A key role for zebrafish in the development of exon-skipping therapies for USH2A-associated retinitis pigmentosa

Mutations in the USH2A gene are a major cause of inherited retinal degeneration (retinitis pigmentosa; RP) and Usher syndrome (USH). The latter is a devastating combination of RP and congenital hearing impairment. Two of the most frequent mutations in USH2A both reside in the 13th exon of the gene. We recently showed that skipping of the mutated ush2a exon 13 in zebrafish can restore localization of the ush2a-encoded protein usherin in the retinal photoreceptors, as well as photoreceptor function in zebrafish larvae. Further preclinical development of exon-skipping therapy for mutations in USH2A exon 13 was done by ProQR therapeutics (Leiden, the Netherlands), who developed the investigational new drug QR-421a to induce skipping of USH2A exon 13 in humans.

We recently published the proof-of-concept studies in zebrafish, and the in-vitro validation of QR-421a, together with ProQR Therapeutics in the esteemed journal “Molecular Therapy”. Treatment of patients with QR-421, as part of a phase-I clinical trial (NCT03780257), has recently yielded promising results. To our knowledge, this is the first time that proof-of-concept for a molecular treatment that went into clinical trials, was solely obtained in zebrafish. This unique achievement highlights the value of the zebrafish in translational science.

Return of usherin immunoreactivity (green) at the photoreceptor periciliary region (anti-centrin, red) upon morpholino (PMO)-induced ush2a exon 13 skipping in the ush2armc1 zebrafish larvae.