Disease modelling to decipher the role and pathogenic mechanism underlying a novel gene defect in rod- cone dystrophy – RP_SOLVEANDCURE

Inherited retinal diseases (IRDs) are a major cause of retinal degeneration leading to progressive blindness with limited therapeutic options. The last decades have seen promising therapeutic development urging for a better characterization and understanding of IRDs. The genetics of IRDs is heterogeneous but the advent of high throughput sequencing including whole genome sequencing have greatly accelerated our capacity to identify their genetic cause, which is a prerequisite for adequate genetic counseling and developing innovative treatments. The success rate in detecting the genetic cause is however far from being complete with about 30% of cases that remains unresolved. One challenge with current genomic-based technologies is the capacity to unravel numerous genetic variants that are difficult to interpret in the context of the disease. Therefore, there is a need to conduct systematic studies associated with relevant functional validation to better decipher underlying gene defects that will lead to an enhanced understanding of the disease and improve patients' care. The goal of this ongoing project is to functionally characterize a novel gene defect identified in patients with autosomal recessive rod-cone dystrophy also called retinitis pigmentosa (RP) and to correct the disease-causing variant by innovative gene-editing technologies. This includes in vitro studies using RPE cells and retinal organoids (ROs) derived from available patient’s induced pluripotent stem cells and in vivo studies, using an available zebrafish model. Available and generated transcriptomic and proteomic data will help to decipher the disease mechanism of this novel candidate and the establishment of novel gene-editing tools will pave the way for therapies. The proposed project will lead to a better understanding of novel proteins implicated in normal and pathologic retina and provide the proof-of-concept of innovative treatment strategies, which can be applied to other IRDs.