Inherited retinal disease (IRD) is a major cause of early-onset vision loss for which gene therapy is entering the clinic. Since gene augmentation is limited to relatively small disease genes, antisense oligonucleotides (ASOs) are an emerging strategy due to their easy design, chemical synthesis, and high target specificity. However, current ASOs are mostly mutation-specific and therefore applicable to very small patient cohorts, given the tremendous allelic heterogeneity that is typical for IRD.

We aim to develop a new ASO therapy to increase protein abundance of IRD disease genes by targeting cis-regulatory elements that repress translation. In this project, we will first perform a systematic ASO screening in 2D in vitro models. Next, efficacy of lead ASOs will be evaluated in patient-derived 3D retinal organoids at the protein and functional level, and off-targets will be assessed.