About 350 million people worldwide suffer from a rare disease, which is defined as a disorder that affects less than 1 in 2,000 individuals. Over 7,000 different rare disease entities have been identified, 80% of which have a genetic cause. Recent large-scale sequencing technologies enable fast and accurate genetic diagnosis, which is a prerequisite for genomic-based precision medicine. Major efforts are currently ongoing for therapy development.
This project aims to develop novel antisense oligonucleotide (ASO) therapies for rare disorders. ASOs modulate gene expression by either RNA degradation or RNA occupancy mechanisms and are more cost effective, broadly applicable, and less immunogenic compared to classic small-molecule drugs directed to proteins. In this project we will study inherited retinal diseases (IRDs), a major cause of early-onset vision loss, as a proof of concept. The human eye is ideally suited for local administration of gene therapy because of its small size, easy access, immune-privileged state, and its duplicity, and several clinical trials are ongoing for ocular gene therapy. IRDs are monogenic but genetically heterogeneous: over 260 disease genes have been identified so far. Here, we will identify and characterize IRD genes amenable to ASO therapy and develop a platform for functional evaluation of ASO treatment in 2D and 3D retinal models. In specific, we will generate patient-derived induced pluripotent stem cells and differentiate these to photoreceptor precursor cells, retinal pigment epithelium or retinal organoids, enabling ASO evaluation and optimization in the patient’s genetic background. The resulting platform for design and evaluation of ASO treatments will also be applicable to other rare disorders studied at Ghent University.