Children with Usher syndrome type 1 are born deaf and have an inactive balance organ. In childhood, the first symptoms of night blindness and an increasingly narrow field of vision begin.
For USH 1B the Stichting Ushersyndroom is having talks with Dr. L.I. van den Born of Oogziekenhuis Rotterdam, Dr. R.J.E. Pennings of the National Usher Syndrome Expert Centre in Nijmegen and Dr. A. Auricchio from Naples (Italy) about the possibilities to have Dutch patients participate in the upcoming trial with a double AAV vector (USHTher) and for which financial support has been asked from our foundation.
Mutations in the CDH23 (= USH1D) and PCDH15 (= USH1F) genes are the fourth and fifth important causes of the development of Usher Syndrome with patients (together ~15% of all Usher Syndrome patients). According to a rough estimate, over 58,000 people around the world lose their eyesight as a result of mutations in CDH23 and PCDH15. However, the facts that these genes are extremely large and a proper model system does not exist block the ‘prospect of retaining eyesight’ for the patients involved. This means that there is an urgent need of:
a) development of an effective treatment method and
b) development of a suitable model to test the effectiveness of this treatment method. It will be essential to find a solution for these challenges and so be able to stop the progression of CDH23- and PCDH15-related retina degeneration in the future.
The objective of the project is to show that the exon-skipping method works with zebrafishes that have been mutated with 1D and 1F mutations.
The mutations in the CDH23 gene and the PCDH15 gene are found with only a few patients and are spread over the gene. These mutations include missense changes, frame-shift mutations, nonsense mutations and mutations that affect the splicing. With respect to retina degeneration caused by mutations in these genes it is generally assumed that these mutations lead to a loss of the functioning of the coding proteins. An alternative for gene replacement therapy (gene therapy) is to cover (= ‘skip’) the protein-coding pieces of a gene (= ‘exons’) containing causal mutations: exon skipping.
This method has already proven its therapeutic value in connection with the hereditary disorders Duchenne Muscular Dystrophy and CADASIL. Additionally, this method is presently tested with patients having mutations in USH2A exon 13 in the phase I/II STELLAR trial. This method is particularly interesting for large genes that code for (structural) proteins consisting of strings of repetitive protein domains, such as NOTCH3, dystrophin, USH2A, CDH23 and PCDH15. An additional advantage is that this exon-skipping method does not affect the expression level of the gene concerned.
This project will be conducted in Radboud UMC under the management of Dr. Erwin van Wijk, Dr. Erik de Vrieze and Dr. Ronald Pennings.
The amount required is € 250.000,=