Usher syndrome type 2C (USH2C) is a rare inherited disorder affecting about 40,000 people worldwide. Mutations in the ADGRV1 gene cause congenital hearing loss and a gradual decline in vision. No treatments exist for this vision loss, partly because an appropriate animal model was lacking. This thesis describes the development of the first USH2C zebrafish model with early, measurable retinal dysfunction, enabling the testing of treatment strategies. Developing a genetic therapy is challenging because ADGRV1 is one of the largest human genes and does not fit into current ‘viral vectors’ used for gene-replacement therapy. Therefore, alternative gene-size-reduction approaches were explored. A shortened ADGRV1 minigene was successfully expressed in the zebrafish retina—an important first step toward a future minigene therapy. In addition, targeted removal of mutated exons (parts of the ADGRV1 gene) through ‘exon-skipping’ restored retinal function in the model. These findings provide a promising foundation for future treatments for ADGRV1-associated retinal degeneration.
Merel Stemerdink obtained her Master’s in Medical Biology at the Radboud University in 2020, after which she started her PhD in the research group of Dr. Erwin van Wijk, investigating genetic therapies for ADGRV1-associated retinitis pigmentosa. From June 2025, she continued as a postdoctoral researcher, aiming to advance therapy development for ADGRV1-associated RP using zebrafish and patient-derived retinal organoids.