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Minigenes USH2A: General status

4 December 2021

By Erwin van Wijk, lead researcher Radboudumc

Errors in the code of the USH2A gene explain the development of Usher syndrome in about 50% of all patients.
In addition to Usher syndrome, these errors can also lead to non-syndromic Retinitis Pigmentosa; loss of sight but without the hearing problems.
The USH2A gene contains the code for the protein usherin. After translation, the mistakes in the genetic code of USH2A also end up in the usherin protein, with the result that this protein loses its function and people lose their sight (and hearing). Giving patients a new copy of the USH2A gene that does not contain these errors could be an obvious solution. This is the principle of gene therapy.

However, for USH2A this is not as easy as it sounds.

New copies of genes are delivered with inactivated viruses, into which the genes are packaged. These viruses can be seen as small trucks. However, the loading platforms of the viruses are small. So small, in fact, that the USH2A gene simply doesn’t fit. Developing a classical gene therapy for USH2A is therefore extremely difficult from a technical point of view.

As an alternative, we have the “genetic patch” methodology, also known as exon skipping. The first patch tested is performed on patients tested in clinical trials.

Good news, but only for a limited target audience. QR-421a works for people with errors in a specific part of the USH2A gene: exon 13. This method can be extended to other USH2A genes and even to other Usher genes, but always remains only applicable for a limited number of patients.

Is there no alternative?

A few years ago we started with a new idea: can we not artificially shrink the USH2A gene, so that it fits in the loading platform of a virus and can therefore be delivered to the place where it is needed and can be used by all people with USH2A-related retinitis pigmentosa?

The main advantage is that, if effective, this method may be of value to all patients with USH2A-related retinal problems. The project “Minigenes USH2A” was born and made possible in part by a contribution from the Dutch Usher Syndrome Foundation (Stichting Ushersyndroom).

Four shortened USH2A genes were made and inserted into the retina of the USH2A zebrafish model. The shortened usherin proteins made from these minigenes in the zebrafish eye ended up in the right place in the light-sensitive cells of the retina, rods and cones. Functional tests by measuring electroretinograms (= ERG) indicate that these mini-usherin proteins are indeed (partially) functional. We have patented these results. How well they work remains to be investigated, but it is a promising starting point for further developing this method.

In the meantime, we are also looking into cultured cells to see where these mini-proteins go and whether they do not accumulate in a place where we would not want this. Fish, of course, are not people. It is therefore important to translate these results into models that are closer to humans.

We are currently trying to establish a partnership with a company that can help us take these important next steps.

Swim at night and take a nap during the day

26 July 2021

Zebrafishes suffering from USH2A have a disturbed sleep rhythm

Are patients suffering from Usher Syndrome so tired because of the huge efforts made in connection with their poor hearing and eyesight or is something else going on? Researchers in the Radboudumc try to find an answers to this question. There are indications that perhaps there is more going on, a genetic cause. The people of the Radboudumc have been busy trying to unravel Usher Syndrome for decades already. This summer, the research into ‘The recognition of sleeping problems with patients with the USH2A gene’ will start. Stichting Ushersyndroom (Dutch Usher Syndrome Foundation) will finance a large part of this study.

Researchers have used the zebrafish model since several years. In the laboratory of the Radboudumc both healthy zebrafishes and fishes suffering from Usher Syndrome are swimming about. Researchers noticed that the sleeping pattern shown by the fishes with a mutated USH2A gene differs from that of their healthy congeners. Actually, they sleep more often during the day and less often at night. According to Erwin, project leader of the zebrafish lab and engaged in research into Usher Syndrome for years already, the sleeping fishes are quite remarkable. It is day, there is sufficient light in the aquarium and the eyesight of the fishes is still good enough to be able to properly see light and dark. Still, they regularly fall asleep during the day.

Sleep-wake rhythm
The sleep-wake rhythm is strongly controlled by light. The retina sends signals to the pineal gland in the brains to make the sleeping hormone melatonin when the light intensity decreases. It is known that a decreasing light perception can disturb this system. However, RP patients regularly mention sleeping problems and fatigue in an early stage already, independent of the seriousness of their visual impairment.

Fatigue
Usher Syndrome is also called ‘fragmentary observation’: both hearing and seeing are done in small fragments that subsequently have to be made into a whole. This is hard work for the brain. Therefore it is not surprising that many people suffering from Usher Syndrome are tired quickly and have a higher chance of getting overstimulated and loosing energy. The energy-absorbing process of continuously compensating the one sense with the other leads to fatigue.

Sleep enables the body to recover, such as replenish energy sources, adjust muscles and other cells and reduce stress. While sleeping, we also process all we have seen, heard and done during the day. The brains are stimulated all day and have to process all this information.

