New research: testing gene therapy

With extra large vectors on mini retinas 

Prof. Dr. Jan Wijnholds and promovendus Rossella Valenzano

Stichting Ushersyndroom [ Dutch Usher Syndrome Foundation] is funding the majority of the new research “Genetic drugs preventing blindness due to loss of USH2A function” which has recently started. The research team led by Jan Wijnholds, who works at the Leiden University Medical Center (LUMC), will test two treatment methods on ‘mini-retinas’ made from human stem cells. The researchers want to determine if the light sensitive cells in the mini-retinas can be activated by the light-sensitive cells after administration of gene therapy. Can the USH2a gene in the retina be replaced or is it also possible to repair the defective gene at the same time?

 

Gene therapy looks very promising and developments in this area are moving very quickly. It is a treatment method for hereditary disorders where healthy copies of genes, with errors (= mutations) have been found, in patients are replaced or repaired in the cells of an organ.

Research shows that after gene therapy, the retina can make normal connections with other cells, which can lead to a light response again. After delivering a healthy copy of the gene or repairing the gene, the retina makes the proteins it needs to see properly. With gene therapy you treat the entire gene so that it does not matter what kind of mutations you have.

Means of transport for the large USH2A gene
In gene therapy, a healthy copy of the gene is delivered to a specific location in the retina of the eye using a molecular truck, or a means of transport. This is usually done using a virus that has first been rendered harmless so that a vector remains, a kind of ‘packaging’. The most commonly used vector is the adeno-associated viral vector (AAV).
However, there is a problem. The USH2A gene is much too large for a normal AAV vector, so another alternative must be sought to deliver the large healthy copy of the USH2A gene into a patient’s eye.

Large trucks as vector
Previously, in collaboration with Dr Manuel A.F.V Gonçalves (Department of Chemical Cell Biology), the researchers in Jan Wijnholds’ lab at the LUMC, have developed new vectors into which very large genes fit, the so-called High-Capacity Adenoviral Vectors (HcAdV).
The large USH2A gene fits completely into this vector. As a result, this vector can serve as a molecular truck and can be used as a vector for gene therapy.

Mini retinas
In the research project “Genetic drugs preventing blindness due to USH2A function”, human mutant USH2A iPSC retinal organoids are used to test several new high-DNA capacity gene therapy vectors. These USH2A ‘organoids’ are ‘mini-retinas’ made from cell lines derived from USH2A patients.

These ‘mini-retinas’ are used because they allow to study the effect of loss of USH2A protein (Usherin) in the cilium of the photoreceptor. The cilium transports the essential proteins in the retina. These ‘organoids’, made from patient cell lines, could also be used in the future to test gene therapy for retinal disorders due to mutations in other Usher genes.

Replace gene and/or edit gene
In the research project of Jan Wijnholds, two types of gene therapy are being tested on the ‘mini retinas’. The first type of therapy candidate is an HcAdV vector containing a healthy copy of the USH2A gene that, after delivery, replaces the defective USH2A gene in the retina. We call this gene replacement therapy. The healthy copy of the gene must activate the gene in the photoreceptors of the ‘mini retinas’, the ‘organoids’.

The second type of therapy candidate is an HcAdV vector containing ‘a repair kit’ and, after delivery into the retina, repairs the defective USH2A gene in the eye itself. This is also known as gene editing therapy, CRISPR-Cas9 is used for this. CRISPR are pieces of DNA with codes that can detect the defective gene. The Cas9 is an enzyme that ‘cuts’ out the defective gene and ‘sticks’ a new healthy piece of DNA in it.

Both the CRISPR and Cas9 are transported in a cassette and delivered into the retina by an HcAdV vector. The USH2A gene is edited and repaired at its destination.

Promises for large groups of patients
Both technologies for genetherapeutic application are not dependent on the type of mutations in the USH2A gene. If the USH2A gene is found to be expressed in the light-sensitive cells of the mini-retinas thanks to one or both techniques, the treatment may become available to all patients with USH2A. When more money becomes available for research for these two techniques , the research team of Jan Wijnholds could also test these for other Usher genes, and could possibly also be a solution for patients with mutations in Usher genes other than USH2A.

