If you slowly become become deaf and blind

Ronald Pennings, MD, PhD, ENT consultant and Usher syndrome specialist

Slowly become both deaf and blind. It is hard to imagine. Still, this is reality for people suffering from Usher Syndrome. Usher Syndrome, actually what type of disorder is this? And much more important: is there a treatment for stopping or slowing down the process of becoming both deaf and blind?Ronald Pennings, MD, PhD, ENT consultant and Usher syndrome specialist of the national Usher Syndrome Expert Centre in Radboudumc Nijmegen, the Netherlands, tells about this and answers the most burning questions.

‘Usher Syndrome is a hereditary disorder which affects both hearing and eyesight. In principle, the loss of hearing is always congenital. As opposed to hearing, the eyesight is normal at birth, but this will deteriorate in the course of the years.
There are three different types of Usher Syndrome: types 1, 2 and 3. People suffering from type 1 are born completely deaf and they have a poor balance. This is because the organ of balance – which is connected with the cochlea – does not work. These children will develop their first problems with eyesight at the age of eight or ten. They find it more and more difficult to see in the dark, also called night-blindness. Subsequently – as they get older – their fields of vision narrow down and as a result they will see through a kind of tunnel at a certain moment. The things they can still see will eventually become less sharp. This means that the eyesight gradually deteriorates.’

People suffering from type 2 have a congenital loss of hearing for which hearing aids can be used. These people slowly lose their hearing. The first problems with the eyesight show around puberty, a bit later than with people suffering from Usher type 1. Their eyesight will gradually deteriorate as well. Finally, we also have Usher type 3, which is very rare in the Netherlands. This type is more progressive, so here the loss of hearing as well as the loss of eyesight can go very fast.’

What is the cause of Usher Syndrome? 
‘It is a recessive hereditary disorder. Here both parents carry a fault (mutation) in one of the Usher genes without experiencing any trouble. These genes play a major role in the ears and eyes of people, making sure that we can hear and see well. We have two ‘copies’ of each gene. If one copy has a fault, you are carrier but you will not suffer from Usher, because you also have a normal copy. At the moment that both parents pass on their faulty copies of the gene to their child, the child will suffer from Usher Syndrome. In this case the child does not have a normal copy of this gene left.

The copy in which the fault is present will prevent the gene from properly producing its protein. This protein is important for both hearing and eyesight. If you have another good copy, you will have a normal protein on that side. At the moment that both copies are faulty, you will no longer produce a normal protein. When the proteins are not working well, there will be loss of hearing and deterioration of eyesight.’

How big is the change of developing Usher Syndrome?
‘The syndrome is rare, which makes the chance of a child suffering from Usher very small. A child with normal hearing has virtually no chance of Usher Syndrome. In case of congenital hardness of hearing this chance will be larger, about three to six percent. For each form of congenital loss of hearing it is advised to conduct a genetic test for the cause of this. This test can confirm Usher Syndrome, even if there are no problems with seeing yet. When both parents are carriers of a mutation in the same Usher gene, they have 25 percent chance of getting a child with the syndrome.”

How often does this occur?
‘We do not have any exact numbers, but we think that about 800 people suffer from Usher Syndrome in the Netherlands. So this really is a rare syndrome.’

How do people suffering from Usher Syndrome cope with the knowledge that they will slowly become both deaf and blind?
‘In very different ways and with ups and downs. You sometimes see people being seriously confronted with their impairments, as everything costs more energy. On the other hand, there are also periods in which they really try to make things work and make the most of their lives.
There is a lot of power behind this and that is the nice thing about this group of people. That they are still very active despite their impairments. This shows, for instance, in a foundation that have been set up by patients and their relatives, such as Stichting Ushersyndroom. This are a very active foundation that try to improve the lives of people suffering from Usher.’

Is there a treatment?
‘The deaf children suffering from type 1 can be given a cochlear implant. This is an implantable hearing aid with which we place an implant with an electrode in the cochlea. The implant converts sounds into an electric pulse, which then is passed on to the cochlea. After a rehabilitation process, people will be able to hear with this. This makes sure that these children instead of growing up as deaf children grow up as children with a hearing impairment, but they can go to a regular school. To type 2 applies that both children and adults can be rehabilitated with a hearing aid. Sometimes older people suffering from type 2 need a cochlear implant because of the progress of the loss of hearing.

So there is a lot we can do to improve the hearing with the current state of affairs. With respect to eyesight, however, there still really is a problem. Genetic therapies are being developed at this moment, but for this we need to know what is genetically going on. It is important to investigate this and to make a diagnosis based on this. By now, the first steps towards developing gene therapies for the three types have been taken. We are also working on a future treatment for type 2 in our laboratory. However, it will still take many years for a treatment to become available. For the time being, the objective of this study is to slow down or even stop the deterioration of the eyesight in particular.

At this moment, we do not expect that we will be able to give someone who has become blind his or her eyesight again. However, if we indeed manage to slow down or even stop the deterioration process, we have really achieved a lot for the younger patients. This is all still in the future. The first clinical trials have started and we have to wait for the results of these and whether they will lead to medicines for this group of people.’

What can people do themselves?
‘There are indications that exposure to intense (sun)light – also on cloudy days on which the light is intense – it is useful to wear a hat and sunglasses. This could partly protect against increasing damage of the retina. Another important thing is: people suffering from Usher should be careful with their ears, for instance at festivals, clubs or loud music. In these situations they’d better take off their hearing aids or not stand very close to the loudspeakers, although most people suffering from Usher Syndrome will sufficiently take this into account by themselves.’

Dr. Ronald Pennings is ENT specialist and otologist at Radboudumc in Nijmegen, the Netherlands. The Radboud University Medical Centre is an academic hospital and cooperates with the Radboud University of Nijmegen.

Source: Gezondheidsnet [Health net] and NU.nl

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.