Inherited retinal diseases (IRDs) are a major cause of early-onset vision loss or blindness. They represent a group of rare, genetically heterogeneous disorders for which precision medicine is entering the clinic. Since gene augmentation therapy is limited to relatively small disease genes, antisense oligonucleotide (ASO) strategies are emerging. These are, however, mostly mutation-specific, theoretically requiring the development of hundreds of individual ASO therapies. In this project, we aim to design and validate a novel type of ASO therapy which targets upstream open reading frames (uORFs) in order to increase translation of the primary protein-coding transcript. As a proof of concept, this strategy will be applied to autosomal dominant IRDs characterized by haploinsufficiency, where protein augmentation should be therapeutically beneficial. First, we will identify novel uORF ASO targets by characterization of IRD genes containing functional uORFs through ribosome profiling in adult human donor retina. Next, we will design novel uORF ASOs and evaluate their therapeutic efficiency in both wild-type cell lines and human retinal explants. Finally, we aim to evaluate and fine-tune uORF ASOs in patient-derived 2D and 3D retinal models. Overall, this innovative study represents a unique proof of concept of a novel, mutation-independent ASO therapy with a potentially broad application in inherited blindness as well as other genetic diseases.