The mission of Stichting Ushersyndroom
Annouk van Nunen, secretary of Stichting Ushersyndroom, is very pleased with the start of this research. Stichting Ushersyndroom’s mission is “In 2025, Usher Syndrome will be treatable!”.Annouk: “We want all patients to have a realistic prospect in 2025 of a treatment that can slow down, stop or even restore the further deterioration of their hearing and vision”.

The big challenge for scientists is to explore multiple research routes in order to eventually develop a treatment for all people with Usher syndrome. Stichting Ushersyndroom therefore stimulates as many lines of research as possible, so that people with Usher Syndrome can make their dreams come true. “It is fantastic that so much research is being done into Usher Syndrome in the Netherlands. This type of research is hopeful for all USH2A patients. But if it works, it could also be a solution for patients with mutations in other Usher genes, Annouk van Nunen.

This four-year study, which started in November, has been budgeted at € 250.000. Stichting Ushersyndroom is contributing € 85.000 to this research. Other funds that have contributed are: Rotterdamse Stichting Blindenbelangen, LSBS, Stichting Blindenhulp and a partial contribution from the LUMC Ophthalmology Departmen

Minigenes USH2A: General status

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.

Read also:

Stichting Ushersyndroom good cause Zandvoort Circuit Run

The popular Zandvoort Circuit Run will be held again on Sunday 27 March 2022. As a runner you must have run this unique race once in your life. The Zandvoort Circuit Run is known as the most varied track in the Netherlands. This year Stichting Ushersyndroom (the Dutch Usher Syndrome Foundation) was selected the official good cause.

© Zandvoort Circuit

Sprint from the pit lane into the direction of the hills and the compound banking. All distances run a full lap on the circuit. After this the long-distance track goes into the direction of the beach, the dunes and the village. The start and finish are on the Formula 1 circuit of Zandvoort.

Start and finish on the Formula 1 circuit!
You start and finish on the circuit and run a few kilometres on the beach, in the dunes and through the nice coastal village. You can choose between the 10 English Miles (16.1 km), 12 kilometres (competition run) of the 4 km (one lap). There also is the Circuit Run Specials and the Kids Circuit Run for children. Children (between 4 and 12 years old) with a wheeler or RaceRunner can also participate!

It is also possible to participate in the Zandvoort Circuit Business Run with your colleagues. This is a perfect opportunity for team building. Challenge your team to appear at the start of the 13th edition of the Zandvoort Circuit Run on Sunday 27 March.

There will be nice activities for the children around the paddock.

Rotary Club Zandvoort and Stichting Ushersyndroom 
Special attention will be paid to the funding of good causes. The formula in ‘Zandvoort’, which includes the organisation of fund raising for good causes in cooperation with the Rotary Club, is unique.

The organisation hopes to collect donations by means of voluntary contributions from the entrants and by making use of special Rotary teams. The Rotary Club Zandvoort will make known the proceeds some weeks after the Zandvoort Circuit Run.

We are really proud and grateful that the Usher Syndrome Foundation is the good cause of the Zandvoort Circuit Run edition 22.

Heading for the point on the horizon
Whatever track you choose, you can create your own sponsor campaign and ask people to sponsor you for the Usher Syndrome Foundation. The proceeds of the Zandvoort Circuit Run and your sponsor campaign will be used to finance scientific research into a treatment for Usher Syndrome. At this moment, there is no treatment yet that can stop people from becoming both deaf and blind caused by Usher Syndrome, but there is hope! The mission of Stichting Ushersyndroom is ‘There will be a treatment for Usher Syndrome in 2025!’. This is the point on the horizon we are heading for!

Entry and registration

  1. Quickly register for the Zandvoort Circuit Run! You can do this here.
  2. If you run together with your running buddy because you are visually impaired or (deaf) blind? Please send us an e-mail through run4usher@ushersyndroom.nl and you will receive the instructions for how your buddy can register.
  3. Start a sponsor campaign after your registration and raise money for Stichting Ushersyndroom. You can create a campaign here.

Run4Usher team
It will be even more fun to be part of the sociable Run4Usher team and to run in our nice shirt with our mascot USHIE.

After your registration for the Zandvoort Circuit Run, also present yourself for the Run4Usher team through run4usher@ushersyndroom.nl and receive all the practical information you need.