Quality of sleep
The quality of sleep depends on the deep sleep, the so-called REM sleep. This makes the body recover. A good night’s rest means quickly falling asleep and sleeping all night through. In case of insufficient REM sleep, you do not feel refreshed well when you have to get up. Non-optimal REM sleep over a longer period will lead to chronic fatigue with a risk of other physical complaints.

Not tired at all
At the end of the day, when it begins to grow dark and the lights are switched off in the zebrafish lab, the last round is made in the lab. Many fishes have become less active already and are hanging around in the water without moving. They also do not react when Erwin van Wijk is walking along the aquariums.

When visiting the zebrafish lab in the evenings, he tries to make as little noise as possible and the lights are dimmed. When he switches off the lights to close the lab and leaves the lab, some groups of zebrafishes stay awake and active. The zebrafishes with mutations in the USH2A gene are not going to sleep, they are not yet tired at all.

Expression in the pineal gland
The most frequently mutated RP genes (USH2A and EYS) are both highly expressed in the pineal gland of various animal models. Researchers show that the proteins of these genes involved are not only present in large quantities in the eyes and ears, but in the pineal gland as well. This may mean that the proteins concerned also play an important role in the pineal gland and in the regulation of the day and night rhythm.

Zebrafishes with mutations in the USH2A gene show a deviating sleep-wake rhythm, while these test animals hardly show any retina degeneration.
Based on these findings researchers suspect that the sleeping problems of these groups of patients are the cause of the disorder and not just the consequence of a reduced visual function.

Comprehend
A treatment for sleep-related complaints with people who have mutations in the USH2A and EYS genes, may substantially improve their quality of life. In this project clinical and fundamental research are combined in order to comprehend these problems. The common results of these two research lines may give some tools to improve the care of patients suffering from RP and Usher Syndrome together with ophthalmologists and sleep experts.

Various research institutes are involved in this project: the Radboudumc under the leadership of Erwin van Wijk, Slaap/Waakcentrum SEIN, Hospital Gelderse Vallei, Radboud University and the Donders Institute.

This four-year study will start this summer and the costs are estimated to be € 285.000,=. Stichting Ushersyndroom (Dutch Usher Syndrome Foundation) makes a contribution of € 125.000 with co-financing by the Dutch Dr. Vaillantfonds. Other funds that have contributed are: LSBS, ANVVB, Support Fund UitZicht (Beheer ’t Schild), the Gelderse Blindenstichting, FNWI/IWWR.

Onderzoekers en patiënten met Ushersyndroom overhandigen een cheuq ter warde van €285.000 voor het slaaponderzoek. Ze staan voor de kast met aquaria met zebravissen.

In the zebrafish lab Radboudumc. From left to right: Erik de Vrieze, Thijs Bouwman, Niels Bouwman, Ivonne Bressers. Jessie Hendricks, Devran Braam, Erwin van Wijk and Juriaan Metz.

Stichting Ushersyndroom [Dutch Usher Syndrome Foundation] Awards Grant to Usher III Initiative to Support Patient Database

19 July 2021

A global Usher III patient (USH3) database for future clinical trials

This year, the North-American foundation Usher III Initiative has taken preliminary steps towards collecting the information necessary to establish the first comprehensive global USH3 patient database. This resource will be critical to the design of future clinical trials and will significantly advance knowledge of the disease and its impact on patients. Dr Ronald Pennings from the Radboudumc is one of several physicians and experts around the world collaborating with the Initiative in this effort.

Cindy Elden and her father Richard, co-founders of the Usher III Initiative

Usher III Initiative
Usher III Initiative is a US based non-profit organization dedicated to developing a treatment for Usher Syndrome type 3 a rare genetic disorder characterized by progressive loss of both hearing and vision. It is estimated that over 400.000 people around the world suffer from Usher Syndrome, of which type 1 and 2 are the most common types. Only 2 percent of the patient population suffers from USH3, which is most prevalent among Finnish and Ashkenazi Jewish populations.

Preliminary clinical trial design
The Initiative has developed BF844, a new therapeutic candidate for the treatment of USH3.
The Initiative is completing pre-clinical toxicity studies to demonstrate that BF844 can be safely administered in humans in compliance with US Food and Drug Administration (FDA) regulations. They expect that clinical trials will commence in 2022. These studies are supported by a $1M grant the Initiative recently received from the Foundation Fighting Blindness.

Consortium
Together with the Usher III Initiative and a global consortium of physicians, Dr Ronald Pennings will participate in the establishment of the USH III Patient Database. “Aggregating comprehensive genetic and clinical data on USH3 patients is necessary to determine inclusion and eligibility criteria as well as the most effective design for clinical trials.”, commented Cindy Elden, President and Co-Founder of the Initiative and an USH3 patient.

