Research “Development of exon excision therapy”


This study aims at permanently removing specific exons, which include hereditary mutations when patients are concerned, from the DNA of the photoreceptors in the retina and/or the hair cells of the inner ear with the help of the CRISPR/Cas9 gene editing technique. The objective of this strategy is to stop the deterioration of eyesight (and hopefully in the longer term that of hearing as well) with larger groups of patients who have mutations in these exons of the USH2a gene with a one-off treatment.

Dr Erwin van Wijk and his colleague Dr Erik de Vrieze (both working at Radboudumc) will study the effect of a new strategy for treating Usher Syndrome. The research group of these scientists will cooperate with Vasiliki Kalatzis of the University of Montpellier in France and apply the CRISPR/Cas9 in this study.

Development of exon excision therapy
Exon excision is a new treatment strategy for modifying genes that code larger structural proteins consisting of chains of repetitive protein domains. These protein domains are the functional parts within a protein. The idea is that a protein can do without one or more of these domains without losing its function. This can be compared with a chain. A large number of separate links that individually look the same together forms a chain. When a few links are taken out, the chain will indeed become a bit shorter, but it will still be functional.
At least four of the known Usher Syndrome-related proteins, being usherin (USH2a), ADGRV1 (USH2c), cadherin23 (USH1d) and protocadherin15 (USH1f), consist of a chain of repetitive ‘links’, called protein domains. Using the molecular pair of scissors ‘CRISPR/Cas9’, the genetic regions in the USH2a gene that code for such a repetitive protein domain and which also include hereditary defects when patients are concerned will be permanently removed from the DNA of photoreceptors. This will shorten the USH2a protein by one or more ‘links’ and the study is meant to find out whether it will still be functional. Mutations in the genes related to USH2a, USH2c, USH1d and USH1f together account for the underlying cause in as many as 75% of all Usher Syndrome patients! This emphasises the potential of this therapeutic strategy.

Jorden Leuverman: “It is particularly great to know that the interview has also resulted in something much bigger than just my sponsor campaign”

Personal involvement
It was an article in the Tubantia, which caught the eye of Inge Wessels. In the newspaper there was an interview with Jorden Leuverman in which he told about living with Usher Syndrome. Inge Wessels: “I was deeply touched. Jorden was very hard of hearing already and he would also slowly lose his eyesight.” Jorden was diagnosed with Usher Syndrome, just like his grandfather was. As Jordan knows the impact of this, he started a sponsor campaign for the Usher Syndrome Foundation. Together with his running buddy he participated in the footrace in Zutphen, the Netherlands, and with this collected € 5000.- for the Usher Syndrome Foundation, hoping that there will timely be a treatment for Usher Syndrome.
Inge Wessels: “When I read the interview in the newspaper, I felt such a deep respect for this man. I know from experience what it means to be deaf in daily life. Much information can be received by looking at the mouths of people talking and other non-verbal communication. When Usher Syndrome takes away your eyesight as well, I think this is really terrible.”

Can I help?
Inge Wessels supported the sponsor campaign of Jorden and also made a donation to Stichting Ushersyndroom. “Can I help you with the funding of a promising study?” Inge Wessels asked early this year.
Jorden: “I hoped to collect as much money as possible for Stichting Ushersyndroom with my sponsor campaign. This amount suddenly became a lot higher thanks to the fact that I was interviewed by a reporter of the Tubantia newspaper. It is particularly great to know that the interview has also resulted in something much bigger than just my sponsor campaign.”

Stop the process of becoming deaf and blind
About 400.000 people globally suffer from Usher Syndrome, of which about 1.000 in the Netherlands. Faults in about ten different genes lead to Usher Syndrome. These genes code for proteins that are crucial for the functioning of the eyes and the ears. At this moment, there still is no treatment for any type of Usher Syndrome that can slow down, stop or recover the process of becoming both deaf and blind.

Reggeborgh supports research the 4-year study ‘Development of the exon excision therapy’. We are really grateful to the Reggeborgh for its donation for this promising study!

f.l.t.r. Shannon Leuverman, Erik de Vrieze, Ivonne Bressers, Jorden Leuverman, Erwin van Wijk