DEVELOPMENT ANTISENSE OLIGONUCLEOTIDEN EXON 13
Erwin van Wijk of the Radboudumc in Nijmegen, the Netherlands, studies the therapeutic effect of antisense oligonucleotides (AON) for the future treatment of Usher Syndrome.AONs can be regarded as a “genetic patch” that covers the area of the mutation and makes it invisible. In this way, the cause of Usher Syndrome is removed and, hopefully, the deterioration of the eyesight (and possible the hearing) of this group of patients is stopped.
Zebrafishes turned out to be perfect models for studying the vision problems caused by mutations in Usher genes. Therefore, with the help of the CRISPR/Cas9 system a mutation (= small deletion) was made in exon 13 of the USH2A gene of the zebrafish. The result of this was that USH2A protein was no longer produced in these zebra fishes and that the eyesight of these fishes deteriorated.
By injecting “genetic patches” working against the USH2A exon 13 of the zebrafish, this exon was effectively skipped, making the part of the USH2A gene being translated into protein a bit smaller. Zebrafish larva that were given this treatment showed, apart from a partly recovered production of the USH2A protein, a significant improvement of eyesight. The next step will be to translate these findings from the zebrafish model to human beings. The molecule (= genetic patch) optimised for treating people is called QR-421a. The analysis of mouse eyes injected with QR-421a showed that the molecule indeed goes to the photoreceptors. Subsequently, it was demonstrated that QR-421a does not have any toxic properties.