Collaboration
Stichting Ushersyndroom [Dutch Usher Syndrome Foundation] has committed to making a $ 10,000 contribution to support this effort. This grant aligns with the mission of the Stichting Ushersyndroom, to find treatments for all types of Usher syndrome.

“Usher Syndrome is a serious disorder, which has a deep impact on the lives of patients and their social environments. We want to stop this disorder from the bottom of our hearts”, commented Ivonne Bressers, chairwoman and co-founder of the Stichting Ushersyndroom and USH2 patient. “We are happy to be able to participate in an international study for USH3-patients.”

Cindy Elden: “On behalf of the Usher III initiative, but also personally, I find it very inspiring to meet other people with Usher syndrome who would like to be active in the search for a treatment for all of us!”

The consortium will not be collecting any information that identifies specific patients, so the database cannot be used to recruit participants for clinical trials. Patients interested in participating in future clinical trials are encouraged to register with My Retina Tracker and the Ush Trust. Once trial investigators and sites have been identified, treating physicians may also recommend individual patients to the appropriate officials. Pursuant to global patient privacy protections, the Usher III Initiative cannot receive confidential patient data. If patients, family or friends want to connect with the Usher III Initiative for more information, they are invited to email info@usheriii.org or connect on Facebook.
Dutch patients can contact Stichting Ushersyndroom for more information on Usher syndrome and contact with fellow sufferers.
For medical advice on Usher syndrome, information on (preclinical) developments of therapeutic approaches to treat Usher syndrome or additional (genetic) diagnostics, they can reach out to the expertise center of the Radboudumc via ushersyndroom@radboudumc.nl.

Jack Weeda, draagt een bril en witte doktersjas

A view on the RUSH2a study

7 May 2021

In the international RUSH2a study of Jacque Duncan MD, University of California, San Francisco, 120 patients spread over nine different clinics are monitored for four years. This study includes only syndromic (USH2a) and non-syndromic patients with mutations in the USH2a gene (nsRP).

The study “Rate of progression of USHer Syndrome” is done at about 20 clinical centres around the world, including the Radboudmc in Nijmegen, the Netherlands and is financed by the Foundation Fighting Blindness. Researcher Jack Weeda is working as a research optometrist in the Radboudumc on the RUSH2a study. He takes us with him in his work and gives us a view of the study.

The RUSH2a study and the CRUSH study
Recently, we already could read about the current state of affairs of the CRUSH study. Read here.
Also thanks to the Medical Advisory Council of the Stichting Ushersyndroom, the content of the CRUSH study has been aligned to RUSH2a study. This means that the research questions and the study measurements are largely similar, allowing the results of RUSH2a study to be compared with those of the CRUSH study. This comparison of the results is of scientific value.

The differences between both studies are mainly in the working area of the ENT department. For instance, the CRUSH study includes more audiological research and a one-off balance test is done. This study is conducted under the leadership of Dr Ronald Pennings. The RUSH2a study includes a one-off smelling test. The RUSH2a is conducted under the leadership of Dr Carel Hoyng. 40 patients are participating in the CRUSH study, while the RUSH2a study has about 120 international participants, nine of which are Dutch.

Here read about the similarities and the differences between the RUSH2a and the CRUSH studies.

Jack Weeda, research optometrist at the Radboudumc Nijmegen, the Netherlands

Curious patients group
Jack Weeda is research optometrist at the ophthalmology department of the Radboudumc in Nijmegen. Since 2012 he has mainly worked for all scientific studies done at the department through the Trial centre of Prof Hoyng. In 2018, Jack Weeda took up the coordination of the RUSH2a study and a year later the ophthalmology part of the CRUSH study as well. In the past few years, Jack Weeda has seen about 60 Ushers and he still sees many of them on an annual basis.

Jack Weeda: “By now, I have got to know the patients group as a curious, positively critical, well-organised and really active patients group. I regularly see participants of the study I know appear in various ways in the media and thanks to one participant I almost even made my first appearance on television.”

