Allele-independent increase of protein translation for adIRD genes displaying haplo-insufficiency
IRD is at the forefront of gene therapy development. This PhD project aims to explore a novel therapeutic approach to increase protein expression of IRD disease genes that display haploinsufficiency by targeting cis-acting, non-coding elements. We previously performed both in silico and wet-lab analyses to identify cis-acting elements that modulate expression of IRD genes in the retina. The PhD student (DC8) will first functionally dissect novel cis-acting elements using in vitro reporter assays in cellular models. Next, DC8 will design and evaluate both antisense oligonucleotides and base editing tools to modulate cis-acting elements and as such increase protein expression in wild-type retinal models. Finally, the efficacy of the most promising therapeutic molecules will be assessed in patient-derived mutant cellular models and retinal organoids. This project will provide new scientific insights in IRD gene regulation by elucidating the function of novel cis-regulatory elements, and will evaluate a novel, mutation-independent therapeutic strategy to modulate IRD gene expression, which is highly valuable in view of the allelic heterogeneity that is typical for IRD.