Pathogenic variants in the USH2A gene are the leading cause of autosomal recessive inherited retinal dystrophy worldwide for which currently no treatment options exist. Mutations in this gene can either result in progressive loss of vision due to retinitis pigmentosa (RP), a non-syndromic rod-cone dystrophy or Usher syndrome type 2a (USH2a), which is characterized by congenital hearing impairment and progressive RP.

Given the loss-of-function disease mechanism, gene augmentation would represent a rational therapeutic strategy. However, the USH2A coding sequence (~15.6 kb) by far exceeds the packaging capacity of the currently used viral vectors for gene delivery. To overcome this challenge, we adopted an innovative alternative approach: antisense oligonucleotide (ASO)-based skipping of frequently mutated in frame exons to halt the progression of USH2A-associated vision loss.

In our lecture we will highlight the challenges and opportunities that we encountered during our endeavor to develop innovative therapeutic interventions for inherited retinal dystrophies. This will include the identification of skippable target regions, the pipeline for preclinical evaluation of therapeutic efficacy, interactions with patient advocacy groups and patient identification, determining the right clinical endpoints and appropriate clinical trial design, and difficulties in translating promising preclinical findings into a (commercially) viable therapy for a(n) (ultra)rare condition.