The first results
The RUSH2a study started about a year before the start of the CRUSH study and by now the first results appear. For instance, an article was recently published about the ophthalmological and otological differences between people suffering from Usher Syndrome and people suffering from autosomal recessive RP (AR-RP) or non-syndromic RP (nsRP). Patients suffering from AR-RP do have mutations in the USH2a gene, but there is no or hardly any loss of hearing. The first findings have shown that patients with Usher Syndrome have more severe loss of field of vision than patients with nsRP do. Read more: https://pubmed.ncbi.nlm.nih.gov/32446738/

From the RUSH2a study an article was published about the FST study, a relatively new study that is conducted in the CRUSH and RUSH2a studies. In this FST study light flashes in three colours, being red, blue and white, are offered and of each colour it is determined which intensity of the flash is just perceived. The values resulting from this study appear to be a good indicator of the seriousness and the duration of retinitis pigmentosa. Possibly, these values can also be used to measure the effectiveness of any future therapy, but this needs further research. For the researchers it is interesting to see whether comparable results can be measured using the data from the CRUSH study. The researchers will soon start working on this. Read this article: https://pubmed.ncbi.nlm.nih.gov/33133772/

Jack Weeda hopes that together with the participating patients he will be able to make more minor and perhaps even major discoveries in both studies and in this way further solve the Usher mystery.

How are things going with the ‘minigenes USH2c’ study?

19 April 2021

By now, the USH2c minigenes study was started almost a year ago. A four-year study which was made possible by co-financing of the Stichting Ushersyndroom, CUREUsher and LSBS. Thanks to many contributors this study was started early in the year 2020 in the research group of Erwin van Wijk, in the Radboudumc. Merel Stemerdink is working as a doctoral candidate on the development of a minigene therapy for USH2c. In this news report, Merel tells more about the progress that she has been able to make with respect to the study during the past year!

Merel in the aquarium holding the tank in which the USH2c zebrafishes are swimming.

The minigenes
USH2c is caused by mutations in the USH2c gene (ADGRV1) and these faults in the gene result in progressive hereditary deafblindness. In the eye these faults make the retina slowly die. The objective of the project is to develop a minigene therapy specifically for treating this retina degeneration.

What makes the development of a therapy a challenge is that the ADGRV1 gene is really big, so big that it cannot be packed in the ‘lorry’ (‘viral vector) that is to deliver a new, healthy copy of the gene at the correct place in the retina. This is the reason why we are making an artificial short version of the ADGRV1 gene. These minigenes will be small enough to fit in a ‘viral vector’, but at the same time the minigenes have to function well enough to make good the negative effect of the mutations in the ADGRV1 gene.

Based on various bioinformatics analyses we have developed four ADGRV1 minigenes. These minigenes contain the most important pieces of the healthy ADGRV1 gene. In the past year, we managed to isolate all these individual pieces of ADGRV1 and I will start assembling these parts and so eventually make the minigenes in the coming months. However, this obviously is not all: after this we will study whether these minigenes are actually able to take over the function of the mutant ADGRV1 gene.

Zebrafishes with USH2c
In order to test the therapeutic effect of minigenes, we made an USH2c zebrafish last year. Zebrafishes also have the ADGRV1 gene and we see with healthy zebrafishes that ADGRV1 is expressed in the retina, just as with humans. By means of CRISPR/Cas-9 technology, we deliberately made small faults in the ADGRV1 gene of zebrafishes so as to simulate the disease in the fish. Last month was really exciting, as we started the first experiments to see of the faults made in the gene really prevent the ADGRV1 protein from being produced in the eyes of the USH2c zebrafishes and this appeared to be the case indeed! In the coming year, we will do additional research in order to get a complete picture of the visual function of this USH2c zebrafish. This is important because this will be the basis of the testing of the minigenes in the USH2c zebrafishes so as to allow us to see if and to what extent the minigenes are able to recover the functioning of the retina.

This means that the first important steps were taken in the past year: the minigenes have been developed and the first results indicate that we have developed a zebrafish model suitable for testing the minigenes!

Do you have any questions about the study further to this news report? You can contact Merel via the mail.

Also read:

Positive results of QR-421a Phase 1/2 Clinical Trial for Usher Syndrome and non-syndromic Retinitis Pigmentosa

24 March 2021

ProQR has published positive results from its Phase 1/2 Stellar trial of QR-421a, an investigational RNA therapy for the treatment of Usher syndrome and retinitis pigmentosa (RP) due to mutation(s) in exon 13 of the USH2A gene.

Stellar study
The Stellar study is a first-in-human clinical trial of the medicine QR-421a. The Phase 1/2 study includes adults that experience different levels of vision loss due to mutation(s) in exon 13 of the USH2A gene. This trial aims to study the safetly profile and efficacy of QR-421a.

QR-421a is an investigational RNA therapy designed to skip exon 13 in the RNA with the aim to stop vision loss.

A total of 20 clinical trial participants took part in the Stellar study. The trial design consisted of four study groups of which three groups received QR-421a at three different dose levels. A fourth group received sham treatment, where an intravitreal injection is mimicked but no injection or study drug is given. For each participant one eye was treated with a single injection of QR-421a or sham, and the fellow untreated eye was a control.

Summary

QR-421a was observed to be well tolerated with no serious adverse events reported.
QR-421a also demonstrated benefit in multiple measures of vision, including best corrected visual activity (BCVA), static perimetry, and retinal imaging (OCT).

