Inherited retinal diseases (IRDs) are a major cause of early-onset blindness for which over 280 disease genes have been identified so far. IRD is at the forefront of gene therapy development. However, current approaches are mostly gene-specific, resulting in a limited treatable patient cohort. Here, we aim to develop a generic IRD treatment by focussing on the NRF2 pathway, which plays a pivotal role in the retina as a cytoprotective anti-oxidant mechanism. Specifically, we hypothesize that NRF2 can be modulated by taking advantage of upstream open reading frames (uORF), an emerging class of cis-regulatory elements. Therefore, we aim to unravel the role of uORFs in translational regulation of the NRF2 pathway and to develop an uORF antisense oligonucleotide (ASO)-based gene therapy targeting NRF2 to increase protein levels and thereby improve retinal survival and function. First, we will dissect the uORF network in the NRF2 pathway, both in basal and oxidative stress conditions, by combining Ribo-seq and N-terminomics in various cell types and tissues. Next, selected uORFs will be functionally validated by distinct reporter assays. Finally, ASOs against NRF2 uORFs will be evaluated in wild-type retinal models as well as in patient-derived retinal cultures. Overall, this study represents a unique proof-of-concept of the development of a generic ASO gene therapy for IRDs, targeting the cytoprotective anti-oxidant NRF2 pathway.