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Portret van oogarts Ingeborg van den Born

Is a treatment for USH 1B in sight?

De story of ophthalmologist Dr. Ingeborgh 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? Ingeborgh 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’.