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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

Report CRUSH study

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 met een zwarte bril, een lach en hij draagt zijn witte doktersjas

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, draagt een bril en witte doktersjas

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.”

Een hele vrolijke blik van 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.”

Een vrolijke Hedwig Velde met haar in de staart en ze draagt een witte jas

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.”

 

Nobel lecture CRISPR/Cas9 

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 2020the 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]

Worldwide research study for patients with USH 1c

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?

story of ophthalmologist Dr. Ingeborg van den Born

Portret van oogarts 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: 

Erwin van Wijk links in beeld, rechts naast hem een waterbak met kleine zwemmmende zebravisjes

The developments in the research laboratory

Erwin van Wijk links in beeld, rechts naast hem een waterbak met kleine zwemmmende zebravisjes

Despite the corona crisis, which has dominated our country for some time and as a result of which the research laboratory of Erwin van Wijk in the Radboud UMC for some time, quite some progression was made in the past year. Below you will find an overview of the most important achievements of last year. 

‘Genetic patches’ 

  • ProQR Therapeutics published the very promising intermediate results of the Stellar last April! In this Stellar trial the first group of people (with ‘faults in a specific part of the USH2A gene (exon13)) were treated on an experimental basis with the QR-421a molecule, the scientific basis of which was laid in the Radboud UMC. For this also take a look at ProQR publishes the first results of STELLAR’ or the website of ProQR Therapeutics, which Erwin and his colleagues closely cooperate with.
  • This year also saw significant progression in the development of ‘genetic patches for four other parts of the USH2A gene. More information will be provided about this in the course of the year 2021. 
  • We set up the Dutch Center for RNA Therapeutics together with the LUMC. In this centre we will develop genetic patches for covering extremely rare hereditary faults. Extremely rare means that they occur only once or twice in the whole world. The development of the layout and the set-up of the centre portal is still in full swing. Here you can read additional information about the foundation of the DCRT: A genetic patch for very rare mutations. An update will follow in the course of this year.  
  • In cooperation with the research group of Dr Monte Westerfield and Dr Jennifer Phillips (University of Oregon, USA) and the USH1f Collaborative, we expanded the genetic patch methodology to the PCDH15 gene (= Usher syndrome type 1F). 

Minigene therapy 

  • The development of a minigene therapy for Usher syndrome type 2C was started in April 2020. This is a four-year PhD project financed with contributions from the Usher Syndrome Foundation, LSBS and CureUsher. A part of this project also included further optimisation of USH2A minigenes

Study into quality of life: Sleep study 

  • Apart from their visual impairment, many people suffering from hereditary poor eyesight and Usher Syndrome also have sleeping problems, possibly as a result of a deviating day-night rhythm. These problems have a great impact on the well-being of patients suffering from hereditary blindness, but they are hardly recognised as a part of the disorder. We wrote a four-year research proposal aimed at gaining a better understanding of this problem, making the scientific world, care professionals and health insurance companies recognise this and, finally, solving this by having it included as a part of the current care paths. After assessment by a scientific committee, the project ended up in the top 3 of best projects! About two thirds of the required funds have been assigned by ANVVB, LSBS, Stichting Beheer het Schild, the Gelderse Blindenstichting en the Usher Syndrome Foundation. At this moment we are raising the remaining part of the required funding so that we can actually start this important study by mid-June 2021! Read more about ‘Recognition of sleeping problems with patients’.