Next steps
Based on the safety profile and early evidence of efficacy observed to date, ProQR plans to conduct two final stage/pivotal Phase 2/3 clinical trials.

The two-final stage/pivotal Phase 2/3 clinical trials, named: Sirius and Celeste, will study two different patient populations.
The Sirius study is a Phase 2/3 trial that will focus on advanced clinical trial participants with BCVA of equal or worse than 20/40. The preliminary design for Sirius is a doublemasked, randomized, controlled, 24-month, multiple-dose study.
In parallel to Sirius, the Celeste study is a Phase 2/3 trial focusing on early-moderate clinical trial participants with BCVA of better than 20/40. The preliminary design for Celeste is a double-masked, randomized, controlled, 24-month, multiple-dose study.

This study is based on the research and findings of Dr. Erwin van Wijk at the Radboudumc

Report CRUSH study

10 March 2021

CRUSH: The natural history study

An interim report

The CRUSH study is a study done at the Radboud UMC into the natural development of progression with Usher Syndrome type 2a and USH2A-associated, non-syndromic retinitis pigmentosa (nsRP). CRUSH stands for Characterizing Rate of progression in USHer syndrome. This study is financed by Stichting Ushersyndroom and the co-financing of the Dutch Dr. Vaillantfonds and the Oogfonds.

Usher Syndrome and non-syndromic retinitis pigmentosa (nsRP)
With Usher Syndrome changes in the DNA (the hereditary material) affect the functioning of the cells in the ear and the retina of the eye, which leads to hardness of hearing and possibly balance problems and, additionally, deterioration of the eyesight in the course of time (retinitis pigmentosa). There are three types of Usher Syndrome of which Usher Syndrome type 2 is the most common type with over 50% of the cases. About 80% of the cases of Usher Syndrome type 2 involves type 2a, which is caused by mutations in the USH2A gene. Patients suffering from USH2A nsRP have the same kind of changes in the DNA, but they are not or less hard of hearing.

CRUSH study
This study examines the deterioration of the eyesight, balance and hearing of 40 patients suffering from Usher Syndrome type 2a and USH2A-associated nsRP. In view of the major individual differences in the level of deterioration of hearing and eyesight between people suffering from Usher Syndrome, we hope that the results of this study will provide more insight into the development of these disorders. Although there is no treatment yet at this moment, the results of this study will be indispensable for determining the effect of future treatments.

Current state of affairs
The participants of the CRUSH study are annually tested. In a four-year period they are subjected to tests concerning hearing, eyesight and balance by means of various questionnaires. Because of COVID-19, we have had some trouble scheduling the second visits with respect to the study. By now, all measurements of the first two years have been done and, despite COVID 19, we are steadily proceeding towards the end.

People involved
Various people are involved in the study and we are pleased to introduce them to you:

Dr. Ronald Pennings

Dr Ronald Pennings, ENT specialist and head researcher
“My name is Ronald Pennings and as head researcher I am responsible for the CRUSH study, which means that I coordinate this study. This includes determining which people are subjected to which studies, adjusting protocols when a pandemic comes along, keeping an eye on finances, maintaining contact with the Usher Syndrome Foundation about the progress of the study and a lot of other things. The CRUSH study is really important, as with this study we can collect a lot more details about the deterioration of eyesight and hearing with people having mutations in the USH2A gene. These types of studies are essential for the preparation of future gene therapies. In short, with this study we are working together towards a treatment for Usher Syndrome.”

Erwin van Wijk in zijn lab en kijkt recht in de camera met een lach

Dr. Erwin van Wyk

Dr Erwin van Wijk, head researcher
“My name is Erwin van Wijk. As co-project leader I am involved in the set-up of the study and in selecting the participating patients who based on their genetic diagnose match well with the present developments in the area of gene therapies within my research group.”

Carel Hoyng kijkt serieus in de camera, hij draagt overhemd, colbert met een stropdas

Prof. dr. Carel Hoyng

Prof Dr Carel Hoyng: ophthalmologist and head researcher
“My name is Carel Hoyng, I am professor in ophthalmology and head of the Clinical Research Centre Ophthalmology. I am the head researcher of the ophthalmology part of the CRUSH study. I know most of the participants in the CRUSH study from my consultations. Unfortunately, I cannot often have a talk with the participants during their visits in connection with the study, but I know that Jack Weeda and the other researchers will take very good care of them. We surely have consultations about the participants on a regular basis.

The CRUSH study is a very important study for us, particularly in view of future treatments and other developments. We expect that the next few years will be exciting years for ophthalmology and people suffering from hereditary retina disorders.”

