides, they later develop a bad eyesight as a result of Retinitis Pigmentosa (RP), an eye disorder that affects the retina. The consequences of RP mostly reveal themselves in the teenage years, but in some cases earlier. Sometimes the functioning of the organ of balance is affected as well.

Usher Syndrome comes in three different varieties: types 1, 2 and 3. People with type 1 are born deaf or very hard of hearing and they have problems with their balance. Their eyesight deteriorates already at an early age. People with type 2 are born hard of hearing and their eyesight increasingly deteriorates in their puberty or in their young adultery. Usher type 2 is the most common type. With the rare type 3 the hearing of people increasingly deteriorates, but less is known about the further development of the disease. The number of people suffering from the Usher Syndrome in the Netherlands is estimated to be 600-1000.

Source: Oogmagazine nr. 2, mei 2015
Text: Jeroen Wapenaar & Joke van der Leij