Development of gene therapy for large USH2C gene

Patient and researcher form a tandem in scientific research into Usher Syndrome

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

Read also:

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.

REGISTER

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

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Into daily life with an artificial organ of balance

A major subsidy, making available a treatment for patients suffering from imbalance problems in a shorter time

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

Research into the natural development of Usher Syndrome is essential in the phase of therapeutic scientific developments. Many and detailed eyesight and hearing measurements are to be recorded in order to be able to measure the effectiveness of a future therapy. Only after studies have demonstrated the effectiveness of a therapy, this will be made available to patients on a large scale.

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

International cooperation with Irish and UK patients.

Photo fltr: Carol Brill, Deborah Heffernan, Liesbeth Geerits, Ivonne Bressers, Joanne White, Ariella Ellenkamp

Stichting Ushersyndroom have had close ties with Usher patients from Ireland and the UK for some years. Patients with Usher syndrome in Ireland and the UK have no central organisation specifically for those with the disease. CUREUsher was officially established at the beginning of this year. At the end of January, the board members of CUREUsher and the board of Stichting Ushersyndroom visited the Radboudumc to discuss cooperation between the two groups and to exchange information. CUREUsher will host the ‘Jo’s Scafell Pike Challenge’ in early April, with which they will raise money for Stichting Ushersyndroom for the pioneering research of Erwin van Wijk in the Radboudumc in Nijmegen.

Currently, major steps are being taken worldwide in scientific research into treatment for and unravelling Usher Syndrome. International cooperation between patient organizations, researchers and doctors is very important at this time. By working together, we can raise larger grants and funds for scientific research, researchers can share their knowledge and doctors can diagnose and map patients in the right way. International cooperation can also lead to smoother regulations within Europe, so that trials can be started earlier and medicines or treatments become cheaper for all patients.

CUREUsher
CUREUsher, a patient-led organisation, was founded by Joanne White in the UK, with co-founders Deborah Heffernan and Carol Brill in Ireland. Their main objective is to raise funds and donations to go towards scientific research into the causes and treatment of Usher Syndrome for all patients worldwide. Joanne, Deborah and Carol hope with the establishment of the organisation it will give a strong message to the government and the care services in their countries to acknowledge deafblindness by Usher Syndrome, so that patients can gain better access to the right care and services.

Jo’s Scafell Pike Challenge
Joanne White, chairperson and founder of CUREUsher: “For the first time I hope for a remedy for Usher Syndrome. With a lot of courage, determination and positivity – I think we all have this power – there is a solution for Usher Syndrome.” Joanne wants to do the ‘Jo’s Scafell Pike Challenge’ together with you. A challenge to climb the highest mountain peak in The Lake District on the weekend from 5 to 7 April 2019 under the guidance of a guide. You can find more information about this challenge by clicking the link below. https://www.largeoutdoors.com/event/jos-scafell-pike-challenge/?fbclid=IwAR0H83Ef6c4paHmBB6KLhpnvHs5v8p7Y-ew36ncBQ04AWh43sMBP_hQIyc0

Joanne and her ‘Usher friends’ invite as many people as possible to join. All funds raised and sponsoring will be earmarked through Stichting Ushersyndroom and will benefit the promising research by Erwin van Wijk. Also enthusiastic people from the Netherlands are cordially invited to join this challenge in the Lake District!

The RUSH2a and the CRUSH studies

By now, both the RUSH2a and the CRUSH studies have been started in the Usher Syndrome Expertise Centre in Radboud UMC in Nijmegen, the Netherlands. What are the differences and the similarities? We will explain below.

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.

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