Chris Lanting, kijkt met een open blik in de camera

Dr. Cris Lanting

Dr Cris Lanting, clinical physicist and audiologist
“My name is Cris Lanting and I am involved in the CRUSH study as a clinical physicist and audiologist. It is my job to support and supervise the audiological measurements and data analyses with respect to the various audio-vestibular results. Apart from this, I can give advice about the personal outcomes and revalidation options.”

Jack Weeda

Jack Weeda, research optometrist
“My name is Jack Weeda and I started working at the Radboud UMC in the year 2006. I have worked as a research optometrist at the Clinical Research Centre Ophthalmology of professor Hoyng since the year 2012. In connection with the CRUSH study, all participants come to me for their screenings and follow-up visits. I examine the participants, for instance to determine their visual acuity and fields of vision and to make photos. Some participants recently came here for their third visits already and we start to know each other a bit. For me this is one of the nice aspects of this work, as contacts are more superficial at the clinic.

I hope that the results of the CRUSH study will make a contribution to gaining even more insight into Usher Syndrome and, of course, that we will soon be able to use them in treatment studies.”

Een vrolijk kijkende vrouw staat voor een muur met een kunstwerk en draagt haar verplegersjas

Addy Loeffen-van Dijk

Addy Loeffen-van Dijk, nurse
“Hi, my name is Addy Loeffen. I have worked at the ENT clinic as a nurse since May 2019. I temporarily take over the job of Lieke Knorth. This makes me responsible for various administrative tasks, but I also have direct contacts with our participants. I really like being able to add my share to this study.”

Een vrouw met blonde bos haren kijkt je recht aan in de camera

Patricia Gerrits-van Haren

Patricia Gerrits-van Haren, secretary
“My name is Patricia Gerrits van Haren, secretary patient care ENT. I have taken over the scheduling of the CRUSH study since mid-January of this year. I make sure that patients are invited and that all people involved are informed about this. In order to make this schedule run smoothly, I am in close contact with Jack Weeda, Addy Loeffen and Sybren Robijn.”

Sybren Robijn

Sybren Robijn, research physician ENT
“My name is Sybren Robijn and I have as a doctoral candidate of Dr Pennings been involved in the CRUSH study since 2018. I have several tasks within the study. For example, I am responsible for various administrative matters, but I also often have direct contacts with our participants. In the course of the year, I will in full confidence pass on my tasks to my colleague Hedwig Velde. The thing that I will remember most from this study is the privilege of being given the chance to work with such highly motivated and zealous patients.”

Hedwig Velde

Hedwig Velde, research physician ENT
“My name is Hedwig Velde and I recently started as a doctoral candidate of Dr Pennings. I will take over the tasks of Sybren Robijn within the CRUSH study. I am looking forward to making a contribution to this link in the process towards a treatment for this patients group.”

The RUSH2a and the CRUSH studies

Nobel lecture CRISPR/Cas9

2 February 2021

with a digital tour of the fish lab

The Radboud PUC of Science has in cooperation with Radboudumc organised an on-line lecture about CRISPR/Cas9. This lecture was given on 10 December 2020, the day that the Nobel prizes were presented. Researchers of the Ear Nose Throat (ENT) department of the Radboudumc explain the CRISPR/Cas9 technique in the light of their research into Usher Syndrome.

Poof!
The Nobel Prize in Chemistry was presented this year to the discoverers of the CRISPR/Cas9 technique, Emmanuelle Charpentier and Jennifer Doudna. The prize for the technique had been pending for some years already, because Crispr/Cas has been acknowledged as revolutionary examination technique for a long time already. And suddenly – poof! – we can change everything genetically’, is how Doudna describes the importance of this technique.

Previously, scientists always had to make genetic changes in organisms ‘on the off-chance’, for example by shooting at cells with radiation. However, Crispr/Cas works with an enzyme that searches the DNA for exactly the spot that scientists have indicated beforehand. This makes it possible to very precisely make changes in genetic material.

Development of genetic treatment
Researchers Erwin van Wijk and Erik de Vrieze of the Ear Nose Throat (ENT) department of the Radboudumc explain the CRISPR/Cas9 technique in the light of their research into Usher Syndrome.

Since the discovery of CRISPR/Cas9, they have applied this technology many times to make zebrafish models for Usher Syndrome, a rare hereditary disorder which causes people to be born hard of hearing and makes them slowly loose their eyesight as well. These genetically modified zebrafishes and the easy way in which they can be produced thanks to the discovery of Emmanuelle Charpentier and Jennifer Doudna, are the basis of the development of new genetic treatments for Usher Syndrome.