Take action together with us and John Williams and join in the run!

Let’s collect money together to finance research into a treatment. In this way we can stop the process of becoming both deaf and blind caused by Usher Syndrome.

See you on the Formula 1 Circuit on Sunday 27 March!

Look here for additional information about the Zandvoort Circuit Run

Two generations on the big screen

Living with Usher and at the same time wanting to be a role model for others

On the International Usher Awareness Day 2021, the documentary Stilte in de Nacht [Silence in the night] had its premiere on television and after this it was shown through YouTube. This made the documentary accessible for the general public.
Lisanne van Spronsen and Milou op ten Berg, the makers of this documentary, followed Joyce de Ruiter and Nikki de Punder with their cameras for a few months.
Two generations with Usher. Both strong women who hold a positive view of life, who know what they want and who act as role models for their own generations as well. 

Sandra Vijverberg talked with both ladies to hear how they experienced their participation in this documentary.

More than a school project 
Joyce was in particular positively surprised by the professional way of working and passion of Lisanne and Milou and that it turned out to be a lot more than just a ‘school project’. Professional photos were made for the promotion and film poster and Lisanne and Milou started a crowd funding action, which enabled them to make a very nice donation to the Stichting Ushersyndroom (Dutch Usher Syndrome Foundation). The ladies did not limit themselves to making the documentary, but they also made various podcasts for Stilte in de Nacht.
As speaker and author, Joyce is used to sharing her story on stage and in her book. Accepting the presence of the camera near her made her feel vulnerable, but at the same time it was a nice thing to do.
Nikki really liked being part of it. She tells us that she does not talk a lot about Usher and about what it means to her. However, especially the approach of Lisanne and Milou made things feel very safe. “Because they managed to make me feel so comfortable, I dared to honestly answer all questions.”

On the big screen 
The question of how they felt about seeing themselves on the big screen and later on television makes Joyce laugh out loud. Terrible!”, she laughs. It really is very strange to realise that a lot of people who are completely unknown to you know about you.” Nikki thought it was very special. “It always is strange to look at yourself, in particular on a film screen of 50×25 metres!” The documentary had already been shown to the ladies when it was nearly finished, later at  the premiere in the theatre and then again recently on television. Nikki continues: “We watched the television premiere together at the home of Lisanne’s parents. My parents had also come, Joyce was present with her family and, of course, Milou was there as well. This made it feel like a kind of reunion.”

Role model for fellow-sufferers 
The ladies received really a lot of reactions to the documentary. Very nice and positive reactions, but Joyce also received a reaction from someone who has a person suffering from RP in her environment. Joyce: “She told me that his person has so much problems with this, that he or she finds it unbearable to live with the diagnosis. This was really heavy. On the other hand, it confirmed to me how important it is to have role models in fellow-sufferers. Role models who can inspire you, who can support you. Persons who inspire me personally give me a lot of strength every day again. Hopefully Nikki and I can also be that for our fellow-sufferers. To me understanding this is the best thing the documentary has brought me.”

In the spotlights 
Joyce tells us that, despite the fact that this also is a part of her work, it sometimes is quite difficult for her to always put herself in the spotlights again.
Trying to find the spotlights for the Usher Syndrome Foundation is something she does for the good cause: It gives me the confirmation and the strength that we, people suffering from Usher, have to keep shouting from the rooftops what the impact is of this disease and that more money is needed for treatment.”

Inspiring for others
Nikki received a lot of reactions through Insta from friends as well as from people unknown to her. Besides, the documentary resulted in a nice article about her in the newspaper (insert link). This article led to an invitation for the talk show ‘M’ of Margriet van de Linden (insert link) and she also visited Anky van Grunsven. This has resulted in a steady friendship.” She continues: “this is again one of the best things that participating in this documentary has brought me. Apart from this, a lot of people will by now understand why I sometimes cannot follow things, do not hear well or why I sometimes am a bit careful in the dark, for instance. The very best thing is, however, that there are people telling me that I inspire them. This never was my intention, but it certainly is very nice to hear.”

