SOLVE-RET : Solving missing heritability in inherited retinal diseases using integrated omics and gene editing in human cellular and animal models

Inherited retinal diseases (IRD) represent a clinically and genetically heterogeneous group of rare diseases that are a major cause of early-onset blindness in 350,000 people in Europe. Our group has discovered almost 30 percent of over 260 IRD genes. These significant advances have culminated in novel therapies entering the clinic. Despite this progress, there are important knowledge gaps that hamper a molecular diagnosis in half of the cases. We have provided proof-of-concept for an emerging role of non-coding DNA variation in unsolved IRD. We demonstrated there is an unmet need for a shift from classical coding genomics to integrative omics. Here, it is our main goal to establish a framework to solve missing heritability in IRD using multi-omics and gene editing in human cellular and animal models. First, we will dissect the regulation of IRD genes in human retina to improve functional genome annotation. Second, we will revisit clinical diagnoses and generate relevant cellular models derived from unsolved monoallelic cases with suspected recessive IRD. Third, we will integrate omics performed on these cells to accelerate diagnosis in unsolved IRD. Fourth, we will unravel novel regulatory mechanisms underlying dominant IRD in human cellular and animal models. Finally, we will transfer research findings to the clinic. Our multidisciplinary approach combined with a strong track record and international network offer a unique opportunity to address unmet needs to accelerate diagnosis and to understand mechanisms of IRD, and to pave the way to precision medicine in IRD.