Tour of the zebrafish lab
Following the lecture, both researchers will give a virtual tour of the zebrafish facility of the Faculty of Mathematics, Natural Sciences and Informatics, and show how the CRISPR/Cas9 technique is applied in practice.

The subtitling has been automatically generated and is therefore not always correct.

Do you want to read more?
Research into Usher Syndrome on the Usher Syndrome Knowledge Portal
The research projects for which the Usher Syndrome Foundation collects donations and funds
In de Volkskrant, a Dutch daily paper: Nobelprijs scheikunde voor techniek waarmee we – poef! – opeens alles genetisch kunnen veranderen [Nobel Prize in Chemistry for the technique with which we – poof! – can suddenly genetically change everything].

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Worldwide research study for patients with USH 1c

28 January 2021

If you have Usher Syndrome Type 1C, your participation is critical to developing treatments. History studies are an essential part of bringing treatments to patients. As researchers get closer to developing therapies that will help slow, stop or reverse the degeneration of sight caused by Usher Syndrome, and specifically USH 1C, it is important to understand the history of progression of the disease in patients in order to confirm the effectiveness of those treatments.

There are 3 natural history studies that are ongoing for individuals with USH1C. The entry level study is open to all ages and does not require travel. Participation involves questionnaires and requesting medical records that can be done over the phone, via email, and/or video conferencing.

The other 2 studies – one for vision and one for balance – require travel to the US or Canada to see the doctors that specialize in Usher syndrome.

Usher 2020 Foundation are supporting therapies that include gene augmentation, drug therapies, and stem cell therapies. To move these treatments to clinical trials, they will need a thorough understanding of Usher Syndrome patients, and for some of these treatments, specifically USH 1C patients, the worldwide prevalence, and the clinical history of the disease.

Do you want to help and participate in this study? Then read the letters below and contact Dr. Jennifer Lentz.

Read more about the history study for USH 1c.
Read the letter here to participate.

Portret van oogarts Ingeborg van den Born

Is a treatment for USH 1B in sight?

6 January 2021

story of ophthalmologist Dr. Ingeborg van den Born

A natural development study for people diagnosed for Usher Syndrome type 1B was started already some time ago. This study is conducted in preparation to the clinical treatment trial (the project as a whole is called UshTher). How is this development study going and can on the basis of this study something be said already about the development of the disorder with people having mutations in the MYO7A gene? When will the UshTher clinical trial start and who will benefit from this gene therapy? Ingeborg van den Born, ophthalmologist and specialist in retina pigmentosa working in the Oogziekenhuis in Rotterdam, the Netherlands, tells about this and answers our questions.

How can someone find out exactly which disorder he or she is suffering from and in which Usher gene the changes (mutations) are found?
It is to be determined by means of an extensive examination of the eyes and ears whether (serious) loss of hearing and retinitis pigmentosa (retina degeneration – RP) are involved. A DNA test is required for making the correct diagnosis. As a matter of fact, more syndromes are known (although very rare) that also affect these two senses.
For a DNA test a small vial of blood is taken and a special laboratory will examine this for changes that can explain the loss of hearing and eyesight. Sometimes a vial of blood from one of the parents is needed as well to see if the changes are coming from one parent or have been inherited from both parents.

Why is it so important to have a DNA test done?
Usher Syndrome is rare, which makes the chance of a child suffering from Usher very small. For each form of congenital loss of hearing it is advised to conduct a genetic test to find the cause of this.

This test can confirm Usher Syndrome, even if there are no problems with the eyesight yet. Promising therapies are being developed, but in order to be eligible to these, it is necessary to know what is genetically going on. Therefore it is really important to have this examined. The first steps towards developing a gene therapy for USH 1B have been taken.

THE DEVELOPMENT OF GENE THERAPY
Gene therapy development is complicated and costs a lot of time and money. For instance, it took many years to develop the gene therapy product Luxturna®, which can now be used in the USA and Europe to treat patients suffering from retinitis pigmentosa (RP) caused by mutations in the RPE65 gene (Leber congenital amaurosis) in an early stage. Here the healthy gene is surgically placed below the retina. We hope this medicine will be available for Dutch patients in a couple of months. Currently, gene therapy studies are running for other RP-genes as well, but not for genes causing a type of Usher Syndrome.

What is gene therapy and do you have any experience with this?
The objective of gene therapy is to cure a hereditary disease or to mitigate the complaints. There are various possibilities for this. For instance, a healthy gene can be added to the own DNA from outside. The healthy gene is inserted into the cell using a weakened virus, which is called a vector.
The AAV virus is suitable for bringing DNA into the cell, but this can only contain small pieces of DNA. Professor Alberto Auricchio of the TIGEM Institute in Naples has worked for many years on a technique that can bring the MYO7A in two pieces into the cell and there put the pieces together again (double AAV vector). If this turns out to be successful, this may be really promising for a number of other genes.