Silence in the night (Stilte in de Nacht)
The documentary Stilte in de Nacht can be watched with Dutch and English subtitling

Spanish film festival 
By now, it has become known that Stilte in de Nacht has been selected for the Spanish film festival Certamen Raras.” This special film festival is about rare diseases and health.

The jury will announce the best documentary on 15 November 2021. Also an audience prize will be presented for which can be voted from the Netherlands as well. Voting for Stilte in de Nacht can be done through via the button below. You can vote for Silence in the night via the button below.

VOTING

Read also:
Colour me blind

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Colour me blind – Usher Awareness Day 2021

Singer-songwriter Jasper Steverlinck sings about Usher syndrome

Singer-songwriter Jasper Steverlinck

Flemish singer-songwriter Jasper Steverlinck released a song in 2018 that he wrote in response to a friend’s personal story. Her son had been diagnosed with Usher syndrome and is slowly becoming deaf and blind. This story grabbed Jasper Steverlinck so much that he wrote the song ‘Colour me blind’. The words ‘Cannot change it / It’s inevitable’ suddenly takes on a completely different meaning.

The song ‘Colour me blind’ was written for Jackson and Jasper Steverlinck added the sensitive song to his hit album “Night Prayers”. ‘Colour me blind’ is tailor-made for everyone who is suffering from Usher Syndrome. The melody enchants and the lyrics will take everyone’s breath away.

We think ‘Colour me blind’ is a beautiful song for Usher Awareness Day 2021!

Usher Awareness Day
Every year on the third Saturday of September, we celebrate ‘Global Usher Awareness Day. On this day, which falls on the same day as the autumn equinox, the sun is directly above the equator and the day and the night have the same length. Following the autumn equinox, there will be less light every day; days get shorter and nights get longer.

The autumn equinox is the ultimate metaphor for the Usher Syndrome, because this experience of seeing increasingly less light is an irreversible process for people suffering from Usher Syndrome. The light-sensitive eye cells that have died in the eyes and the cilia in the ears will never come back.
Being diagnosed for Usher Syndrome is a frightening experience.
Therefore we want to make Usher Syndrome known around the world and so create a better understanding of the impact of getting both deaf and blind. Besides, everyone in the world must know that people suffering from Usher Syndrome are remarkably driven and well-motivated to keep participating in society. 

To raise awareness for the most common genetic cause of deaf blindness, we are raising awareness more than ever.
This year the Global Usher Awareness Day falls on September 18th and in the run-up to this day, we will daily share the song ‘Colour me blind’.

*Jackson is Caroline’s son: Ushermom / Colour me blind
Colour Me Blind · Jasper Steverlinck Night Prayer ℗ 2018 Sony Music Entertainment Belgium NV/SA

LYRICS: COLOUR ME BLIND

I’m holding on but now those days are gone
They seem like half forgotten dreams
Where everything was as white as snow
Now the black is in everything

We cannot change it
It is inevitable
But how much longer will it take?
Before we slide into the great unknown
Oh how I know your heart will break

Colour me blind colour me blind
I don’t think I want to know
Colour me blind colour me blind
I don’t think I want to know

My hands are my ears
My fingers are my eyes
I’ll let my memories be my guide
When I fall into the great unknown
I’ll have you here by my side

Colour me blind colour me blind
I don’t think I want to know
Colour me blind colour me blind
I don’t think I want to know

Colour me blind colour me blind
I don’t think I want to know
Colour me blind colour me blind
I don’t think I want to know

But I know, I know, I know

I’m holding on but now those days are gone
They seem like half forgotten dreams
Where everything was as white as snow
Now the black is in everything


GLOBAL USHER AWARENESS DAY
Saturday September 18th 2021

Do you want to help us stop the process of becoming deaf and blind?
Join us and donate to scientific research!

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Swim at night and take a nap during the day

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

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. 

Related links:
www.usheriii.org
www.radboudumc.nl/expertisecentrum/ushersyndroom
www.ushersyndrome.nl
www.ushersyndrome.nl/knowledgeportal

Jack Weeda, draagt een bril en witte doktersjas

A view on the RUSH2a study

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, draagt een bril en witte doktersjas

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?

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:
Development of gene therapy for large USH2c gene

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

 

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.

Read more about the results of the Stellar study here.

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

Read also: Leiden ProQR is further expanding Radboudumc research