Development of gene therapy for large USH2C gene

Usher Syndrome patients and researchers of Radboudumc set the tandem in motion again for scientific research into a treatment for Usher Syndrome, this time concerning type 2C. After the successful USH2A Minigenes study, the results of which will be known early in the year 2020 there will be a follow-up. Stichting Ushersyndroom (Dutch Usher Syndrome Foundation) finances, with a contribution from CUREUsher from the UK/Ireland and the Landelijke Stichting voor Blinden en Slechtzienden (LSBS), the new study into Minigenes for USH2C. In order to celebrate this milestone, five researchers of the national Usher Syndrome Expertise Centre of the Radboudumc involved surprised the same number of patients with a ride on the tandem. 

In their white coats head researcher Erwin van Wijk, Erik de Vrieze and ENT specialist Ronald Pennings cycled in a good humour as co-pilots to the agreed place. Only Ivonne Bressers, chairwoman of Stichting Ushersyndroom (Usher Syndrome Foundation) was involved in the plot. Like a string another two half-empty tandems followed with 2 young researchers who are daily engaged in doing research into a treatment for Usher Syndrome, a disorder which slowly makes 400,000 patients around the world both deaf and blind.

With rare diseases like this, the contact between physicians, researchers and patients is crucial. Patients, parents and relatives are the drive force behind the scientific research into a treatment by collecting donations, acquiring resources and close consultation with physicians and researchers. This interaction brings a treatment for progressive deafblindness closer at a faster pace.

“We are unmistakably united as a duo on a tandem; the researcher as co-pilot, the patient as firer.”
Erwin van Wijk, head researcher in the Radboudumc

“The input and knowledge that patients bring up themselves is not only highly inspiring for me and my colleagues, these also put us on new tracks in unravelling Usher Syndrome. We are unmistakably united as a duo on a tandem; the researcher as co-pilot, the patient as firer,” the head researcher of Radboudumc Erwin van Wijk tells us.

Five Usher patients are sitting at a table in a café drinking coffee; some with their backs to the window. Patient Rick Brouwer gets up surprised when Erwin van Wijk appears within his tunnel vision. Rick is one of the people for whom the Minigenes USH2C study gives hope. He has been involved as from the foundation of Stichting Ushersyndroom (Usher Syndrome Foundation) and suffers from Usher Syndrome type 2C himself.
“Today really is an important day! Thanks to the positive results of the Minigenes USH2A study a step is made to USH2C. There soon will be a treatment for all people suffering from Usher!”, Rick calls out deliriously happy.

“For the first time in my life I really have hope that there will be a treatment for all Usher patients all over the world!”
Carol Brill, Usher patient and member of the Board of CUREUsher

Carol Brill of CUREUsher from Ireland is there as well and starts laughing when the researchers seduce them to take a ride on the tandem after having expressed their thanks for their cooperation. Carol: “What a great experience to cycle together through the city! I will come over to live here! For the first time in my life I really have hope that there will be a treatment for all Usher patients all over the world!”

Promising preliminary investigation
In the year 2016, Stichting Ushersyndroom (Usher Syndrome Foundation) made a financial contribution to the study into the functioning of USH2A Minigenes as a future treatment method. Usher Syndrome is a rare genetic disease in which faults (= mutations) in about ten different genes lead to a progressive form of deafblindness. The large size of the genes in which the most causal mutations are found with most patients makes classic gene therapy impossible. This is because these mutated genes are simply too big to be packed in the available viral vectors that are required for delivering the gene at the correct place in the retina. This is an ultimate challenge for the researchers. A creative solution is needed to still process the gene in a viral vector.

Erwin van Wijk expects to be able to publish the first study results of the USH2A Minigenes study early in the year 2020. Van Wijk will now start a similar study for USH2C, titled ’Pre-clinical development of a minigene augmentation therapy for the future treatment of USH2C-associated retinitis pigmentosa’. Never before a research institute has had the courage to start developing a gene therapy for this huge USH2C gene. Stichting Ushersyndroom (Usher Syndrome Foundation) will subsidise this 4-year study of Erwin van Wijk (and Erik de Vrieze and Ronald Pennings) with € 250,000 with co-financing from CUREUsher and L.S.B.S.

The Medical Advisory Council of Stichting Ushersyndroom (Usher Syndrome Foundation) is very positive about this study because of the highly promising preliminary investigation with the USH2A Minigenes, which has demonstrated that it is possible to make minigenes and that these work in the correct/expected way.

According to the members of the Medical Advisory Council, the applicants have the appropriate knowledge, expertise and material at their disposal to carry out the proposed experiments for the USH2C gene (ADGRV1). As far as the members of the Medical Advisory Council know, no study is presently done into USH2C, while this is the third most common form of Usher Syndrome which about 40,000 people around the globe are suffering from.
Cindy Boer (member of the Medical Advisory Council, doctoral candidate internal medicine, faculty of human genomics, ErasmusMC and suffering from Usher Syndrome herself): “In consultation with Erwin van Wijk and Erik de Vrieze the Medical Advisory Council has made an addition to this study proposal. We would like to apply this to humans by making use of human skin cells. In this way we can investigate whether the minigenes behave well in human cells and whether the proteins properly unfold. This may sometimes be different in human models as it is in animal models and therefore it gives a good indication about the functioning of the gene therapy for humans.”
The USH2C Minigenes study is completely in line with the objective of Stichting Ushersyndroom (Usher Syndrome Foundation): “There will be a treatment for Usher Syndrome in 2025!”

The tandems with patients and researchers will continue their journeys; these will be bumpy, but their confidence in the process will drive them and this will bring a treatment for Usher Syndrome closer than ever before. Difficult ways will lead to great destinations. 

The CRUSH study as a preparation for future trials
Earlier this year, Stichting Ushersyndroom (Usher Syndrome Foundation) also financed the CRUSH study of the Radboudumc with co-financing from the Oogfonds and the Dr. Vaillantfonds, a study in which researchers will map out the natural development of Usher Syndrome in great detail. Researchers really intensively follow the Usher Syndrome patients. Expectations are that during a research period of five years more knowledge will have been gained about the development of the deafblindness related to various types of Usher Syndrome.
In case of a positive result of the new study into Minigenes for USH2C the research team will be well prepared for any next phase 1 / 2 clinical trial.

Text: Maartje de Kok
Photo and video: Richard Brusse

Read also:

• Developelopment of gene therapy for large USH2c gene
• How are things going with the minigenes USH2c study?
• The very first ADGRV1-zebrafish model has been presented!
• Patient and researcher: a dynamic duo once again cycling together
• An important next step in USH2c research