Usher Syndrome is a rare hereditary disorder. The children suffering from this disorder are born deaf or hard of hearing and apart from night-blindness they also experience a progressive loss of eyesight. Eventually, people suffering from Usher Syndrome become both deaf and blind. Usher Syndrome is the most common type of hereditary deaf-blindness. There is no treatment yet that can stop the deterioration of both hearing and eyesight, but there is hope.
Mutations in the USH2A gene are mostly responsible for the occurrence of Usher syndrome in patients (in > 50% of all Usher patients). In at least 10 % of patients with recessive hereditary nonsyndromic retinal degeneration (retinitis pigmentosa), defects in this gene are responsible. It is estimated that over 400.000 people worldwide lose their eyesight because of mutations in the USH2A gene. However, the extremely large size of this gene and the lack of an adequate model system are blocking the view of preservation of sight from patients involved.However, the sheer size of this gene and the lack of an adequate model are obstructing the preservation of sight for patients involved.
So there is an urgent need for:
a) The development of a working method of treatment
b) The development of a suitable model in order to test the effectiveness of this method of treatment
Although more than half of all people suffering from Usher Syndrome have mutations in the USH2A gene, this gene is not a target in the current studies into the development of gene replacement therapy. This is because of the size of the protein coding sequence of the USH2A gene (>15,000 bases!). A DNA fragment of such a length does simply not fit into the currently used gene therapeutic vectors (harmless viruses used for packaging genetic material and delivering this at its destination).
Time-consuming and specific
In the Radboudumc, researchers are also conducting other studies that may offer solutions for smaller groups of people with specific mutations in the USH2A gene. However, this study, which tests the therapeutic potential of exon skipping, is a very time-consuming study as a specific treatment is to be developed for each mutated exon. All the more because over 500 different mutations have been identified in the USH2A and these are spread over the entire gene. Even when the developments in the ‘exon skipping’ study show positive progress, this method still does not offer a solution for a significant part of the people with a mutation in the USH2A gene, because the build-up of the gene and protein are not suitable for this.
What about those zebrafishes?
The animal model in mind for testing the therapeutic effect is the zebrafish. Zebrafish, with the USH2A gene disabled, have problems with hearing and sight. Which makes them a perfect model for people with Usher syndrome type 2A.
Zebrafish offer us hope for the future because they are deployed as an animal model in testing the therapeutic effect of a new method. Usher-mutant zebrafish do go deaf and blind contrary to mice with mutations in the Usher genes. This makes these fish utterly suitable for gene therapeutic research into Usher syndrome.
View the infographic ‘What about those zebrafishes?’
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