Exon-skipping as future treatment option for EYS-associated retinitis pigmentosa

Retinitis pigmentosa (RP) is an inherited retinal disease with an overall prevalence of 1 in 4000 individuals. Mutations in EYS (Eyes shut homolog) are among the most frequent causes of non-syndromic autosomal recessively inherited RP and act via a loss-of-function mechanism. Zebrafish were previously shown by researchers from Radboudumc and others to be excellent models for EYS-associated RP.

In light of the recent successes for other IRDs, Renske Schellens and colleagues from the departments of Otorhinolaryngology and Human Genetics investigated the therapeutic potential of exon skipping for EYS-associated RP. They employed CRISPR/Cas9 to generate zebrafish from which the region encompassing the orthologous exons 37-41 of human EYS (eys exons 40-44) was excised from the genome. Although the eysdelta-exon 40-44 transcript was found at levels comparable to wild-type eys, expression of the Eys delta-exon40-44 protein could not be detected in the larval zebrafish retina. Visual motor response experiments revealed that eys delta-exon 40-44 larvae were visually impaired.

Although the published results did not provide indications for the skipping of EYS exons 37-41 as an effective future treatment, the work of Schellens et al is a perfect example how the CRISPR/Cas9 system can be exploited to investigate the functional consequences of exon-skipping therapies in zebrafish.

Read the full paper here.

Renske Schellens, Erik de Vrieze, Pam Graave, Sanne Broekman, Kerstin Nagel-Wolfrum, Theo Peters, Hannie Kremer, Rob W. J. Collin and Erwin van Wijk. Zebrafish as a Model to Evaluate a CRISPR/Cas9-Based Exon Excision Approach as a Future Treatment Option for EYS-Associated Retinitis Pigmentosa. Int. J. Mol. Sci. 2021, 22(17):9154