At this moment, this technique is further developed and if the results are fine, we hope it can also be tested on people in a phase 1-2 study. Presently, it is too early to tell whether this can already be done in 2021.

In Florida, USA, Shannon Boy started a study into the development of a gene therapy for USH 1B using a double AAV vector with the help of a large subsidy from Fighting Blindness.
This study is needs testing on a large animal model before the therapy can be tested for effectiveness and safety in a trial on test persons.

What are the differences between these two studies?
I do not know the details of the study of Dr Sannon Boye, but the technique seems to be similar to that of Professor Auricchio. It is a good thing when several laboratories are focusing on the same disease and on the same technique, for this will eventually lead to a higher quality and probably accelerate the process. At this moment, it is impossible to predict whether both studies will eventually result in a properly working medicine.

NATURAL DEVELOPMENT STUDY
In 2019, a natural development study on people suffering from USH 1B was started in Naples, Madrid and the Oogziekenhuis in Rotterdam, the Netherlands. This study is done in preparation to the gene therapy trial. In this study the development and any deterioration of the eyesight is monitored for a period of two years by means of three detailed eye tests. The information gained from this study will eventually be very important to be able to compare the effect of gene therapy with ‘doing nothing’ over some period of time. Many patients yearly go to their ophthalmologists for a check and there they undergo a number of eye tests, such as a field of vision test.

What are the differences between the natural development study and an annual check?
A study visit often includes more tests than the annual check by your own ophthalmologist. For instance, in this study two types of field of vision tests are done instead of one and each year photos and a scan are made of the retina. Additionally, these tests are to be done following a fixed procedure, making the data gained from the tests conducted in Naples, Madrid and Rotterdam easy to compare.

Have you been able to include sufficient patients in this study?
In view of collecting proper data about the natural development of this type of RP, it was agreed to include 50 patients spread over the three countries. Usher 1B is a very rare disorder and therefore we are happy to have eight Dutch patients participating. Some of them will soon come for their third and last visits.

It is still possible to participate in this study. Of course, this will take extra time and effort to go to the Oogziekenhuis in Rotterdam for a full day, but expenses and the like are compensated. The study includes a total of three study visits always with one year in between.

Patients who want to participate in this natural development study can contact me (Dr Ingeborgh van den Born) or Ms Marja Scheeres (tel.: 010-4023437, e-mail: roi@oogziekenhuis.nl).

THE PATH TO A TREATMENT
The Usher Syndrome Foundation wants to stimulate scientific research into the unravelling of and treatment for Usher Syndrome. Our mission is to have a treatment for Usher Syndrome in the year 2025. We want this for all patients, so for patients diagnosed for USH 1B as well. In the laboratory of the Radboud UMC research is mainly done into USH 1F, 2A and 2C and probably soon 1D as well. At this moment, no research is done into a treatment for USH 1B in the Netherlands.

Can patients who are participating in the natural development study also participate in the UshTher clinical trial when this will be started?
We have highly detailed information about the eyes of the people participating in the natural development study and we assume that some of them will be eligible to participation in the treatment study. Participation in treatment studies is often subject to strict criteria.

Can Dutch patients who have not participated in the natural development study for USH 1B be eligible for participation in the UshTher clinical trial?
This will probably be possible, provided that these people meet the inclusion criteria.

Is the UshTher gene therapy promising for all patients suffering from USH 1B?
The objective of gene therapy is to make the new, healthy gene improve the functioning of the affected retina cells and so slow down the process of the disease. This implies that this therapy can only work if there still is a minimum number of functioning retina cells. Consequently, patients who are blind and have no or hardly any functioning cells left, will not benefit from this type of therapy.

Are there any hopeful developments for older patients suffering from USH 1B who have already lost many light-sensitive photoreceptors?
As said above, unfortunately gene therapy will not help everyone and this means that research into other types of treatment, such as stem cells and, for instance, a light-sensitive chip is just as important.

What do you think is the quickest and most effective path to a treatment for Dutch patients suffering from USH 1B?
I think an important step has already been taken, being the cooperation from the Netherlands with the institute of Prof Auricchio. It is also very important that the Usher Syndrome Foundation itself also actively keeps in contact with him and the TIGEM institute. Eventually, it is all about cooperation between patients (associations), scientists and physicians.

Additionally, we are working with rare disorders and therefore registration of patients is essential too. Besides, as you have also mentioned yourself, DNA tests are important to gain a good overview of the various mutations and genes of Dutch patients. By participating in the Ushther project we hope to make a contribution to the development of a treatment for Usher 1B.

The Usher Syndrome Knowledge Portal provides additional background information about, among other things: