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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

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